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  • 1.
    Axelsson, Stina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Cheramy, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Åkerman, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Pihl, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Cellular and Humoral Immune responses in Type 1 Diabetic patients participating in a Phase III GAD-alum Intervention Trial2013Ingår i: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 36, nr 11, s. 3418-3424Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVEGAD formulated in aluminum hydroxide (GAD-alum) has previously been shown to induce preservation of residual insulin secretion in recent-onset type 1 diabetes, but recent phase II and III GAD-alum trials failed to reach primary outcomes. The European phase III study was therefore closed after 15 months, and only a minority of patients completed the 30 months of follow-up.RESEARCH DESIGN AND METHODSThis study aimed to characterize cellular and humoral responses in the Swedish patients (n = 148) participating in the phase III trial, receiving four (4D) or two (2D) GAD-alum doses or placebo. Serum GAD(65) antibody (GADA) levels, GADA IgG1-4 subclass distribution, cytokine secretion, and proliferative responses in peripheral blood mononuclear cells (PBMCs) were analyzed.RESULTSThe GAD(65)-induced cytokine profile tended to switch toward a predominant Th2-associated profile over time both in the 2D and 4D group. The groups also displayed increased GADA levels and PBMC proliferation compared with placebo, whereas GADA IgG subclass distribution changed in 4D patients.CONCLUSIONSBoth 2D and 4D patients displayed GAD(65)-specifc cellular and humoral effects after GAD-alum treatment, but at different time points and magnitudes. No specific immune markers could be associated with treatment efficacy.

  • 2.
    Axelsson, Stina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Chéramy, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Hjorth, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Pihl, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Åkerman, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Martinuzzi, Emanuela
    St Vincent de Paul Hospital.
    Mallone, Roberto
    St Vincent de Paul Hospital.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Long-Lasting Immune Responses 4 Years after GAD-Alum Treatment in Children with Type 1 Diabetes2011Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 12Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A phase II clinical trial with glutamic acid decarboxylase (GAD) 65 formulated with aluminium hydroxide (GAD-alum) has shown efficacy in preserving residual insulin secretion in children and adolescents with recent-onset type 1 diabetes (T1D). We have performed a 4-year follow-up study of 59 of the original 70 patients to investigate long-term cellular and humoral immune responses after GAD-alum-treatment. Peripheral blood mononuclear cells (PBMC) were stimulated in vitro with GAD(65). Frequencies of naive, central and effector memory CD4+ and CD8+ T cells were measured, together with cytokine secretion, proliferation, gene expression and serum GAD(65) autoantibody (GADA) levels. We here show that GAD-alum-treated patients display increased memory T-cell frequencies and prompt T-cell activation upon in vitro stimulation with GAD(65), but not with control antigens, compared with placebo subjects. GAD(65)-induced T-cell activation was accompanied by secretion of T helper (Th) 1, Th2 and T regulatory cytokines and by induction of T-cell inhibitory pathways. Moreover, post-treatment serum GADA titres remained persistently increased in the GAD-alum arm, but did not inhibit GAD(65) enzymatic activity. In conclusion, memory T- and B-cell responses persist 4 years after GAD-alum-treatment. In parallel to a GAD(65)-induced T-cell activation, our results show induction of T-cell inhibitory pathways important for regulating the GAD(65) immunity.

  • 3.
    Axelsson, Stina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Chéramy, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Åkerman, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Pihl, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Preserved C-peptide 30 months after GAD-alum treatment of children and adolescents with recent-onset type 1 diabetes, and its relation to immune markersManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Glutamic acid decarboxylase 65 kDa isoform (GAD65) is a major autoantigen in type 1 diabetes (T1D). Although alum-formulated GAD65 (GAD-alum) induced preservation of residual insulin secretion in a previous clinical Phase II trial, recent Phase II and Phase III trials failed to reach their primary end-points. The European Phase III trial was therefore closed after 15 months, and the 30 months follow-up period was completed only for a minority of the patients. This study aimed to assess whether GAD-alum preserved β-cell function in those recent-onset T1D patients who completed their 30 months visit in the European Phase III trial, and to characterize their GAD65-induced cytokine secretion and proliferation. Peripheral blood mononuclear cells (PBMC) were isolated at baseline and after 1, 3, 9, 15 and 21 months from the 148 Swedish subjects included in the Phase III GAD-alum trial, and also at 30 months from 45 patients who had reached the final visit before the trial was closed. Patients had been randomly assigned into three arms: 4 doses of GAD-alum (4D), 2 doses of GAD-alum followed by two doses of placebo (2D), or 4 doses of placebo. Cytokine secretion was detected in cell culture supernatants by Luminex, after 7 days of in vitro culture. Cell proliferation was determined by 3H thymidine incorporation assay. Fasting and stimulated C-peptide was analysed in serum.

    Patients treated with 2 doses of GAD-alum had less decline of both fasting (p=0.040) and stimulated C-peptide (p=0.012) after 30 months, and a larger proportion of these patients preserved >25% of their initial stimulated C-peptide AUC compared to placebo (p=0.012). Both 2D and 4D patients showed increased PBMC proliferation to GAD65 and a cytokine profile that tended to switch towards a more predominant Th2 associated profile over time.

    The results support the concept of GAD-alum treatment, but no specific immune markers have been identified.

  • 4.
    Axelsson, Stina
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik.
    Faresjö, Maria
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik.
    Hedman, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Ludvigsson, Johnny
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Casas, Rosaura
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik.
    Cryopreserved peripheral blood mononuclear cells are suitable for the assessment of immunological markers in type 1 diabetic children2008Ingår i: Cryobiology, ISSN 0011-2240, E-ISSN 1090-2392, Vol. 57, nr 3, s. 201-208Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cryopreserved peripheral blood mononuclear cells (PBMC) are commonly used when assessing immune responses in clinical trials, both for practical reasons and to minimize interassay variation, as samples are often collected and studied over time. This study investigated the effect of cryopreservation on cytokine and chemokine secretion, and on expression of regulatory T-cell associated markers, in samples from children with type 1 diabetes. PBMC were cultured before and after cryopreservation either with GAD(65) or PHA. Secretion of cytokines (IL-5, -6, -10, -12, -13 -17, IFN-gamma and TNF-alpha) and chemokines (IP-10, MCP-1, MIP-1 alpha, MIP-1 beta and RANTES) was analysed in cell supernatants using multiplex fluorochrome technique (Luminex). Expression of FOXP3 and TGF-beta mRNA was detected by multiplex real-time RT-PCR. Increased spontaneous secretion of IL-6, -10, -12, -13, IFN-gamma and MCP-1, and mRNA expression of FOXP3 and TGF-beta, was detected after cryopreservation. Stimulation with GAD65 induced higher levels of IL-6, IFN-gamma, TNF-alpha and MIP-1 alpha, whereas lower secretion was found for IL-10 and IL-13 in cryopreserved PBMC. Stimulation with PHA induced lower secretion of IP-10, MCPA and RANTES and FOXP3 mRNA expression after cryopreservation. Thus, cryopreserved PBMC were suitable to assess the immunological markers included in this study, even though their expression could differ from freshly handled cells.

  • 5.
    Axelsson, Stina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Hjorth, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Akerman, L
    Linköpings universitet, Hälsouniversitetet.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Treatment with alum-formulated GAD65 in type 1 diabetic children results in early induction of Th2 responses2009Ingår i: in DIABETOLOGIA, vol 52, 2009, Vol. 52, s. S193-S193Konferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 6.
    Axelsson, Stina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Hjorth, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Decreased GAD(65) -specific Th1/Tc1 phenotype in children with Type 1 diabetes treated with GAD-alum.2012Ingår i: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 29, nr 10, s. 1272-1278Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim  The balance between T helper cell subsets is an important regulator of the immune system and is often examined after immune therapies. We aimed to study the immunomodulatory effect of glutamic acid decarboxylase (GAD) 65 formulated with aluminium hydroxide (GAD-alum) in children with Type 1 diabetes, focusing on chemokines and their receptors. Methods  Blood samples were collected from 70 children with Type 1 diabetes included in a phase II clinical trial with GAD-alum. Expression of CC chemokine receptor 5 (CCR5) and CCR4 was analysed on CD4+ and CD8+ lymphocytes after in vitro stimulation with GAD(65) using flow cytometry, and secretion of the chemokines CCL2, CCL3 and CCL4 was detected in peripheral blood mononuclear cell supernatants with Luminex. Results  Expression of Th1-associated CCR5 was down-regulated following antigen challenge, together with an increased CCR4/CCR5 ratio and CCL2 secretion in GAD-alum-treated patients, but not in the placebo group. Conclusion  Our results suggest that GAD-alum treatment has induced a favourable immune modulation associated with decreased Th1/Tc1 phenotypes upon antigen re-challenge, which may be of importance for regulating GAD(65) immunity. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

  • 7.
    Axelsson, Stina
    et al.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Hjorth, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Åkerman, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Casas, Rosaura
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Early induction of GAD(65)-reactive Th2 response in type 1 diabetic children treated with alum-formulated GAD(65)2010Ingår i: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 26, nr 7, s. 559-568Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background We have previously shown that two injections of 20 mu g alum-formulated glutamic acid decarboxylase 65 (GAD(65)) (GAD-alum; Diamyd (R)) in children with recent-onset type 1 diabetes lead to preservation of residual insulin secretion. In vitro cytokine production at the 15 months follow-up indicated immunomodulation. In the present study, we took advantage of peripheral blood mononuclear cells, cryopreserved during early follow-ups, to investigate whether the immunomodulatory effect of GAD-alum was apparent earlier after treatment, preceding the changes previously reported at 15 months.<p>Methods Peripheral blood mononuclear cells from 70 type 1 diabetic children, randomly assigned GAD-alum (n = 35) or placebo (n = 35), that had been frozen at baseline (n = 27) and after 1 (n = 58), 3 (n = 67) and 9 (n = 66) months, were stimulated in vitro with GAD(65), tyrosine phosphatase-like protein IA-2 peptide, insulin peptide, GAD-alum, alum formulation or phytohaemagglutinin. Interleukin (IL)-5, -6, -10, -12, -13, -17, tumour necrosis factor and interferon-gamma were measured in cell supernatants and serum samples using Luminex. Expression of FOXP3 and transforming growth factor-beta was determined by real-time reverse transcription polymerase chain reaction.</p><p>Results Already 1 month after the first injection, GAD(65)-induced IL-5 and IL-13 together with FOXP3 were enhanced in GAD-alum-treated patients compared to those with placebo. The in vitro response at 3 and 9 months was characterized by a broader range of cytokines in the treated group. Notably, only the T-helper 2-associated cytokines IL-5 and IL-13 together with FOXP3 increased continuously over time.</p><p>Conclusions Treatment with GAD-alum in type 1 diabetic children induced an early T-helper 2 immune enhanced response to GAD(65), followed by a wider spectrum of cytokines at 3 and 9 months. Copyright (C) 2010 John Wiley &amp; Sons, Ltd.</p>

