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  • 1.
    Axelsson, Stina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Cheramy, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Åkerman, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Pihl, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Cellular and Humoral Immune responses in Type 1 Diabetic patients participating in a Phase III GAD-alum Intervention Trial2013In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 36, no 11, p. 3418-3424Article in journal (Refereed)
    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.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Chéramy, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Hjorth, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Pihl, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Åkerman, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Martinuzzi, Emanuela
    St Vincent de Paul Hospital.
    Mallone, Roberto
    St Vincent de Paul Hospital.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Long-Lasting Immune Responses 4 Years after GAD-Alum Treatment in Children with Type 1 Diabetes2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 12Article in journal (Refereed)
    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.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Chéramy, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Åkerman, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Pihl, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Preserved C-peptide 30 months after GAD-alum treatment of children and adolescents with recent-onset type 1 diabetes, and its relation to immune markersManuscript (preprint) (Other academic)
    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.
    Casas, Rosaura
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Hjorth, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Axelsson, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Chéramy, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Pihl, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Specific immunomodulatory effect of GAD(65) in type 1 diabetics2009In: in DIABETOLOGIA, vol 52, 2009, Vol. 52, p. S194-S194Conference paper (Refereed)
    Abstract [en]

    n/a

  • 5.
    Chéramy, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Characteristics of GADA in Type 1 Diabetes following Immunomodulation with GAD652012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Type 1 diabetes (T1D) is a serious autoimmune disease which increases worldwide and affects children at a young age, but there still is no cure available. Clinical intervention trials in recent onset T1D patients are therefore very important, since even a modest preservation of β-cell function has proven to reduce end-organ complications. Glutamic acid decarboxylase 65 (GAD65) is one of the major antigens in T1D, to which autoantibodies (GADA) are formed. Immunomodulation with aluminum-formulated GAD65 (GAD-alum) has been considered both in the prevention and intervention of T1D. In a phase II trial using GADalum we showed clinical benefits in C-peptide preservation, but unfortunately a following larger European phase III trial failed to reach primary end-point. The general aim of this thesis was to study the characteristics and phenotypes of GADA following immunomodulation with GAD-alum in T1D patients during a phase II and III trial.

    In the phase II trial, a transient increase of the GADA IgG3 and IgG4 subclasses, and a decrease in IgG1 was detected as part of the treatment-induced GADA levels after 2 GADalum doses, a result interpreted to be T helper (Th) 2-associated. This Th2-associated immune response was also observed, in parallel to increased GADA levels, during the following phase III trial including a larger group of patients. However, enhanced Th2-like IgG subclass distribution, reflected as increased IgG4 frequency, was in contrast only observed in the group treated with 4 doses of GAD-alum. In addition, the GADA fold-change was associated with in vitro GAD65-stimulated cytokine secretion, but only in patients receiving 2 GAD-alum doses. Furthermore, a 4-year follow-up of the phase II trial showed that the effect of GAD-alum treatment was long-lasting as GADA titers remained elevated. Even though the phase III trial did not reach primary end-point, and was closed after 15 months, preservation of β-cell function was observed in the small sub-group of Swedish patients receiving 2 GAD-alum doses that completed the 30 months trial-period. During the trials, concerns were raised whether the elevated GADA titers might induce Stiff person syndrome (SPS), a disease affecting the nervous system, but in vitro analysis of GADA phenotypes showed that the GAD65-enzyme activity and GADA epitope distribution differed from that detected in SPS patients.

    Continued research to clarify how immunomodulation with autoantigens affects immune responses and also to identify which patients are suitable for treatment, is crucial for optimizing future T1D intervention- and prevention trials.

    List of papers
    1. GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD(65) enzyme activity and humoral response
    Open this publication in new window or tab >>GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD(65) enzyme activity and humoral response
    Show others...
    2010 (English)In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 137, no 1, p. 31-40Article in journal (Refereed) Published
    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.

    Place, publisher, year, edition, pages
    Elsevier Science B.V., Amsterdam, 2010
    Keywords
    Immunotherapy, GAD(65), GAD-alum, GADA, Type 1 diabetes, T1D, IgG, IgG subclass
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-60511 (URN)10.1016/j.clim.2010.06.001 (DOI)000282204900005 ()
    Note

    Original Publication: Mikael Chéramy, Camilla Skoglund, Ingela Johansson, Johnny Ludvigsson, Christiane S Hampe and Rosaura Casas, GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD(65) enzyme activity and humoral response, 2010, CLINICAL IMMUNOLOGY, (137), 1, 31-40. http://dx.doi.org/10.1016/j.clim.2010.06.001 Copyright: Elsevier Science B.V., Amsterdam http://www.elsevier.com/

    Available from: 2010-10-15 Created: 2010-10-15 Last updated: 2017-12-12Bibliographically approved
    2. Characteristics of in-vitro phenotypes of glutamic acid decarboxylase 65 autoantibodies in high-titre individuals
    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
    3. Long-Lasting Immune Responses 4 Years after GAD-Alum Treatment in Children with Type 1 Diabetes
    Open this publication in new window or tab >>Long-Lasting Immune Responses 4 Years after GAD-Alum Treatment in Children with Type 1 Diabetes
    Show others...
    2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 12Article in journal (Refereed) Published
    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.

