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Casas, Rosaura
Publications (10 of 48) Show all publications
Ludvigsson, J., Wahlberg Topp, J. & Casas, R. (2017). Letter: Intralymphatic Injection of Autoantigen in Type 1 Diabetes in NEW ENGLAND JOURNAL OF MEDICINE, vol 376, issue 7, pp 697-699 [Letter to the editor]. New England Journal of Medicine, 376(7), 697-699
Open this publication in new window or tab >>Letter: Intralymphatic Injection of Autoantigen in Type 1 Diabetes in NEW ENGLAND JOURNAL OF MEDICINE, vol 376, issue 7, pp 697-699
2017 (English)In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 376, no 7, p. 697-699Article in journal, Letter (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
MASSACHUSETTS MEDICAL SOC, 2017
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-136061 (URN)10.1056/NEJMc1616343 (DOI)000396402700022 ()28199812 (PubMedID)
Note

Funding Agencies|Barndiabetesfonden (the Swedish Child Diabetes Foundation); Diabetesfonden (the Swedish Diabetes Foundation); Forskningsradet i Sydostra Sverige (the Research Council of Southeast Sweden); Diamyd Medical

Available from: 2017-03-27 Created: 2017-03-27 Last updated: 2018-05-02
Ludvigsson, J., Chéramy, M., Axelsson, S., Pihl, M., Åkerman, L. & Casas, R. (2014). GAD-treatment of children and adolescents with recent-onset Type 1 diabetes preserves residual insulin secretion after 30 months. Diabetes/Metabolism Research Reviews, 30(5), 405-414
Open this publication in new window or tab >>GAD-treatment of children and adolescents with recent-onset Type 1 diabetes preserves residual insulin secretion after 30 months
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2014 (English)In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 30, no 5, p. 405-414Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2014
Keywords
arrays; celiac disease; children; gene expression; gluten-free diet; IL-17; mucosa; Th17
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-108613 (URN)10.1002/dmrr.2503 (DOI)000339416900007 ()24302596 (PubMedID)
Available from: 2014-07-01 Created: 2014-07-01 Last updated: 2017-12-05Bibliographically approved
Paulsson, J., Ludvigsson, J., Carlsson, A., Casas, R., Forsander, G., Ivarsson, S. A., . . . Westermark, G. T. (2014). High Plasma Levels of Islet Amyloid Polypeptide in Young with New-Onset of Type 1 Diabetes Mellitus. PLoS ONE, 9(3), 0093053
Open this publication in new window or tab >>High Plasma Levels of Islet Amyloid Polypeptide in Young with New-Onset of Type 1 Diabetes Mellitus
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 3, p. 0093053-Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Public Library of Science, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-106686 (URN)10.1371/journal.pone.0093053 (DOI)000333677000107 ()
Available from: 2014-05-21 Created: 2014-05-19 Last updated: 2017-12-05
Lahdenperä, A., Ljungberg, M., Lundberg, A., Korpela, R., Casas, R., Ludvigsson, J. & Vaarala, O. (2014). Probiotics and innate immune response in infants.
Open this publication in new window or tab >>Probiotics and innate immune response in infants
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2014 (English)Manuscript (preprint) (Other academic)
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.

