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Chéramy, Mikael
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Publications (10 of 16) Show all publications
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
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., Åkerman, L., Axelsson, S., Chéramy, M., Hjorth, M., Mallone, R., . . . Casas, R. (2013). Regulatory T cell phenotype and function 4 years after GAD–alum treatment in children with type 1 diabetes. Clinical and Experimental Immunology, 172(3), 394-402
Open this publication in new window or tab >>Regulatory T cell phenotype and function 4 years after GAD–alum treatment in children with type 1 diabetes
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2013 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 172, no 3, p. 394-402Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2013
Keywords
CD4 T cells (T helper, Th0, Th1, Th2, Th3, Th17), diabetes, immune regulation, regulatory T cells (Treg), therapy/immunotherapy
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-93379 (URN)10.1111/cei.12078 (DOI)000318073000004 ()
Note

Funding Agencies|Swedish Research Council|K2008-55x-20652-01-3|Swedish Child Diabetes Foundation (Barndiabetesfonden)||Medical Research Council of Southeast Sweden||JDRF|1-2008-106|Ile-de-France CODDIM||Inserm Avenir Program||

Available from: 2013-05-31 Created: 2013-05-31 Last updated: 2017-12-06Bibliographically approved
Chéramy, M. (2012). Characteristics of GADA in Type 1 Diabetes following Immunomodulation with GAD65. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Characteristics of GADA in Type 1 Diabetes following Immunomodulation with GAD65
2012 (English)Doctoral 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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. p. 83
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1337
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84842 (URN)978-91-7519-774-6 (ISBN)
Public defence
2012-11-15, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2012-10-24 Created: 2012-10-24 Last updated: 2012-10-30Bibliographically approved
Skoglund, C., Chéramy, M., Casas, R., Ludvigsson, J. & Hampe, C. S. (2012). GAD autoantibody epitope pattern after GAD-alum treatment in children and adolescents with type 1 diabetes. Pediatric Diabetes, 13(3), 244-250
Open this publication in new window or tab >>GAD autoantibody epitope pattern after GAD-alum treatment in children and adolescents with type 1 diabetes
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2012 (English)In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 13, no 3, p. 244-250Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2012
Keywords
Type 1 diabetes, autoantibody, epitope, GAD
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-64592 (URN)10.1111/j.1399-5448.2011.00802.x (DOI)000303194000004 ()
Note
funding agencies|Swedish Child Diabetes Foundation (Barndiabetesfonden)||Medical Research Council of Southeast Sweden||Diamyd Medical AB||National Institutes of Health| DK26190 DK53004 DK17047 |American Diabetes Association||Available from: 2011-01-28 Created: 2011-01-28 Last updated: 2017-12-11Bibliographically approved
Martinuzzi, E., Gagnerault, M. C., Fourlanos, S., Harrison, L., Axelsson, S., Chéramy, M., . . . Mallone, R. (2012). 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-A5. In: DIABETES and METABOLISM (pp. A5-A5). Elsevier Masson, 38(2)
Open this publication in new window or tab >>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-A5
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2012 (English)In: DIABETES and METABOLISM, Elsevier Masson , 2012, Vol. 38, no 2, p. A5-A5Conference paper, Published paper (Refereed)
Abstract [en]

n/a

Place, publisher, year, edition, pages
Elsevier Masson, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77337 (URN)000302819400022 ()
Available from: 2012-05-11 Created: 2012-05-11 Last updated: 2012-05-11
Ludvigsson, J., Hjorth, M., Chéramy, M., Axelsson, S., Pihl, M., Forsander, G., . . . Casas, R. (2011). Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial. DIABETOLOGIA, 54(3), 634-640
Open this publication in new window or tab >>Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial
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2011 (English)In: DIABETOLOGIA, ISSN 0012-186X, Vol. 54, no 3, p. 634-640Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Springer Science Business Media, 2011
Keywords
C-peptide, Children, GAD-alum treatment, Immune modulation, Type 1 diabetes
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-66310 (URN)10.1007/s00125-010-1988-1 (DOI)000286987000021 ()
Note
The original publication is available at www.springerlink.com: Johnny Ludvigsson, Maria Hjorth, Mikael Chéramy, Stina Axelsson, Mikael Pihl, G Forsander, N -O Nilsson, B-O Samuelsson, T Wood, J Aman, E Ortqvist and Rosaura Casas, Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial, 2011, DIABETOLOGIA, (54), 3, 634-640. http://dx.doi.org/10.1007/s00125-010-1988-1 Copyright: Springer Science Business Media http://www.springerlink.com/ Available from: 2011-03-11 Created: 2011-03-11 Last updated: 2011-03-24
Pihl, M., Chéramy, M., Mjösberg, J., Ludvigsson, J. & Casas, R. (2011). Increased expression of regulatory T cell-associated markers in recent-onset diabetic children. Open Journal of Immunology, 1(3), 57-64
Open this publication in new window or tab >>Increased expression of regulatory T cell-associated markers in recent-onset diabetic children
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2011 (English)In: Open Journal of Immunology, ISSN 2162-450X, E-ISSN 2162-4526, Vol. 1, no 3, p. 57-64Article in journal (Refereed) Published
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. 

Place, publisher, year, edition, pages
Irvine, CA. USA: Scientific Research Publishing, 2011
Keywords
Regulatory T cells; Type 1 Diabetes; Autoantibodies
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-75890 (URN)10.4236/oji.2011.13007 (DOI)
Available from: 2012-03-15 Created: 2012-03-15 Last updated: 2017-12-07
Axelsson, S., Chéramy, M., Hjorth, M., Pihl, M., Åkerman, L., Martinuzzi, E., . . . Casas, R. (2011). Long-Lasting Immune Responses 4 Years after GAD-Alum Treatment in Children with Type 1 Diabetes. PLoS ONE, 6(12)
Open this publication in new window or tab >>Long-Lasting Immune Responses 4 Years after GAD-Alum Treatment in Children with Type 1 Diabetes
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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
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