  • 8.
    Besser, Rachel E J
    et al.
    University of Exeter, England .
    Shields, Beverley M
    University of Exeter, England .
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Hattersley, Andrew T.
    University of Exeter, England .
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Lessons From the Mixed-Meal Tolerance Test Use of 90-minute and fasting C-peptide in pediatric diabetes2013Ingår i: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 36, nr 2, s. 195-201Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE-Mixed-meal tolerance test (MMTT) area under the curve C-peptide (AUC CP) is the gold-standard measure of endogenous insulin secretion in type 1 diabetes but is intensive and invasive to perform. The 90-minMMTT-stimulated CP andgt;= 0.2 nmol/L (90CP) is related to improved clinical outcomes, and CP andgt;= 0.1 nmol/L is the equivalent fasting measure (FCP). We assessed whether 90CP or FCP are alternatives to a full MMTT. less thanbrgreater than less thanbrgreater thanRESEARCH DESIGN AND METHODS-CP was measured during 1,334 MMTTs in 421 type 1 diabetes patients aged, 18 years at 3, 9, 18, 48, and 72 months duration. We assessed: 1) correlation between mean AUC CP and 90CP or FCP; 2) sensitivity and specificity of 90CP andgt;= 0.2 nmol/L and FCP andgt;= 0.1 nmol/L to detect peak CP andgt;= 0.2 nmol/L and the equivalent AUC CP; and 3) how the time taken to reach the CP peak varied with age of diagnosis and diabetes duration. less thanbrgreater than less thanbrgreater thanRESULTS-AUC CP was highly correlated to 90CP (r(s) = 0.96; P andlt; 0.0001) and strongly correlated to FCP (r(s) = 0.84; P andlt; 0.0001). AUC CP andgt;= 23 nmol/L/150 min was the equivalent cutoff for peak CP andgt;= 0.2 nmol/L (98% sensitivity/97% specificity). A 90CP andgt;= 0.2 nmol/L correctly classified 96% patients using AUC or peak CP, whereas FCP andgt;= 0.1 nmol/L classified 83 and 85% patients, respectively. There was only a small difference seen between peak and 90CP (median 0.02 nmol/L). The CP peak occurred earlier in patients with longer diabetes duration (6.1 min each 1-year increase in duration) and younger age (2.5 min each 1-year increase). less thanbrgreater than less thanbrgreater thanCONCLUSIONS-90CP is a highly sensitive and specific measure of AUC and peak CP in children and adolescents with type 1 diabetes and offers a practical alternative to a full MMTT. Diabetes Care 36:195-201, 2013

  • 9.
    Casas, Rosaura
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Transfer of humoral immunity from the mother to her off-spring2001Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Background. It has been established that T cell responses of foetal origin to inhalant allergens are present in most cord blood samples. These immune responses could possibly be explained by transplacental passage of peptides, either as free antigens or in complexes with IgG, providing the foetus with a trigger for the priming of the T cell system already in utero. Antibodies to food antigens to which the mother is commonly exposed are present in the milk, but their relationship to allergy is unknown. IgA antibodies to inhalant allergens have not been previously detected in human milk.

    Objective. The aim of this thesis was to explore whether inhaled allergens in serum and IgA antibodies in breast milk could contribute to the allergic immune responses to allergens in the children.

    Methods. The presence of cat allergen Fel d 1 was analysed by ELISA in serum samples from cat allergic asthmatic children. To detect IgG immune complexes (IC), affmity chromatography purification and Western blotting were performed. Iri:nnune complexes with Fel d 1-IgE were detected by a modification of MagicLite, and their specificity was assessed by different approaches. Serum samples from allergic and non-allergic mothers, and cord blood from their infants, were measured for the presence of Fel d 1-IgG immune complexes by an amplified ELISA. Cord blood mononuclear cells (CBMC) of babies from allergic and non-allergic mothers were stimulated with cat allergen and the production of IFN-γ, IL-5, IL-10 and IL-13 was determined by ELISA and the levels related to the presence of IC. Furthermore, IgG1 and IgG4 antibodies to cat were measured by ELISA. Colostrum and samples of mature milk from allergic and non-allergic mothers were analysed for IgA antibodies to cat, P-lactoblobulin (BLG) and ovalbumin (OVA) by an amplified ELISA.

    Results. The cat allergen Fel d I was detected in 70% of sera from cat allergic chilch'en, but not in any of the controls. The allergen was present in complexes with IgE and IgG antibodies as corroborated by different approaches. Immune complexes with IgG were detected in sera from allergic and non-allergic mothers, as well as in the cord blood from their babies, but neither the prevalence nor the levels of complexes were related to maternal allergy. This was also the case for IgG antibodies to cat. The production of IL-5, IL-10, IL-13 and IFN-γ by CBMC was not influenced by maternal atopy. Interferon-y secretion by CBMC after stimulation with cat allergen, however, was less conunonly detected in samples with immune complexes. Secretory IgA to cat and OVA allergens were frequently detected in colostrum and mature milk, while antibodies to BLG were less common. The antibody levels to cat and BLG were similar in allergic and non-allergic mothers.

    Conclusion. The presence of IC with allergens may contribute to maintaining immune responsiveness and sensitivity in allergic individuals. Low levels of transplacentally transferred IC can conceivable provide the foetus with the signal for priming ofT cell responses to inhalant allergens. This seems to be a nonnal mechanism, as the immune responses are not related to maternal allergy. Low level exposure of the maternal mucosa, e.g. by inhalant allergens, can induce IgA antibody secretion in breast milk, but this mechanism is not related with any protective effect against allergy.

    Delarbeten
    1. Circulating cat allergen and immune complexes in cat- allergic children
    Öppna denna publikation i ny flik eller fönster >>Circulating cat allergen and immune complexes in cat- allergic children
    Visa övriga...
    1998 (Engelska)Ingår i: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 28, nr 10, s. 1258-1263Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background

    The first encounters with allergens seem to influence the development of allergy. Food antigens have been detected in sera as free antigens and in complexes with IgG but less is known about the presence of inhalant allergens.

    Objective

    To investigate the presence of the major cat allergen Fel d 1, either as free allergen and/or in complexes with IgG and IgE antibodies in sera from atopic children.

    Methods

    Serum samples from 33 cat allergic asthmatic children, 7–17 years old, and 15 non-allergic controls were investigated for the presence of Fel d 1 by ELISA (detection limit 0.13 μg/L). To detect immune complexes (IC), the IgG fraction from Fel d 1 positive sera was purified by affinity chromatography. Purified and non-absorbed material was then analysed for allergen content and specific IgG antibody levels. Immune complexes with Fel d 1 IgE were detected by coupling anti-Fel d 1 MoAb to paramagnetic particles.

    Results

    Fel d 1 was detected (0.15–1.8 μg/L) in 23 of the 33 patients (70%) but not from any of the controls. Eighteen samples contained IgE-Fel d 1 IC and two of four tested samples contained Fel d 1 in the IgG fraction. Electrophoresis and Western blotting of IgG purified material using anti-Fel d 1 MoAb corroborated the presence of IgG-Fel d 1 IC.

    Conclusion

    Free-circulating inhalant allergen and IC with allergens may contribute to maintaining immune responsiveness and sensitivity.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-80093 (URN)10.1046/j.1365-2222.1998.00384.x (DOI)
    Tillgänglig från: 2012-08-20 Skapad: 2012-08-20 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
    2. Presence of Fel d 1 - IgE immune complexes in sera from cat allergic individuals
    Öppna denna publikation i ny flik eller fönster >>Presence of Fel d 1 - IgE immune complexes in sera from cat allergic individuals
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background: We have recently reported the presence of immune complexes (IC) with the inhalant allergen Fel d I, in serum samples from cat allergic children. It was not entirely excluded however that these findings were due to the presence of human antibodies against cat serum albumin. The objective of this work was to confirm the presence of the major cat allergen Fel d I in complexes with IgE and to assess the specificity of the human IgE antibodies to cat allergen.

    Methods: Serum samples from 27 cat allergic children were investigated. For the detection of Fel d 1-IgE IC, a chemiluminescent immunoassay was modified by coupling an anti-Fel d I monoclonal antibody to paramagnetic particles. Levels of IgE antibodies to cat allergens were determined by chemiluminiscense and RAST, and IgG4 antibody levels by RAST.

    Results: Fifteen samples contained IgE-Fel d I IC. The levels of IC correlated with the levels of specific lgE antibodies to cat allergen correlated (r=0.48; p<0.05). All the samples of the 27 cat allergic children contained IgE and IgG4 antibodies against cat allergen, while IgE and IgG4 antibodies to cat serum were only demonstrated in 4/27 (14 %) and 6/27 (22%) samples respectively. Conclusions: Immune complexes with the major cat allergen, Fel d I, were commonly present in serum samples from cat allergic children.