Keywords
Probiotics, monocytes, innate immunity, TLR, LTA, LPS
National Category
Clinical Medicine Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-110686 (URN)
Available from: 2014-09-19 Created: 2014-09-19 Last updated: 2018-01-11Bibliographically approved
Axelsson, S., Cheramy, M., Åkerman, L., Pihl, M., Ludvigsson, J. & Casas, R. (2013). Cellular and Humoral Immune responses in Type 1 Diabetic patients participating in a Phase III GAD-alum Intervention Trial. Diabetes Care, 36(11), 3418-3424
Open this publication in new window or tab >>Cellular and Humoral Immune responses in Type 1 Diabetic patients participating in a Phase III GAD-alum Intervention Trial
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2013 (English)In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 36, no 11, p. 3418-3424Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Diabetes Association, 2013
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-99798 (URN)10.2337/dc12-2251 (DOI)000326274100013 ()23863909 (PubMedID)
Available from: 2013-10-21 Created: 2013-10-21 Last updated: 2017-12-06Bibliographically approved
Chéramy, M., Hampe, C. S., Ludvigsson, J. & Casas, R. (2013). Characteristics of in-vitro phenotypes of glutamic acid decarboxylase 65 autoantibodies in high-titre individuals. Clinical and Experimental Immunology, 171(3), 247-254
Open this publication in new window or tab >>Characteristics of in-vitro phenotypes of glutamic acid decarboxylase 65 autoantibodies in high-titre individuals
2013 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 171, no 3, p. 247-254Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2013
Keywords
GAD65 immunotheraphy; GADA; stiff-person syndrome; type 1 diabetes
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84840 (URN)10.1111/cei.12026 (DOI)000314655100003 ()
Note

The title of the article in manuscript form was "Characteristics of GAD65 autoantibodies (GADA) in high titer individuals".

Available from: 2012-10-24 Created: 2012-10-24 Last updated: 2017-12-07Bibliographically approved
Pihl, M., Axelsson, S., Cheramy, M., Reijonen, H., Ludvgisson, J. & Casas, R. (2013). GAD-alum treatment induces GAD-specific CD4 T cells in a phase III clinical trial.
Open this publication in new window or tab >>GAD-alum treatment induces GAD-specific CD4 T cells in a phase III clinical trial
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2013 (English)Manuscript (preprint) (Other academic)
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-98251 (URN)
Available from: 2013-10-04 Created: 2013-10-04 Last updated: 2013-10-04
Besser, R. E., Shields, B. M., Casas, R., Hattersley, A. T. & Ludvigsson, J. (2013). Lessons From the Mixed-Meal Tolerance Test Use of 90-minute and fasting C-peptide in pediatric diabetes. Diabetes Care, 36(2), 195-201
Open this publication in new window or tab >>Lessons From the Mixed-Meal Tolerance Test Use of 90-minute and fasting C-peptide in pediatric diabetes
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2013 (English)In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 36, no 2, p. 195-201Article in journal (Refereed) Published
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

Place, publisher, year, edition, pages
American Diabetes Association, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-90076 (URN)10.2337/dc12-0836 (DOI)000314467100013 ()
Note

Funding Agencies|Diabetes UK||Barndiabetesfonden (The Swedish Child Diabetes Foundation)||Swedish Research Council||Peninsula NIHR Clinical Research Facility||

Available from: 2013-03-21 Created: 2013-03-19 Last updated: 2017-12-06
Åkerman, L., Ludvigsson, J. & Casas, R. (2013). Low C-peptide levels and decreased expression of TNF and CD45 in children with high risk of type 1 diabetes. Clinical Immunology, 148(1)
Open this publication in new window or tab >>Low C-peptide levels and decreased expression of TNF and CD45 in children with high risk of type 1 diabetes
2013 (English)In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 148, no 1Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Type 1 diabetes; Gene expression; PBMC; T1D high risk; T1D autoantibodies; PCR array
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-96458 (URN)10.1016/j.clim.2013.03.011 (DOI)000320427300002 ()
Available from: 2013-08-23 Created: 2013-08-20 Last updated: 2017-12-06
Pihl, M., Verma, D., Fredrikson, M., Söderkvist, P., Ludvgisson, J. & Casas, R. (2013). Polymorphisms in NALP3 inflammasome components NLRP3 and CARD8 affect C-peptide secretion in type 1 diabetes.
Open this publication in new window or tab >>Polymorphisms in NALP3 inflammasome components NLRP3 and CARD8 affect C-peptide secretion in type 1 diabetes
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2013 (English)Manuscript (preprint) (Other academic)
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-98248 (URN)
Available from: 2013-10-04 Created: 2013-10-04 Last updated: 2013-10-04Bibliographically approved
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