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Regulatory T cell phenotype and function 4 years after GAD–alum treatment in children with type 1 diabetes
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
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2013 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 172, no 3, 394-402 p.Article 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. Vol. 172, no 3, 394-402 p.
Keyword [en]
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: urn:nbn:se:liu:diva-93379DOI: 10.1111/cei.12078ISI: 000318073000004OAI: oai:DiVA.org:liu-93379DiVA: diva2:624505
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
In thesis
1. Reign in Blood: Immune Regulation in Type 1 Diabetes
Open this publication in new window or tab >>Reign in Blood: Immune Regulation in Type 1 Diabetes
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 Diabetes (T1D) is an autoimmune disease resulting in insulin deficiency as a result ofautoimmune destruction of pancreatic β-cells. Preserving β-cell function in patients with T1D would be of great benefit since patients with sustained endogenous insulin secretion are known to suffer less from secondary complications due to hyperglycemia. Glutamic acid decarboxylase 65 (GAD65) is a major autoantigen targeted by self-reactive lymphocytes in T1D, and has been used in several attempts at treating T1D by inducing tolerance to β-cell antigens. We showed positive clinical effects of GAD65 formulated with aluminium hydroxide (GAD-alum) on preservation of C-peptide secretion in a phase II clinical trial. Unfortunately, a phase III clinical trial in a larger population failed to confirm this finding. Regulatory T cells (Treg) are instrumental in maintaining peripheral tolerance to self-antigens. Deficiencies in Treg function are thought to influence the pathogenesis of autoimmune diseases, including T1D. One proposed mechanism of achieving tolerance to β-cell antigens in T1D is the induction of antigen-specific Treg through immunomodulation. The general aim of this thesis was to study immune regulation in T1D, the role of Treg and immunomodulatory effects of GAD-alum treatment in particular. Our hypothesis was that Treg biology is altered in T1D and pre-diabetes, and that an induction of GAD65-specific Treg contributes to the clinical efficacy of GAD-alum treatment. We demonstrated that T cells expressing Treg-associated markers were increased in number in patients with recent-onset T1D, as well as in children with high risk of developing T1D. We found that antigen recall 4 years after GAD-alum treatment induced cells with both regulatory and effector phenotypes in GAD-alum treated patients. Furthermore there was no effect on Treg-mediated suppression in GAD-alum treated patients, while patients with T1D, regardless of treatment, exhibited deficient Treg-mediated suppression of Teff that was intrinsic to the Treg population. We followed patients participating in a phase III trial of GAD-alum, and using an extended antibody panel we demonstrated that antigen recall induced mainly Teff cells in treated patients, along  with increased frequencies of memory T cells, non-suppressive CD45RA-FOXP3lo cells and increased GAD65-induced proliferation of mainly Teff and memory T cells. Finally we examined whether SNPs in genes encoding inflammasome components contributed to T1D risk, but found no effects of variant alleles on the risk of developing T1D, or on the efficacy of GAD-alum treatment. We show small effects on C-peptide secretion and autoantibody positivity in patients with T1D. In conclusion, we find that while Treg are deficient in patients with T1D, induction of Treg is an unlikely mechanism of action of GAD-alum treatment.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. 113 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1377
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-98250 (URN)10.3384/diss.diva-98250 (DOI)978-91-7519-533-9 (ISBN)
Public defence
2013-11-08, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
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Available from: 2013-10-04 Created: 2013-10-04 Last updated: 2013-10-07Bibliographically approved

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Pihl, MikaelÅkerman, LindaAxelsson, StinaChéramy, MikaelHjorth, MariaLudvigsson, JohnnyCasas, Rosaura

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Pihl, MikaelÅkerman, LindaAxelsson, StinaChéramy, MikaelHjorth, MariaLudvigsson, JohnnyCasas, Rosaura
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