    Nyckelord
    Allergen, Fel d 1, cat serum albumin, IgE, IgG, IgG4, immune complex
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-80113 (URN)
    Tillgänglig från: 2012-08-21 Skapad: 2012-08-21 Senast uppdaterad: 2012-08-21Bibliografiskt granskad
    3. Detection of Fel d 1–immunoglobulin G immune complexes in cord blood and sera from allergic and non-allergic mothers
    Öppna denna publikation i ny flik eller fönster >>Detection of Fel d 1–immunoglobulin G immune complexes in cord blood and sera from allergic and non-allergic mothers
    2001 (Engelska)Ingår i: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 12, nr 2, s. 59-64Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    It is an established fact that T-cell responses of fetal origin to inhalant allergens are present in most cord blood samples. These immune responses could be explained by trans-placental passage of peptides, either as free antigens or in complexes with immunoglobulin G (IgG), providing the fetus with a trigger for priming the T-cell system already present in utero. The aim of this study was to investigate the presence of the major cat allergen, Fel d 1, in complexes with IgG in cord blood and maternal sera. Serum samples from 75 mothers (38 allergic, 37 non-allergic), and cord blood from their infants, were investigated for the presence of Fel d 1–IgG immune complexes (ICs) by using an amplified enzyme-linked immunosorbent assay (ELISA). Three monoclonal antibodies to Fel d 1 were used for coating. The specificity of the method was confirmed by inhibition experiments. ICs of Fel d 1–IgG were detected in the sera of 45% allergic and 49% non-allergic mothers, and in, respectively, 34% and 41% of their infants. Therefore, neither the prevalence nor the level of ICs were affected by maternal allergy. Low levels of trans-placentally transferred ICs can provide the fetus with a signal for the priming of T-cell responses to inhalant allergens. However, this is not necessarily related to allergic disease.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-25850 (URN)10.1034/j.1399-3038.2001.012002059.x (DOI)10287 (Lokalt ID)10287 (Arkivnummer)10287 (OAI)
    Tillgänglig från: 2009-10-08 Skapad: 2009-10-08 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    4. Detection of Fel d 1–immunoglobulin G immune complexes in cord blood and sera from allergic and non-allergic mothers
    Öppna denna publikation i ny flik eller fönster >>Detection of Fel d 1–immunoglobulin G immune complexes in cord blood and sera from allergic and non-allergic mothers
    2001 (Engelska)Ingår i: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 12, nr 2, s. 59-64Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    It is an established fact that T-cell responses of fetal origin to inhalant allergens are present in most cord blood samples. These immune responses could be explained by trans-placental passage of peptides, either as free antigens or in complexes with immunoglobulin G (IgG), providing the fetus with a trigger for priming the T-cell system already present in utero. The aim of this study was to investigate the presence of the major cat allergen, Fel d 1, in complexes with IgG in cord blood and maternal sera. Serum samples from 75 mothers (38 allergic, 37 non-allergic), and cord blood from their infants, were investigated for the presence of Fel d 1–IgG immune complexes (ICs) by using an amplified enzyme-linked immunosorbent assay (ELISA). Three monoclonal antibodies to Fel d 1 were used for coating. The specificity of the method was confirmed by inhibition experiments. ICs of Fel d 1–IgG were detected in the sera of 45% allergic and 49% non-allergic mothers, and in, respectively, 34% and 41% of their infants. Therefore, neither the prevalence nor the level of ICs were affected by maternal allergy. Low levels of trans-placentally transferred ICs can provide the fetus with a signal for the priming of T-cell responses to inhalant allergens. However, this is not necessarily related to allergic disease.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-25850 (URN)10.1034/j.1399-3038.2001.012002059.x (DOI)10287 (Lokalt ID)10287 (Arkivnummer)10287 (OAI)
    Tillgänglig från: 2009-10-08 Skapad: 2009-10-08 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    5. Cat allergen-induced cytokine secretion and Fel d 1–immunoglobulin G immune complexes in cord blood
    Öppna denna publikation i ny flik eller fönster >>Cat allergen-induced cytokine secretion and Fel d 1–immunoglobulin G immune complexes in cord blood
    2004 (Engelska)Ingår i: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 34, nr 4, s. 591-596Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background We have recently obtained evidence for the presence of immune complexes (IC) in cord blood from allergic and non-allergic mothers. Such complexes could conceivably provide the fetus with the initial trigger for the priming of the T cell system already in utero.

    Objective To relate the presence of Fel d 1–IgG IC to T cell cytokine production in cord blood mononuclear cells (CBMCs) after stimulation with cat allergen.

    Methods CBMC obtained from babies of 15 allergic and 22 non-allergic mothers were cultured in the presence of cat allergen. The production of IFN-γ, IL-5, IL-10 and IL-13 was determined by ELISA. Furthermore, IgG1 and IgG4 antibodies to cat allergen in cord blood samples were measured by ELISA. A more sensitive ELISA was used to measure Fel d 1–IgG IC.

    Results The prevalence and levels of IC were similar in cord blood from children of allergic and non-allergic mothers. The production of IL-5, IL-10. IL-13 and IFN-γ by CBMC was not influenced by maternal atopy, but IFN-γ was less commonly detected in samples with IC. There was no association between the presence of IC and any other cytokines. The levels of IgG1 and IgG4 antibodies were similar in both groups, and tended to be associated with the presence of IC.

    Conclusion Immune complexes in cord blood may represent a normal mechanism for inducing primary immune responses, as the responses in babies from allergic and non-allergic mothers were largely similar. Low levels of IFN-γ seems to be related with the presence of IC in cord blood.

    Nyckelord
    allergen, cord blood, cytokine, Fel d 1, IgG, immune complex
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-22341 (URN)10.1111/j.1365-2222.2004.1924.x (DOI)1542 (Lokalt ID)1542 (Arkivnummer)1542 (OAI)
    Anmärkning
    On the day of the defence day the status of this article was submitted.Tillgänglig från: 2009-10-07 Skapad: 2009-10-07 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
  • 10.
    Casas, Rosaura
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn.
    Björkstén, B
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn.
    Cat-specific IgA antibodies in breast milk from atopic and non-atopic mothers: detection of Fel D 1->IgG immune complexes in cord blood and sera.1999Ingår i: International Archives of Allergy and Immunology, ISSN 1018-2438, E-ISSN 1423-0097, Vol. 118, s. 317-318Artikel i tidskrift (Refereegranskat)
  • 11.
    Casas, Rosaura
    et al.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Björkstén, Bengt
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Detection of Fel d 1–immunoglobulin G immune complexes in cord blood and sera from allergic and non-allergic mothers2001Ingår i: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 12, nr 2, s. 59-64Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    It is an established fact that T-cell responses of fetal origin to inhalant allergens are present in most cord blood samples. These immune responses could be explained by trans-placental passage of peptides, either as free antigens or in complexes with immunoglobulin G (IgG), providing the fetus with a trigger for priming the T-cell system already present in utero. The aim of this study was to investigate the presence of the major cat allergen, Fel d 1, in complexes with IgG in cord blood and maternal sera. Serum samples from 75 mothers (38 allergic, 37 non-allergic), and cord blood from their infants, were investigated for the presence of Fel d 1–IgG immune complexes (ICs) by using an amplified enzyme-linked immunosorbent assay (ELISA). Three monoclonal antibodies to Fel d 1 were used for coating. The specificity of the method was confirmed by inhibition experiments. ICs of Fel d 1–IgG were detected in the sera of 45% allergic and 49% non-allergic mothers, and in, respectively, 34% and 41% of their infants. Therefore, neither the prevalence nor the level of ICs were affected by maternal allergy. Low levels of trans-placentally transferred ICs can provide the fetus with a signal for the priming of T-cell responses to inhalant allergens. However, this is not necessarily related to allergic disease.

  • 12.
    Casas, Rosaura
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik.
    Björkstén, Bengt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Detection of IgA antibodies to cat, Der p 1 and Bet v 1 inhalant allergens in human milk2001Ingår i: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 107, nr 2, s. 97-Konferensbidrag (Övrigt vetenskapligt)
  • 13.
    Casas, Rosaura
    et al.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Björkstén, Bengt
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Presence of Fel d 1 - IgE immune complexes in sera from cat allergic individualsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background: We have recently reported the presence of immune complexes (IC) with the inhalant allergen Fel d I, in serum samples from cat allergic children. It was not entirely excluded however that these findings were due to the presence of human antibodies against cat serum albumin. The objective of this work was to confirm the presence of the major cat allergen Fel d I in complexes with IgE and to assess the specificity of the human IgE antibodies to cat allergen.

    Methods: Serum samples from 27 cat allergic children were investigated. For the detection of Fel d 1-IgE IC, a chemiluminescent immunoassay was modified by coupling an anti-Fel d I monoclonal antibody to paramagnetic particles. Levels of IgE antibodies to cat allergens were determined by chemiluminiscense and RAST, and IgG4 antibody levels by RAST.

    Results: Fifteen samples contained IgE-Fel d I IC. The levels of IC correlated with the levels of specific lgE antibodies to cat allergen correlated (r=0.48; p<0.05). All the samples of the 27 cat allergic children contained IgE and IgG4 antibodies against cat allergen, while IgE and IgG4 antibodies to cat serum were only demonstrated in 4/27 (14 %) and 6/27 (22%) samples respectively. Conclusions: Immune complexes with the major cat allergen, Fel d I, were commonly present in serum samples from cat allergic children.

  • 14.
    Casas, Rosaura
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik.
    Björkstén, Bengt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Jenmalm, Maria
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik.
    Cat allergen induced cytokine secretion and Fel d 1-IgG immune complexes in cord blood2002Ingår i: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 109, nr 1, s. 529-Konferensbidrag (Övrigt vetenskapligt)
  • 15.
    Casas, Rosaura
    et al.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Böttcher, Malin
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Duchén, Karel
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Björkstén, Bengt
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Detection of IgA antibodies to cat, β-lactoglobulin, and ovalbumin allergens in human milk2000Ingår i: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 105, nr 6 part 1, s. 1236-1240Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The relationship between the development of allergy during infancy and breast-feeding remains controversial. This controversy may be due to individual variations in the composition of human milk. Antibodies to food antigens to which the mother is commonly exposed are present in the milk, but their relationship to allergy is still unknown. IgA antibodies to inhalant allergens have not been previously detected.

    Objective: Our purpose was to analyze secretory IgA antibody levels to cat, β-lactoglobulin, and ovalbumin allergens in colostrum and mature milk in relation to maternal allergy.

    Methods: Colostrum and samples of mature milk were obtained after 1 and 3 months of lactation from 53 nursing mothers (17 allergic and 36 nonallergic mothers) and were analyzed for total secretory IgA levels by ELISA and secretory IgA antibodies to cat, β-lactoglobulin, and ovalbumin by an enzyme-amplified ELISA. The specificity of the assays was confirmed by inhibition experiments.

    Results: Secretory IgA to cat, β-lactoglobulin, and ovalbumin allergens were detected in colostrum as well as mature milk. The levels of secretory IgA to ovalbumin were lower in colostrum from allergic mothers with P = .016, whereas the levels to β-lactoglobulin and cat were similar in the 2 groups. IgA antibodies to ovalbumin were detected in 94% of the colostrum samples from allergic and in all samples from nonallergic mothers, in 82% and 96%, respectively at 1 month, and 53% and 65% at 3 months. Fewer samples had detectable secretory IgA antibodies to β-lactoglobulin than to ovalbumin and cat, and only 33% and 10% of the samples from the allergic and nonallergic mothers, respectively, remained positive at 3 months. All the allergic mothers had detectable IgA to cat in colostrum, whereas 83% and 73% of the samples were positive at 1 and 3 months. The corresponding numbers were 93%, 81%, and 81% in the nonallergic mothers (not significant).

    Conclusion: Even a low level of exposure of the mucosa (eg, by inhalant allergens) can induce antibody secretion into the milk, both in allergic and nonallergic mothers. (J Allergy Clin Immunol 2000;105:1236-40.)

