LiU Electronic Press
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Author:
Chéramy, Mikael (Linköping University, Department of Clinical and Experimental Medicine, Pediatrics) (Linköping University, Faculty of Health Sciences)
Title:
Characteristics of GADA in Type 1 Diabetes following Immunomodulation with GAD65
Department:
Linköping University, Faculty of Health Sciences
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics
Publication type:
Doctoral thesis, comprehensive summary (Other academic)
Language:
English
Place of publ.: Linköping Publisher: Linköping University Electronic Press
Pages:
83
Series:
Linköping University Medical Dissertations, ISSN 0345-0082; 1337
Year of publ.:
2012
URI:
urn:nbn:se:liu:diva-84842
Permanent link:
http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-84842
ISBN:
978-91-7519-774-6
Subject category:
Medical and Health Sciences
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.

Public defence:
2012-11-15, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Degree:
Doctor of Philosophy (PhD)
Supervisor:
Casas, Rosaura, Associate Professor (Linköping University, Department of Clinical and Experimental Medicine, Pediatrics) (Linköping University, Faculty of Health Sciences)
Ludvigsson, Johnny, Professor (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)
Opponent:
Landin-Olsson, Mona, Professor (Division of Endocrinology and Diabetology, Department of Clinical Sciences, Lund University, Lund, Sweden)
Available from:
2012-10-24
Created:
2012-10-24
Last updated:
2012-10-30
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