    Place, publisher, year, edition, pages
    Public Library of Science, 2011
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-74156 (URN)10.1371/journal.pone.0029008 (DOI)000298366600057 ()
    Note
    Funding Agencies|Swedish Research Council|K2008-55x-20652-01-3|Swedish Child Diabetes Foundation (Barndiabetesfonden)||Medical Research Council of Southeast Sweden||Juvenile Diabetes Research Foundation (JDRF)|1-2008-106|Ile-de-France CODDIM||Inserm Avenir Program||Available from: 2012-01-20 Created: 2012-01-20 Last updated: 2017-12-08
    4. GAD65 autoantibody (GADA) responses in Type 1 diabetes patients participating in a phase III GAD-alum intervention trial
    Open this publication in new window or tab >>GAD65 autoantibody (GADA) responses in Type 1 diabetes patients participating in a phase III GAD-alum intervention trial
    Show others...
    (English)Manuscript (preprint) (Other academic)
    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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-84841 (URN)
    Available from: 2012-10-24 Created: 2012-10-24 Last updated: 2012-10-24Bibliographically approved
  • 6.
    Chéramy, Mikael
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Axelsson, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Åkerman, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Pihl, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    GAD65 autoantibody (GADA) responses in Type 1 diabetes patients participating in a phase III GAD-alum intervention trialManuscript (preprint) (Other academic)
    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.

  • 7.
    Chéramy, Mikael
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Hampe, Christiane S.
    Department of Medicine, University of Washington, Seattle, WA, USA.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Characteristics of in-vitro phenotypes of glutamic acid decarboxylase 65 autoantibodies in high-titre individuals2013In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 171, no 3, p. 247-254Article in journal (Refereed)
    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.

  • 8.
    Chéramy, Mikael
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Skoglund, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Johansson, Ingela
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Hampe, Christiane S
    University of Washington.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD(65) enzyme activity and humoral response2010In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 137, no 1, p. 31-40Article in journal (Refereed)
    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.

  • 9.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Chéramy, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Axelsson, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Pihl, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Åkerman, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    GAD-treatment of children and adolescents with recent-onset Type 1 diabetes preserves residual insulin secretion after 30 months2014In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 30, no 5, p. 405-414Article in journal (Refereed)
    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.

  • 10.
    Ludvigsson, Johnny
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Faresjö, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Hjorth, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Axelsson, Stina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Chéramy, Mikael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Pihl, Mikael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Forsander, Gun
    Ivarsson, Sten
    Johansson, Calle
    Lindh, Agne
    Nilsson, NO
    Åman, Jan
    Örtqvist, Eva
    Zerhouni, Peter
    Casas, Rosaura
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    GAD treatment and insulin secretion in recent-onset type 1 diabetes2008In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 359, no 18, p. 1909-1920Article in journal (Refereed)
    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.

  • 11.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Hjorth, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Chéramy, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Axelsson, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Pihl, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    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
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial2011In: DIABETOLOGIA, ISSN 0012-186X, Vol. 54, no 3, p. 634-640Article in journal (Refereed)
    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.

  • 12.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Skoglund, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Chéramy, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Hampe, C
    Department Med, Seattle.
    GAD(65) treatment induces high GADA but no changes in epitopes or adverse signs/symptoms in type 1 diabetic children2009In: in DIABETOLOGIA, vol 52., 2009, Vol. 52, p. S192-S192Conference paper (Refereed)
    Abstract [en]

    n/a

  • 13.
    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
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Chéramy, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    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-A52012In: DIABETES and METABOLISM, Elsevier Masson , 2012, Vol. 38, no 2, p. A5-A5Conference paper (Refereed)
    Abstract [en]

    n/a

  • 14.
    Pihl, Mikael
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Chéramy, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Mjösberg, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Increased expression of regulatory T cell-associated markers in recent-onset diabetic children2011In: Open Journal of Immunology, ISSN 2162-450X, E-ISSN 2162-4526, Vol. 1, no 3, p. 57-64Article in journal (Refereed)
    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. 

  • 15.
    Pihl, Mikael
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Åkerman, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Axelsson, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Chéramy, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Hjorth, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Mallone, R.
    St Vincent Paul Hospital, France.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Regulatory T cell phenotype and function 4 years after GAD–alum treatment in children with type 1 diabetes2013In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 172, no 3, p. 394-402Article in journal (Refereed)
    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.

  • 16.
    Skoglund, Camilla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Chéramy, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in 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 diabetes2012In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 13, no 3, p. 244-250Article in journal (Refereed)
    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.

1 - 16 of 16
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