  • 16.
    Casas, Rosaura
    et al.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Djerf, P.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Häggström, P.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Ferrándiz, R.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Björksten, B.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Circulating cat allergen and immune complexes in cat- allergic children1998Ingår i: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 28, nr 10, s. 1258-1263Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    The first encounters with allergens seem to influence the development of allergy. Food antigens have been detected in sera as free antigens and in complexes with IgG but less is known about the presence of inhalant allergens.

    Objective

    To investigate the presence of the major cat allergen Fel d 1, either as free allergen and/or in complexes with IgG and IgE antibodies in sera from atopic children.

    Methods

    Serum samples from 33 cat allergic asthmatic children, 7–17 years old, and 15 non-allergic controls were investigated for the presence of Fel d 1 by ELISA (detection limit 0.13 μg/L). To detect immune complexes (IC), the IgG fraction from Fel d 1 positive sera was purified by affinity chromatography. Purified and non-absorbed material was then analysed for allergen content and specific IgG antibody levels. Immune complexes with Fel d 1 IgE were detected by coupling anti-Fel d 1 MoAb to paramagnetic particles.

    Results

    Fel d 1 was detected (0.15–1.8 μg/L) in 23 of the 33 patients (70%) but not from any of the controls. Eighteen samples contained IgE-Fel d 1 IC and two of four tested samples contained Fel d 1 in the IgG fraction. Electrophoresis and Western blotting of IgG purified material using anti-Fel d 1 MoAb corroborated the presence of IgG-Fel d 1 IC.

    Conclusion

    Free-circulating inhalant allergen and IC with allergens may contribute to maintaining immune responsiveness and sensitivity.

  • 17.
    Casas, Rosaura
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn.
    Ferrándiz, RA
    Wihl, j-Å
    Fernández, B
    Dreborg, S
    Biologic activity of Dermatophagoides siboney and Blomia tropicalis allergens in exposed and unexposed mite-allergic individuals. Effect of patient selection on the biologic standardization of mite extracts.  1999Ingår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 54, s. 392-396Artikel i tidskrift (Refereegranskat)
  • 18.
    Casas, Rosaura
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Hjorth, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Axelsson, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Chéramy, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Pihl, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Specific immunomodulatory effect of GAD(65) in type 1 diabetics2009Ingår i: in DIABETOLOGIA, vol 52, 2009, Vol. 52, s. S194-S194Konferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 19.
    Casas, Rosaura
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik.
    Jenmalm, Maria
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik.
    Björkstén, Bengt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Cat allergen induced cytokine secretion in relation with the detection of Fel d 1-IgG immune complexes in cord blood2002Ingår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 57, s. 135-135Konferensbidrag (Övrigt vetenskapligt)
  • 20.
    Casas, Rosaura
    et al.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Jenmalm, Maria
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Björkstén, Bengt
    Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
    Cat allergen-induced cytokine secretion and Fel d 1–immunoglobulin G immune complexes in cord blood2004Ingår i: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 34, nr 4, s. 591-596Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background We have recently obtained evidence for the presence of immune complexes (IC) in cord blood from allergic and non-allergic mothers. Such complexes could conceivably provide the fetus with the initial trigger for the priming of the T cell system already in utero.

    Objective To relate the presence of Fel d 1–IgG IC to T cell cytokine production in cord blood mononuclear cells (CBMCs) after stimulation with cat allergen.

    Methods CBMC obtained from babies of 15 allergic and 22 non-allergic mothers were cultured in the presence of cat allergen. The production of IFN-γ, IL-5, IL-10 and IL-13 was determined by ELISA. Furthermore, IgG1 and IgG4 antibodies to cat allergen in cord blood samples were measured by ELISA. A more sensitive ELISA was used to measure Fel d 1–IgG IC.

    Results The prevalence and levels of IC were similar in cord blood from children of allergic and non-allergic mothers. The production of IL-5, IL-10. IL-13 and IFN-γ by CBMC was not influenced by maternal atopy, but IFN-γ was less commonly detected in samples with IC. There was no association between the presence of IC and any other cytokines. The levels of IgG1 and IgG4 antibodies were similar in both groups, and tended to be associated with the presence of IC.

    Conclusion Immune complexes in cord blood may represent a normal mechanism for inducing primary immune responses, as the responses in babies from allergic and non-allergic mothers were largely similar. Low levels of IFN-γ seems to be related with the presence of IC in cord blood.

  • 21.
    Casas, Rosaura
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik.
    Lindau, C
    Division of Paediatrics Linköping University.
    Zetterström, Olle
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Allergicentrum. Östergötlands Läns Landsting, Medicincentrum, Allergicentrum US.
    Duchén, Karel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Downregulation of CXCR6 and CXCR3 in lymphocytes from birch-allergic patients2008Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 68, nr 3, s. 351-361Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Preferential expression of chemokine receptors on Th1 or Th2 T-helper cells has mostly been studied in cell lines generated in vitro or in animal models, however, results are less well characterized in humans. We determined T-cell responses through chemokine receptor expression on lymphocytes, and cytokine secretion in plasma from birch-allergic and healthy subjects. The expression of CCR2, CCR3, CCR4, CCR5, CCR7, CXCR3, CXCR4, CXCR6, IL-12 and IL-18R receptors was studied on CD4+ and CD8+ cells from birch-allergic (n = 14) and healthy (n = 14) subjects by flow cytometry. The concentration of IL-4, IL-5, IL-10, IL-12, IFN-γ and TNF-α cytokines was measured in plasma from the same individuals using a cytometric bead array human cytokines kit. The similar expression of CCR4 in T cells from atopic and healthy individuals argues against the use of the receptor as an in vivo marker of Th2 immune responses. Reduced percentages of CD4+ cells expressing IL-18R, CXCR6 and CXCR3 were found in the same group of samples. TNF-α, IFN-γ, IL-10, IL-5, IL-4 and IL-12 cytokines were elevated in samples from allergic individuals. Reduced expression of Th1-associated chemokine receptors together with higher levels of Th1, Th2 and anti-inflammatory cytokines in samples from allergic patients indicate that immune responses in peripheral blood in atopic diseases are complex and cannot be simplified to the Th1/Th2 paradigm. Not only the clinical picture of atopic diseases but also the clinical state at different time points of the disease might influence the results of studies including immunological markers associated with Th1- or Th2-type immune responses. © 2008 The Authors.

  • 22.
    Casas, Rosaura
    et al.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Skarsvik, Susanne
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Lundberg, Anna
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Zetterström, Olle
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Allergicentrum. Östergötlands Läns Landsting, Medicincentrum, Allergicentrum US. Linköpings universitet, Hälsouniversitetet.
    Duchén, Karel
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Impaired maturation of monocyte-derived dendritic cells from birch allergic individuals in association with birch-specific immune responses2007Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 66, nr 5, s. 591-598Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Optimal activation of T lymphocytes requires a costimulatory signal provided by the interaction of molecules on the surface of T cells with their ligands expressed on dendritic cells (DC). We investigated whether DC differentiated from monocytes from healthy and birch allergic asthmatic individuals and further maturated by stimulation with cat and birch allergens and LPS differ in their phenotypic receptor expression. Similar expression of DC surface markers, including HLA-DR, CD80, CD86, CD83, CD1a and CD11c, was detected in monocyte-derived DC from allergic and healthy individuals. Cells from healthy donors stimulated either antigen showed a similar activation of the CD80 and double CD80/CD86 costimulatory molecules when compared with non-stimulated cells. In the case of cells from allergic individuals, birch allergen was unable to produce the same increased expression of CD80 alone or in combination with CD80/CD86, in comparison with cells stimulated with cat and LPS. Levels of IL-6, IL-8, IL-10, MCP-1/MCAF and MIP-1β were similar in the supernatant of non-stimulated DC from both groups of subjects. By contrast, the spontaneous secretion of IL-12p70 and TNF-α was higher in the supernatant of DC from healthy subjects when compared with that from allergic individuals. Stimulation with birch and LPS resulted in an increased secretion of IL-12p70 in samples from healthy when compared with that in allergic individuals. The results suggest an impaired specific maturation of DC from birch allergic individuals in association with birch-specific immune responses. Lower secretion of IL-12p70 from birch-stimulated DC from allergic individuals suggests that not only maturation, but also the specific Th1 function of these cells seems to be affected in those individuals.

  • 23.
    Chéramy, Mikael
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Axelsson, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Åkerman, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Pihl, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    GAD65 autoantibody (GADA) responses in Type 1 diabetes patients participating in a phase III GAD-alum intervention trialManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Glutamic acid decarboxylase 65 kDa isoform (GAD65) is a major autoantigen in type 1 diabetes (T1D). Although aluminum-formulated GAD65 (GAD-alum) induced preservation of residual insulin secretion in a previous clinical phase II trial, recent phase II and III trials failed to reach their primary end-points. The European phase III trial was therefore closed after 15 months, and the entire study period was completed only for a minority of the patients. This study aimed to characterize GAD65 autoantibodies (GADA) and Tyrosine phosphatase IA-2 autoantibody (IA-2A) levels, GADA IgG1-4 subclass distribution, B-cell frequencies/phenotypes and cytokine secretion. We also assessed whether GAD-alum preserved β-cell function in the small subgroup of Swedish patients who completed the 30 months visit. Serum samples and peripheral blood mononuclear cells (PBMC) were collected at baseline and after 1, 3, 9, 15 and 21 months from the 148 Swedish subjects included in the trial, and also at 30 months from the 45 patients who reached the final visit. Patients were randomly assigned to; i) 4 doses of GAD-alum (4D), ii) 2 doses of GAD-alum followed by two doses of placebo (2D), or iii) 4 doses of placebo.

    GADA titers were induced both in the 4D and 2D group compared to placebo, and 4D patients also displayed a higher GADA fold-change after receiving the  two additional injections compared to the 2D group. The 4D group switched to a higher frequency of GADA IgG4, associated to a Th2 type response at 9 months, whereas an association between GADA fold-change and GAD65-induced in vitro cytokine secretion was observed in the 2D group. These findings suggest that the humoral response, induced by the 2D treatment,  seems to be associated with a GAD65-specific cellular response, while 4D induces a distinct humoral response. Even though GADA titers were elevated, no changes in B-cell frequencies or phenotype were observed in any group. IA-2A levels declined at a similar rate in all groups during the trial.The subgroup of patients who completed the 30 month visit receiving 2 doses of GAD-alum had less decline of both fasting and stimulated C-peptide after 30 months compared to placebo. These results support the concept of GAD-alum treatment, but no specific immune markers have been identified.

