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GAD-alum treatment induces GAD-specific CD4 T cells in a phase III clinical trial
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
Benaroya Research Institute at Virginia Mason, Seattle, USA.
Benaroya Research Institute at Virginia Mason, Seattle, USA.
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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.

Place, publisher, year, edition, pages
2013.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-98251OAI: oai:DiVA.org:liu-98251DiVA: diva2:653520
Available from: 2013-10-04 Created: 2013-10-04 Last updated: 2013-10-04
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)
Opponent
Supervisors
Available from: 2013-10-04 Created: 2013-10-04 Last updated: 2013-10-07Bibliographically approved

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Pihl, MikaelAxelsson, StinaLudvgisson, JohnnyCasas, Rosaura

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