  • 24.
    Chéramy, Mikael
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Hampe, Christiane S.
    Department of Medicine, University of Washington, Seattle, WA, USA.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Characteristics of in-vitro phenotypes of glutamic acid decarboxylase 65 autoantibodies in high-titre individuals2013Ingår i: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 171, nr 3, s. 247-254Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Previous studies have indicated phenotypical differences in glutamic acid decarboxylase 65 autoantibodies (GADA) found in type 1 diabetes (T1D) patients, individuals at risk of developing T1D and stiff-person syndrome (SPS) patients. In a Phase II trial using aluminium-formulated GAD65 (GAD-alum) as an immunomodulator in T1D, several patients responded with high GADA titres after treatment, raising concerns as to whether GAD-alum could induce GADA with SPS-associated phenotypes. This study aimed to analyse GADA levels, immunoglobulin (Ig)G1–4 subclass frequencies, b78- and b96·11-defined epitope distribution and GAD65 enzyme activity in sera from four cohorts with very high GADA titres: T1D patients (n = 7), GAD-alum-treated T1D patients (n = 9), T1D high-risk individuals (n = 6) and SPS patients (n = 12). SPS patients showed significantly higher GADA levels and inhibited the in-vitro GAD65 enzyme activity more strongly compared to the other groups. A higher binding frequency to the b78-defined epitope was found in the SPS group compared to T1D and GAD-alum individuals, whereas no differences were detected for the b96·11-defined epitope. GADA IgG1–4 subclass levels did not differ between the groups, but SPS patients had higher IgG2 and lower IgG4 distribution more frequently. In conclusion, the in-vitro GADA phenotypes from SPS patients differed from the T1D- and high-risk groups, and GAD-alum treatment did not induce SPS-associated phenotypes. However, occasional overlap between the groups exists, and caution is indicated when drawing conclusions to health or disease status.

  • 25.
    Chéramy, Mikael
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Skoglund, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Johansson, Ingela
    Linköpings universitet, Institutionen för medicin och hälsa, Kardiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärtcentrum, Kardiologiska kliniken.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Hampe, Christiane S
    University of Washington.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD(65) enzyme activity and humoral response2010Ingår i: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 137, nr 1, s. 31-40Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have previously shown that two injections of 20 mu g GAD-alum to recent onset type 1 diabetic children induced GADA levels in parallel to preservation of insulin secretion. Here we investigated if boosted GADA induced changes in IgG1, 2, 3 and 4 subclass distributions or affected GAD(65) enzyme activity. We further studied the specific effect of GAD-alum through analyses of IA-2A, tetanus toxoid and total IgE antibodies. Serum from children receiving GAD alum or placebo was collected pre-treatment and after 3, 9, 15 and 21 months. At 3 months a reduced percentage of IgG1 and increased IgG3/IgG4 were detected in GAD-alum treated. Further, IA-2A, IgE and tetanus toxoid antibodies, as well as GAD(65) enzyme activity, were unaffected confirming the specific effect of treatment. In the GAD-alum group, higher pretreatment GADA were associated to more pronounced C-peptide preservation. The induced IgG3/IgG4 and reduced IgG1 suggest a Th2 deviation of the immune response.

  • 26.
    Hedman Hjorth, Maria
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Faresjö, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Axelsson, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Impaired CD4+ and CD8+ T cell phenotype and reduced chemokine secretion in recent-onset type 1 diabetic children2008Ingår i: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 153, nr 3, s. 360-368Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Although the role of the T cell-mediated autoimmune reaction in type 1 diabetes (T1D) is conclusive, studies including data from human circulating CD4+ and CD8+ lymphocytes subsets during the disease onset and posterior development are scarce. Further, chemokines and chemokine receptors are key players in the migration of pathogenic T cells into the islets of NOD mice developing T1D, but few studies have investigated these markers in human T1D patients. We studied the expression of T helper 1 (Th1) and Th2 associated chemokine receptors, and the two isoforms of CD45 leukocyte antigen on CD4+ and CD8+ lymphocytes from T1D and healthy children, as well as the secretion of chemokines in cell supernatants in peripheral blood mononuclear cells. Our results showed increased expression of CCR7 and CD45RA, and reduced CD45RO on CD8+ cells among recent-onset T1D patients. The percentages of CD4+ cells expressing CXC chemokine receptor 3 (CXCR3), CXCR6 and CCR5, and the secretion of interferon-γ-induced protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1a and MIP-1β was lower among diabetics. Low expression of Th1-associated receptors and secretion of chemokines, together with an increased amount of CD8+ cells expressing CD45RA and CCR7 in T1D patients therefore might represent suboptimal Th function in T1D, leading to impaired T cytotoxic (Tc) responses or alternatively reflect a selective recruitment of Th1 cells into the pancreas.

  • 27.
    Hjorth, Maria
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Axelsson, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    GAD-alum treatment induces GAD-specific FOXP3+ cells in type 1 diabetic children2009Ingår i: in DIABETOLOGIA, vol 52, 2009, Vol. 52, s. S193-S193Konferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 28.
    Hjorth, Maria
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Axelsson, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Ryden, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Faresjo, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    GAD-alum treatment induces GAD(65)-specific CD4(+)CD25(high)FOXP3(+) cells in type 1 diabetic patients2011Ingår i: CLINICAL IMMUNOLOGY, ISSN 1521-6616, Vol. 138, nr 1, s. 117-126Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Type 1 diabetes results from autoimmune destruction of insulin producing pancreatic beta-cells. We have shown that treatment with alum-formulated glutamic acid decarboxylase 65 (GAD-alum) preserved residual insulin secretion and induced antigen-specific responses in children with recent onset type 1 diabetes. The aim of this study was to further investigate the immunomodulatory effect of GAD-alum, focusing on CD4(+)CD25(high) cells and their association to cytokine secretion. Samples obtained 21 and 30 months after the initial injection of GAD-alum or placebo were included in the present study. GAD(65)-stimulation enhanced the percentage of CD4(+)CD25(high)FOXP3(+) cells, but reduced the percentage of CD4(+)CD25(+) cells, in samples from the GAD-alum treated group. Further, the GAD(65)-induced secretion of IL-5, -10, and -13 correlated with the expression of CD4(+)CD25(high)FOXP3(+) cells, but inversely with CD4(+)CD25(+) cells. These new data suggest that GAD-alum treatment induced GAD(65)-specific T cells with regulatory features.

  • 29.
    Jonson, Carl-Oscar
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Hedman, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Faresjö, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Ilonen, Jorma
    JDRF Center for Prevention of Type 1 Diabetes in Finland and Department of Virology, University of Turku, Turku, Finland .
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Vaarala, Outi
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    CTLA-4 Polymorfism, Type 1 Diabetes-risk Human Leukocyte Antigen-genotypes, insulin gene polymorphism and Regulatory T-cell Marker Expression in 5-year-old children2006Ingår i: Clinical & Experimental Immunology, ISSN 0009-9104, Vol. 145, nr 1, s. 48-55Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Regulatory T cells (Treg) are involved in the maintenance of peripheral tolerance by suppression of autoreactive lymphocytes that have avoided thymic depletion. The defective function of Treg cells has recently attracted attention in autoimmune diseases such as type 1 diabetes (T1D), rheumatoid arthritis and multiple sclerosis. Susceptibility to these diseases is associated with specific human leucocyte antigen (HLA) class II and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene polymorphisms. This study aimed to investigate the relationship between HLA class II and CTLA +49 A/G polymorphisms associated with susceptibility to T1D and the number and characteristics of Treg cells in children. Samples from 47 5-year-old children who participated in the All Babies in South-east Sweden (ABIS) follow-up study were grouped according to the presence of the T1D risk-associated HLA genotype (DQA1*0501–DQB1*0201, DQA1*0301–DQB1*0302) or neutral HLA genotypes. Lower percentages of CD4+ T cells (= 0·03) and CD4+ CD25high cells (= 0·06) expressing intracellular CTLA-4 were detected in samples from children with CTLA-4 +49GG compared to children with the +49AA genotype. Similarly, lower percentages of CD4+ (= 0·002) and CD4+ CD25high (= 0·002) cells expressing CTLA-4 were observed in children positive for HLA DQA1*0501–DQB1*0201 and DQA1*0301–DQB1*0302 (= 0·04 for CD4+ and P = 0·02 for CD4+ CD25high) risk haplotypes when compared to children without these alleles. The percentage of CD25high cells among CD4+ cells was correlated inversely with CTLA-4 mRNA expression in PBMC (r = –0·56, P = 0·03). Decreased levels of CTLA-4 in CD4+ and CD4+ CD25high cells in individuals with CTLA-4 and HLA class II alleles associated with T1D may contribute to the initiation and/or progression of autoimmune response.

  • 30.
    Lahdenperä, Anne
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Ljungberg, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Lundberg, Anna
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Hälsouniversitetet.
    Korpela, Riitta
    Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Vaarala, Outi
    National Institute Health and Welf, Finland .
    Probiotics and innate immune response in infants2014Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    We studied the effects of probiotic treatment on the innate immune system during infancy. The study included a subgroup of infants recruited to the pilot study testing the feasibility of probiotics intervention in infants with genetic risk of type 1 diabetes (T1D). A mixture of Lactobacillus rhamnosus GG (5 x 109 cfu), Lactobacillus rhamnosus LC705 (5 x 109 cfu), Bifidobacterium breve Bbi99 (2 x 108 cfu) and Propionibacterium freudenreichii ssp. Shermani JS (2 x 109 cfu) was given to the infants beginning one to three weeks after birth until the age of 6 months. Blood samples were drawn at the age of 6, 12 and 24 months for the analyses of beta-cell autoantibodies and the phenotype and stimulation response of monocytes with flow-cytometry, including surface markers on circulating CD14+ monocytes and expression of co-stimulatory markers on CD14+ monocytes as response to stimulation with lipoteichoic acid (LTA) and lipopolysaccharide (LPS). Also gene expression of toll-like receptor (TLR) signalling molecules was studied in the peripheral blood mononuclear cell (PBMC) population.

    In the children who received probiotics the number of circulating CD14+ monocytes expressing CD58 was reduced at the age of 6 months, and a tendency for a decreased induction of CCR5, CD80 and CD58 expressing monocytes as response to LTA was seen when compared to the children who received placebo. At the age of 12 months, the number of monocytes expressing CCR5 was decreased in the probiotic group, and a decreased spontaneous expression of TNFRSF1A and an increased spontaneous expression of TLR9 was observed in the PBMC from the children treated with probiotics. In the whole study group, the numbers of circulating monocytes expressing CD80 increased with age as well as the induction of CCR5, CD80 and CD58 on monocytes as response to stimulation. By the age of 24 months one child in both groups developed multiple autoantibodies.

    We demonstrated that probiotics modulated the activation stage and stimulation response of monocytes, and that prolonged effects of the treatment were seen at the age of 12 months. The findings suggest that early microbial exposure may program the function of the innate immune system for later life.

  • 31.
    Ludvigsson, Johnny
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    GAD-Alum Treatment Seems Effective in Slowing ResidualBeta-Cell Function Loss: Significant C-peptide level preservation was found among treated patients.2009Ingår i: Review of Endocrinology, ISSN 1944-9895, Vol. 01, s. 28-32Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    DISCUSSION

    Stimulated C-peptide levels have been considered an endpoint for assessing beta-cell function preservation early in type 1 diabetes. These levels correlate with improved glycemic control and fewer microvascular complications.13,14,29 We found no significant effect of GAD-alum treatment on the change in the primary endpoint of fasting C-peptide, but an effect was seen on stimulated C-peptide level. Both fasting and stimulated C-peptide levels declined to a significantly smaller degree in the GAD-alum group than in the placebo group after 30 months. The observed protective effect of treatment on C-peptide secretion was seen only in patients treated <6 months after diagnosis.

    In our study, the duration and magnitude of the GAD-alum treatment effect appears similar to that reported for anti-CD3 treatment13,14 but without the related adverse events. Especially over the long term, residual insulin secretion affects key clinical outcomes.3 Possible explanations include improved overall metabolic control, reduced fluctuation in blood glucose levels and perhaps increased exposure to C-peptide.30 Our results indicate that two injections of 20 µg GAD-alum may help preserve residual insulin secretion in patients with recent-onset type 1 diabetes. How GAD-alum treatment may work to alter disease progression in type 1 diabetes is unclear. Therapy was otherwise similar in the two study groups, therefore differences in preserved beta-cell function do not appear to be related to more intense insulin treatment or better metabolic control in the GAD-alum group. Although fasting C-peptide level may be influenced by blood glucose level, we found significant C-peptide level preservation before and after adjustment for blood glucose level.

    CONCLUSION

    Treatment with GAD-alum had an effect on slowing the loss of residual beta-cell function up to 30 months after intervention and was associated with GAD-specific immune modulation. This did not, however, change the insulin requirement. Our study provides preliminary proof of concept; large-scale confirmatory studies with GAD-alum are under way in the United States and Europe.

  • 32.
    Ludvigsson, Johnny
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Chéramy, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Axelsson, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Pihl, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Åkerman, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    GAD-treatment of children and adolescents with recent-onset Type 1 diabetes preserves residual insulin secretion after 30 months2014Ingår i: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 30, nr 5, s. 405-414Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: This study aimed to analyse data from two different studies (Phase II and Phase III) regarding the safety and efficacy of treatment with alum formulated glutamic acid decarboxylase GAD65 (GAD-alum), 30 months after administration to children and adolescents with Type 1 diabetes (T1D).

    METHODS: The Phase II trial was a double-blind, randomized placebo-controlled study, including 70 children and adolescents which were followed for 30 months. Participants received a subcutaneous injection of either 20 µg of GAD-alum or placebo at baseline and one month later. During a subsequent larger European Phase III trial including three treatment arms, participants received two or four subcutaneous injections of either 20 µg of GAD-alum and/or placebo at baseline, 1, 3 and 9 months. The Phase III trial was prematurely interrupted at 15 months, but of the 148 Swedish patients, a majority completed the 21 months follow-up and 45 patients completed the trial at 30 months. Both studies included GADA-positive patients with fasting C-peptide ≥0.10 nmol/l. We have now combined the results of these two trials.

    RESULTS: There were no treatment related adverse events. In patients treated with 2 GAD-alum doses, stimulated C-peptide AUC had decreased significantly less (9 m: p < 0.037; 15 m p < 0.032; 21 m p < 0.003 and 30 m p < 0.004) and a larger proportion of these patients were also able to achieve a peak stimulated C-peptide >0.2 nmol/l (p < 0.05), as compared to placebo.

    CONCLUSION: Treatment with two doses of GAD-alum in children and adolescents with recent-onset T1D shows no adverse events and preserves residual insulin secretion. This article is protected by copyright. All rights reserved.

  • 33.
    Ludvigsson, Johnny
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Faresjö, Maria
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik.
    Hjorth, Maria
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik.
    Axelsson, Stina
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik.
    Chéramy, Mikael
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik.
    Pihl, Mikael
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik.
    Vaarala, Outi
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik.
    Forsander, Gun
    Ivarsson, Sten
    Johansson, Calle
    Lindh, Agne
    Nilsson, NO
    Åman, Jan
    Örtqvist, Eva
    Zerhouni, Peter
    Casas, Rosaura
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik.
    GAD treatment and insulin secretion in recent-onset type 1 diabetes2008Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 359, nr 18, s. 1909-1920Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The 65-kD isoform of glutamic acid decarboxylase (GAD) is a major autoantigen in patients with type 1 diabetes mellitus. This trial assessed the ability of alum-formulated GAD (GAD-alum) to reverse recent-onset type 1 diabetes in patients 10 to 18 years of age. Methods: We randomly assigned 70 patients with type 1 diabetes who had fasting C-peptide levels above 0.1 nmol per liter (0.3 ng per milliliter) and GAD autoantibodies, recruited within 18 months after receiving the diagnosis of diabetes, to receive subcutaneous injections of 20 μg of GAD-alum (35 patients) or placebo (alum alone, 35 patients) on study days 1 and 30. At day 1 and months 3, 9, 15, 21, and 30, patients underwent a mixed-meal tolerance test to stimulate residual insulin secretion (measured as the C-peptide level). The effect of GAD-alum on the immune system was also studied. Results: Insulin secretion gradually decreased in both study groups. The study treatment had no significant effect on change in fasting C-peptide level after 15 months (the primary end point). Fasting C-peptide levels declined from baseline levels significantly less over 30 months in the GAD-alum group than in the placebo group (-0.21 vs. -0.27 nmol per liter [-0.62 vs. -0.81 ng per milliliter], P = 0.045), as did stimulated secretion measured as the area under the curve (-0.72 vs. -1.02 nmol per liter per 2 hours [-2.20 vs. -3.08 ng per milliliter per 2 hours], P = 0.04). No protective effect was seen in patients treated 6 months or more after receiving the diagnosis. Adverse events appeared to be mild and similar in frequency between the two groups. The GAD-alum treatment induced a GAD-specific immune response. Conclusions: GAD-alum may contribute to the preservation of residual insulin secretion in patients with recent-onset type 1 diabetes, although it did not change the insulin requirement. (ClinicalTrials.gov number, NCT00435981.) Copyright © 2008 Massachusetts Medical Society. All rights reserved.

  • 34.
    Ludvigsson, Johnny
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Hjorth, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Chéramy, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Axelsson, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Pihl, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Forsander, G
    Queen Silvia Childrens Hospital.
    Nilsson, N-O
    Halmstad County Hospital.
    Samuelsson, B-O
    Boras Hospital.
    Wood, T
    Diamyd Therapeut.
    Aman, J
    Orebro University Hospital.
    Ortqvist, E
    Karolinska University Hospital.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial2011Ingår i: DIABETOLOGIA, ISSN 0012-186X, Vol. 54, nr 3, s. 634-640Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of this study was to investigate the safety and efficacy of alum formulated glutamic acid decarboxylase GAD(65) (GAD-alum) treatment of children and adolescents with type 1 diabetes after 4 years of follow-up. Seventy children and adolescents aged 10-18 years with recent onset type 1 diabetes participated in a phase II, double-blind, randomised placebo-controlled clinical trial. Patients identified as possible participants attended one of eight clinics in Sweden to receive information about the study and for an eligibility check, including a medical history. Participants were randomised to one of the two treatment groups and received either a subcutaneous injection of 20 mu g of GAD-alum or placebo at baseline and 1 month later. The study was blinded to participants and investigators until month 30. The study was unblinded at 15 months to the sponsor and statistician in order to evaluate the data. At follow-up after 30 months there was a significant preservation of residual insulin secretion, as measured by C-peptide, in the group receiving GAD-alum compared with placebo. This was particularly evident in patients with andlt; 6 months disease duration at baseline. There were no treatment-related serious adverse events. We have now followed these patients for 4 years. Overall, 59 patients, 29 who had been treated with GAD-alum and 30 who had received placebo, gave their informed consent. One patient in each treatment group experienced an episode of keto-acidosis between months 30 and 48. There were no treatment-related adverse events. The primary efficacy endpoint was the change in fasting C-peptide concentration from baseline to 15 months after the prime injection for all participants per protocol set. In the GAD-alum group fasting C-peptide was 0.332 +/- 0.032 nmol/l at day 1 and 0.215 +/- 0.031 nmol/l at month 15. The corresponding figures for the placebo group were 0.354 +/- 0.039 and 0.184 +/- 0.033 nmol/l, respectively. The decline in fasting C-peptide levels between day 1 and month 1, was smaller in the GAD-alum group than the placebo group. The difference between the treatment groups was not statistically significant. In those patients who were treated within 6 months of diabetes diagnosis, fasting C-peptide had decreased significantly less in the GAD-alum group than in the placebo-treated group after 4 years. Four years after treatment with GAD-alum, children and adolescents with recent-onset type 1 diabetes continue to show no adverse events and possibly to show clinically relevant preservation of C-peptide. ClinicalTrials.gov NCT00435981 The study was funded by The Swedish Research Council K2008-55X-20652-01-3, Barndiabetesfonden (The Swedish Child Diabetes Foundation), the Research Council of Southeast Sweden, and an unrestricted grant from Diamyd Medical AB.

  • 35.
    Ludvigsson, Johnny
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Krisky, David
    Diamyd Medical, Pittsburgh.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Battelino, Tadej
    University Medical Center–University Children's Hospital, Faculty of Medicine, Ljubljana, Slovenia .
    Castaño, Luis
    Hospital de Cruces–University of Basque Country, Barakaldo, Bizkaia, Spain .
    Greening, James
    Department of Paediatrics, Leicester Royal Infirmary, Leicester, UK.
    Kordonouri, Olga
    Diabetes Center for Children and Adolescents, Kinderkrankenhaus auf der Bult, Hannover, Germany .
    Otonkoski, Timo
    Children's Hospital, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland.
    Pozzilli, Paolo
    University Campus Bio-Medico, Rome, Italy.
    Robert, Jean-Jacques
    Hôpital Necker–Enfants Malades, Université René Descartes Paris 5, Paris, France.
    Veeze, Henk J.
    Stichting Diabeter, Rotterdam, the Netherlands .
    Palmer, Jerry
    Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, USA.
    Samuelsson, Ulf
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Elding Larsson, Helena
    Lunds universitet, Sweden.
    Åman, Jan
    Örebro universitet, Sweden.
    Kärdell, Gunilla
    Neiderud, Jan
    Helsingborgs lasarett, Sweden.
    Lundström, Göran
    Länssjukhuset Kalmar, Sweden.
    Albinsson, Eva
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Annelie
    Skånes universitetssjukhus, Lund, Sweden.
    Nordvall, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Norrköping.
    Fors, Hans
    Sahlgrenska akademin vid Göteborgs universitet, Sweden.
    Arvidsson, Carl-Göran
    Centrallasarettet, Västerås, Sweden.
    Edvardson, Stig
    Centrallasarettet, Växjö, Sweden.
    Hanås, Ragnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Larsson, Karin
    Rathsman, Björn
    Sachsska Barnsjukhuset, Stockholm, Sweden.
    Forsgren, Henrik
    Desaix, Helena
    Forsander, Gun
    Göteborg University, Sweden.
    Nilsson, Nils-Östen
    Lasarettet i Halmstad, Sweden.
    Åkesson, Carl-Göran
    Keskinen, Päivi
    University of Tampere, Finland .
    Veijola, Riitta
    Uleåborgs universitetssjukhus, Finland.
    Talvitie, Timo
    Raile, Klemens
    Charite, Berlin, Germany.
    Kapellen, Thomas
    University of Leipzig, Germany.
    Burger, Walter
    Neu, Andreas
    University Children's Hospital, Tuebingen, Germany.
    Engelsberger, Ilse
    Heidtmann, Bettina
    Catholic Children’s Hospital Wilhelmstift, Hamburg, Germany.
    Bechtold, Suzanne
    Leslie, David
    Blizard Institute, Queen Mary University of London, UK.
    Chiarelli, Francesco
    University of Chieti, Italy.
    Cicognani, Alesandro
    University of Bologna, Italy.
    Chiumello, Giuseppe
    Vita-Salute University, Milan, Italy.
    Cerutti, Franco
    University of Turin, Italy.
    Zuccotti, Gian Vincenzo
    University of Milan, Italy.
    Gomez Gila, Ana
    Rica, Itxaso
    Barrio, Raquel
    Clemente, Maria
    López Garcia, Maria José
    Rodriguez, Mercedes
    Gonzalez, Isabel
    Lopez, Juan Pedro
    Oyarzabal, Mirentxu
    Reeser, H M
    Nuboer, Roos
    Stouthart, Pauline
    Bratina, Natasa
    Bratanic, Nina
    de Kerdanet, Marc
    Weill, Jacques
    Ser, Nicole
    Barat, Pascal
    Bertrand, Anne Marie
    Carel, Jean-Claude
    Reynaud, Rachel
    Coutant, Regis
    Baron, Sabine
    GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus2012Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 366, nr 5, s. 433-442Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes.

    METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels.

    RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences.

    CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period.

  • 36.
    Ludvigsson, Johnny
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Skoglund, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Chéramy, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Hampe, C
    Department Med, Seattle.
    GAD(65) treatment induces high GADA but no changes in epitopes or adverse signs/symptoms in type 1 diabetic children2009Ingår i: in DIABETOLOGIA, vol 52., 2009, Vol. 52, s. S192-S192Konferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 37.
    Ludvigsson, Johnny
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Wahlberg Topp, Jeanette
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Endokrinmedicinska kliniken.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Letter: Intralymphatic Injection of Autoantigen in Type 1 Diabetes in NEW ENGLAND JOURNAL OF MEDICINE, vol 376, issue 7, pp 697-6992017Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 376, nr 7, s. 697-699Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 38.
    Martinuzzi, E
    et al.
    Inserm U986 DeAR Lab Avenir.
    Gagnerault, M C
    Inserm U986 DeAR Lab Avenir.
    Fourlanos, S
    Walter and Eliza Hall Institute Medical Research.
    Harrison, L
    Walter and Eliza Hall Institute Medical Research.
    Axelsson, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Chéramy, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Mallone, R
    Inserm U986 DeAR Lab Avenir.
    Why are the benefits of vaccinations in the helping of beta-cellular antigenes in type 1 diabetes so limited? An analysis of linked immunological biomarkers in DIABETES and METABOLISM, vol 38, issue 2, pp A5-A52012Ingår i: DIABETES and METABOLISM, Elsevier Masson , 2012, Vol. 38, nr 2, s. A5-A5Konferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 39.
    Mjösberg, Jenny
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Svensson, J
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Linköpings universitet, Hälsouniversitetet.
    Johansson, E
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Linköpings universitet, Hälsouniversitetet.
    Hellstrom, L
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Linköpings universitet, Hälsouniversitetet.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Jenmalm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Boij, R
    Ryhov Hospital.
    Matthiesen, L
    Helsingborg Hospital.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Berg, Göran
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Ernerudh, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk immunologi och transfusionsmedicin.
    Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ T-regs in human second trimester pregnancy is induced by progesterone and 17 beta-estradiol2009Ingår i: Journal of Reproductive Immunology(ISSN 0165-0378), vol 81, issue 2, 2009, Vol. 81, nr 2, s. 160-161Konferensbidrag (Refereegranskat)
    Abstract [en]

    CD4+CD25high regulatory T cells (Tregs) are implicated in maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim was to determine the frequency, phenotype and function of circulating Tregs in second trimester human pregnancy and the influence of progesterone and 17β-estradiol on Treg phenotype and frequency. Based on expression of Foxp3, CD127 and HLA-DR, as determined by multi-color flow cytometry, we defined a proper CD4dimCD25high Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4+ population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17β-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4dimCD25highFoxp3+ cells in PBMC from non-pregnant women. By co-culturing FACS-sorted Tregs and autologous CD4+CD25- responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as non-pregnant women in terms of suppressing IL-2, TNF-α and IFN-γ secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Further, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need re-evaluation.

  • 40.
    Mjösberg, Jenny
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Judit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Linköpings universitet, Hälsouniversitetet.
    Johansson, Emma
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Linköpings universitet, Hälsouniversitetet.
    Hellström, Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Geriatrik. Linköpings universitet, Hälsouniversitetet.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Jenmalm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Boij, Roland
    Ryhov Hospital, Jönköping, Sweden.
    Matthiesen, Leif
    Helsingborg Hospital, Helsingborg, Sweden.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Berg, Göran
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Ernerudh, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk immunologi och transfusionsmedicin.
    Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17θ-estradiol2009Ingår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 183, nr 1, s. 759-769Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    CD4+CD25high regulatory T cells (Tregs) are implicated in the maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent, and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim of this study was to determine the frequency, phenotype, and function of circulating Tregs in the second trimester of human pregnancy and the influence of progesterone and 17β-estradiol on Treg phenotype and frequency. Based on expressions of Foxp3, CD127, and HLA-DR as determined by multicolor flow cytometry, we defined a proper CD4dimCD25high Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester of pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4+ population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17β-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4dimCD25highFoxp3+ cells in PBMC from nonpregnant women. By coculturing FACS-sorted Tregs and autologous CD4+CD25 responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as nonpregnant women in terms of suppressing IL-2, TNF-, and IFN- secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Furthermore, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need reevaluation.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • 41.
    Paulsson, Johan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Carlsson, Annelie
    University of Lund Hospital, Sweden .
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Forsander, Gun
    Queen Silvia Childrens Hospital, Sweden .
    Ivarsson, Sten A.
    University Hospital MAS, Sweden .
    Kockum, Ingrid
    Karolinska Institute, Sweden .
    Lernmark, Ake
    Lund University, Sweden .
    Marcus, Claude
    Karolinska University Hospital, Sweden .
    Lindblad, Bengt
    Queen Silvia Childrens Hospital, Sweden .
    Westermark, Gunilla T.
    Uppsala University, Sweden .
    High Plasma Levels of Islet Amyloid Polypeptide in Young with New-Onset of Type 1 Diabetes Mellitus2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 3, s. 0093053-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims/Hypothesis: Islet amyloid polypeptide (IAPP) is a beta cell hormone secreted together with insulin upon glucose stimulation. IAPP participates in normal glucose regulation, but IAPP is also known for its ability to misfold and form islet amyloid. Amyloid fibrils form through smaller cell toxic intermediates and deposited amyloid disrupts normal islet architecture. Even though IAPP and amyloid formation are much discussed in type 2 diabetes, our aim was to study the significance of IAPP in type 1 diabetes. Results: Plasma IAPP levels in children and adolescents with newly diagnosed type 1 diabetes (n = 224) were analysed and concentrations exceeding 100 pmol/L (127.2 - 888.7 pmol/L) were found in 11% (25/224). The IAPP increase did not correlate with C-peptide levels. Conclusions/Interpretation: Plasma levels of IAPP and insulin deviate in a subpopulation of young with newly-diagnosed type 1 diabetes. The determined elevated levels of IAPP might increase the risk for IAPP misfolding and formation of cell toxic amyloid in beta cells. This finding add IAPP-aggregation to the list over putative pathological factors causing type 1 diabetes.

  • 42.
    Pihl, Mikael
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Axelsson, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Cheramy, Mikael
    Benaroya Research Institute at Virginia Mason, Seattle, USA.
    Reijonen, Helena
    Benaroya Research Institute at Virginia Mason, Seattle, USA.
    Ludvgisson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    GAD-alum treatment induces GAD-specific CD4 T cells in a phase III clinical trial2013Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Glutamic Acid Decarboxylase (GAD)65 formulated in aluminium hydroxide (GAD-alum preserved insulin secretion in a phase II clinical trial in recent onset type 1 diabetes. GADalum treated patients up-regulated FOXP3 upon antigen recall at 21 and 30 months after treatment. A 4-year follow-up of the study revealed increased frequencies of both CD25+CD127+ and CD25hiCD127lo cells in treated patients after antigen recall. A subsequent european phase III trial was closed after 15 months after failing to reach primary outcome. We monitored antigen recall induced frequencies of memory, effector and regulatory T cells throughout the phase III trial. Antigen recall induced mainly CD25+CD127+, CD45RO+ and non-suppressive FOXP3loCD45RA- cells in GAD-alum treated patients. In addition, a population of activated FSChiSSChi cells was observed, enriched in CD25+CD127+, CD45RO+ and proliferating cells. GAD65-specific T cells determined by tetramer staining were induced by antigen recall in GAD-alum treated patients and were more frequent in the FSChiSSChi population. Additional doses of GAD-alum increased frequencies of CD25+CD127+, CD45RO+ and FSChiSSChi cells but had no effect on frequencies of CD25hiCD127lo. Our findings indicate that antigen recall after GAD-alum treatment primarily induces memory and activated T cells. In particular, GAD65-specific cells were mainly of a memory or activated phenotype. Additional doses of GAD-alum mainly affect memory T cell frequency and T cell activation.

  • 43.
    Pihl, Mikael
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Chéramy, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Mjösberg, Jenny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Linköpings universitet, Hälsouniversitetet.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Increased expression of regulatory T cell-associated markers in recent-onset diabetic children2011Ingår i: Open Journal of Immunology, ISSN 2162-450X, E-ISSN 2162-4526, Vol. 1, nr 3, s. 57-64Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    CD4+CD25hi T cells are thought to be crucial for the maintenance of immunological tolerance to self antigens. In this study, we investigated the frequencies of these cells in the early stage of type 1 diabetes, as well as in a setting of possible pre-diabetic autoimmunity. Hence, the expression of FOXP3, CTLA-4, and CD27 in CD4+ CD25hi T cells was analyzed using flow cytometry in 14 patients with recent onset type 1 diabetes, in 9 at-risk individuals, and 9 healthy individuals with no known risk for type 1 diabetes. Our results show there were no differences in the frequency of CD4+CD25hi cells between groups. However, compared to controls, recent-onset type 1 diabetic patients had higher expression of FOXP3, CTLA-4, and CD27 in CD4+ CD25hi cells from peripheral blood. The median fluorescence intensity of FOXP3 was significantly higher in CD4+CD25hi cells from patients with type 1 diabetes than from controls. Furthermore, a positive correlation between the frequency of FOXP3+ cells and the median fluorescence intensity of FOXP3 was observed among patients with type 1 diabetes. These data suggest that the frequency of CD4+CD25hi FOXP3+ T cells in the periphery is not decreased but rather increased at onset of type 1 diabetes. Thus, functional deficiencies rather than reduced numbers of CD4+CD25hi cells could contribute to the development of type 1 diabetes. 

  • 44.
    Pihl, Mikael
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Verma, Deepti
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Fredrikson, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Ludvgisson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Polymorphisms in NALP3 inflammasome components NLRP3 and CARD8 affect C-peptide secretion in type 1 diabetes2013Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Interleukin-1β has long been known to have potential roles in type 1 diabetes (T1D) pathogenesis. Production of active Iinterleukin-1β is dependent on the action of a caspase activating protein complex called NALP3 inflammasome. The NALP3 inflammasome is composed of NALP3/Cryopyrin, ASC and CARD8. Polymorphisms in the NLRP3 and CARD8 genes have been linked to several autoinflammatory diseases. The NALP3 inflammasome is crucial for adjuvanticity of aluminium hydroxide, which is used as adjuvant in clinical trials of glutamic acid decarboxylase (GAD)-alum in T1D. Our aim was to investigate the effect of common polymorphisms of NLRP3 on T1D susceptibility as well as on GAD-alum treatment efficacy. The single nucleotide polymorphisms NLRP3 Q705K, CARD8 C10X and an SNP downstream of the NLRP3 gene, rs10733113, were genotyped using a Taqman genotyping assay. The A allele of CARD8 C10X was associated with a lower stimulated insulin secretion 3 months after diagnosis in males. Patients with at least one G allele at rs10733113 were more likely to produce auto-antibodies against two or more of the islet antigens GAD, Insulin or IA-2. None of the genotyped SNPs had any significant influence on efficacy of GAD-alum treatment, but individuals with at least one rs10733113 G allele treated with placebo had lower residual insulin secretion than those with the AA genotype at 9, 15 and 21 months after start of treatment.

  • 45.
    Pihl, Mikael
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Åkerman, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Axelsson, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Chéramy, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Hjorth, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Mallone, R.
    St Vincent Paul Hospital, France.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Regulatory T cell phenotype and function 4 years after GAD–alum treatment in children with type 1 diabetes2013Ingår i: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 172, nr 3, s. 394-402Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glutamic acid decarboxylase (GAD)65 formulated with aluminium hydroxide (GAD-alum) was effective in preserving insulin secretion in a Phase II clinical trial in children and adolescents with recent-onset type 1 diabetes. In addition, GAD-alum treated patients increased CD4+CD25hi forkhead box protein 3+ (FoxP3+) cell numbers in response to in-vitro GAD65 stimulation. We have carried out a 4-year follow-up study of 59 of the original 70 patients to investigate long-term effects on the frequency and function of regulatory T cells after GAD-alum treatment. Peripheral blood mononuclear cells were stimulated in vitro with GAD65 for 7 days and expression of regulatory T cell markers was measured by flow cytometry. Regulatory T cells (CD4+CD25hiCD127lo) and effector T cells (CD4+CD25CD127+) were further sorted, expanded and used in suppression assays to assess regulatory T cell function after GAD-alum treatment. GAD-alum-treated patients displayed higher frequencies of in-vitro GAD65-induced CD4+CD25+CD127+ as well as CD4+CD25hiCD127lo and CD4+FoxP3+ cells compared to placebo. Moreover, GAD65 stimulation induced a population of CD4hi cells consisting mainly of CD25+CD127+, which was specific of GAD-alum-treated patients (16 of 25 versus one of 25 in placebo). Assessment of suppressive function in expanded regulatory T cells revealed no difference between GAD-alum- and placebo-treated individuals. Regulatory T cell frequency did not correlate with C-peptide secretion throughout the study. In conclusion, GAD-alum treatment induced both GAD65-reactive CD25+CD127+ and CD25hiCD127lo cells, but no difference in regulatory T cell function 4 years after GAD-alum treatment.

  • 46.
    Skarsvik, Susanne
    et al.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Tiittanen, Minna
    Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland.
    Lindström, Anna
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Casas, Rosaura
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Vaarala, Outi
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Poor in vitro maturation and pro-inflammatory cytokine response of dendritic cells in children at genetic risk of type 1 diabetes2004Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 60, nr 6, s. 647-652Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Type 1 diabetes (T1D) has been associated with an aberrant maturation of dendritic cells (DC). We studied the maturation of monocyte-derived DC in children with newly diagnosed T1D and in healthy children with genetic risk for T1D. Peripheral blood monocytes from children with newly diagnosed T1D (n = 12; mean age 13.2 years), children with human leukocyte antigen (HLA)-risk genotype of T1D (n = 7; mean age 12.7 years) and healthy children (n = 14; mean age 11.2 years) were in vitro differentiated into DC. Expression of HLA-DR, CD80/86 and CD11c and secretion of interleukin (IL)-12, tumor necrosis factor (TNF)-α, IL-6 and IL-10 were measured using flow cytometry. Lower percentage of DC expressed CD11c and HLA-DR, and decreased production of TNF-α was found in children with newly diagnosed T1D and in children at genetic risk when compared to healthy children. Children with risk genotype also had decreased IL-12 production by DC. Children with T1D and children at genetic risk of T1D appear to have similar aberrancies in the maturation of DC, which may predispose to β-cell autoimmunity.

  • 47.
    Skoglund, Camilla
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Chéramy, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Hampe, Christiane S
    Department of Medicine, University of Washington, Seattle, WA, USA.
    GAD autoantibody epitope pattern after GAD-alum treatment in children and adolescents with type 1 diabetes2012Ingår i: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 13, nr 3, s. 244-250Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims/hypothesis. Previously we have shown that two injections of glutamic acid decarboxylase formulated in alum (GAD-alum) preserved residual insulin secretion in children and adolescents with recent onset type 1 diabetes (T1D), and was accompanied by an increase in GAD autoantibody (GADA) titers. The aim of the present study was to investigate whether GAD-alum treatment affected the GADA epitope pattern.

    Methods. Serum samples of patients treated with GAD-alum (n=33) or placebo (n=27), at baseline and 1, 3, 9, and 15 months after initiation of treatment, were tested for their binding capacity to specific GADA epitopes in an epitope specific radioligand-binding assay with six GAD65-specific recombinant Fab (rFab) (b96.11, DPA, DPD, MICA3, b78 and N-GAD65 mAb).

    Results. For the period included in this study (baseline to 15 months) no difference in variability of binding to any of the tested rFab were observed. However, a higher median response to the b96.11-defined epitope in the first 3 months after the initial injection was observed in GAD-alum treated patients (-8.1%, min -72.4%, max 39.6%) compared to patients receiving placebo (1.5%, min -28.3%, max 28.6%) (p=0.02). This effect was especially evident in GAD-alum treated patients who experienced an increase of more than 100% in their GADA titer from baseline to 3 months (n=27), where we observed an 10.8% (-10.8%, min -72.4%, max 30.5%) increase in binding to the b96.11 epitope over the  first 3 months post initial injection (p=0.04). Subsequently the recognition of the b96.11-defined epitope in the GAD-alum group decreased between 3 and 15 months (8.3%, min -17.1%, max 36.7%) compared to the placebo group (-2.4%, min -32.8%, max 30.1%) (p<0.05) and returned to levels similar to that observed at baseline. Correlations between GADA titer and epitope binding for b96.11 and DPD were observed in the placebo group, but not in the GADalum group, at 3 and 15 months after initial treatment.

    Conclusions/interpretation. We conclude that administration of GAD-alum temporarily induced increased binding to one epitope specificity of GADA.

  • 48.
    Åkerman, Linda
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Casas, Rosaura
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Low C-peptide levels and decreased expression of TNF and CD45 in children with high risk of type 1 diabetes2013Ingår i: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 148, nr 1Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Type 1 diabetes (T1D) patients have numeral and functional defects in peripheral immune cells, but the pre-diabetic period is fairly uncharacterized. Our aim was to analyze expression of immunological markers in T1D high risk children and relate it to clinical/immunological parameters. Children from ABIS (All Babies in Southeast Sweden) with greater than= 2 diabetes related autoantibodies were considered at high risk. Age-matched controls and new-onset T1D patients were included. Expression of genes related to immune cell function and different arms of the immune system was assessed in peripheral blood mononuclear cells using PCR array. Risk children had lower TNF and CD45, and although there were few differences between the groups, expression of many genes differed when comparing children with regard to residual insulin secretion. Hence, expression of immune related genes seemed related not only to the autoimmune process but rather to residual beta-cell function, which was decreased already during the pre-diabetic phase.

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