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Decreased GAD(65) -specific Th1/Tc1 phenotype in children with Type 1 diabetes treated with GAD-alum.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet.
2012 (engelsk)Inngår i: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 29, nr 10, s. 1272-1278Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Aim  The balance between T helper cell subsets is an important regulator of the immune system and is often examined after immune therapies. We aimed to study the immunomodulatory effect of glutamic acid decarboxylase (GAD) 65 formulated with aluminium hydroxide (GAD-alum) in children with Type 1 diabetes, focusing on chemokines and their receptors. Methods  Blood samples were collected from 70 children with Type 1 diabetes included in a phase II clinical trial with GAD-alum. Expression of CC chemokine receptor 5 (CCR5) and CCR4 was analysed on CD4+ and CD8+ lymphocytes after in vitro stimulation with GAD(65) using flow cytometry, and secretion of the chemokines CCL2, CCL3 and CCL4 was detected in peripheral blood mononuclear cell supernatants with Luminex. Results  Expression of Th1-associated CCR5 was down-regulated following antigen challenge, together with an increased CCR4/CCR5 ratio and CCL2 secretion in GAD-alum-treated patients, but not in the placebo group. Conclusion  Our results suggest that GAD-alum treatment has induced a favourable immune modulation associated with decreased Th1/Tc1 phenotypes upon antigen re-challenge, which may be of importance for regulating GAD(65) immunity. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

sted, utgiver, år, opplag, sider
Wiley-Blackwell, 2012. Vol. 29, nr 10, s. 1272-1278
Emneord [en]
Type 1 diabetes, GAD(65), immunomodulation, chemokines, chemokine receptors
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-77745DOI: 10.1111/j.1464-5491.2012.03710.xISI: 000308960400014PubMedID: 22587593OAI: oai:DiVA.org:liu-77745DiVA, id: diva2:528699
Merknad

funding agencies|Swedish Research Council|K2008-55x-20652-01-3|Swedish Child Diabetes Foundation (Barndiabetesfonden) Diamyd Medical||Medical Research Council of Southeast Sweden||

Tilgjengelig fra: 2012-05-28 Laget: 2012-05-28 Sist oppdatert: 2017-12-07
Inngår i avhandling
1. GAD65 An Immunomodulator in Type 1 Diabetes
Åpne denne publikasjonen i ny fane eller vindu >>GAD65 An Immunomodulator in Type 1 Diabetes
2012 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Type 1 diabetes (T1D) is caused by a deficiency of insulin as a result of an autoimmune destruction of the pancreatic ² -cells. A possibility to preserve remaining ² -cells in children with newly diagnosed T1D is of great importance since sustained ² -cell function is recognized to result in reduced end-organ complications. Glutamic acid decarboxylase 65 (GAD65) is one of the major antigens targeted by self-reactive T cells in T1D, and immunomodulation with GAD65 formulated in aluminum (GAD-alum) has been considered both in prevention and treatment of T1D. Results from a Phase II trial have shown clinical effect of subcutaneous injections with GAD-alum, this was unfortunately not fully confirmed in the following larger Phase III trial which therefore was closed after 15 months. The general aim of this thesis was to study the immunomodulatory effect of GAD-alum-treatment in children with T1D participating in the Phase II and Phase III trials. We hypothesized that treatment with GAD-alum contributes to the preservation of residual insulin secretion through deviation of the GAD65-specific immune response from a destructive to a protective process, accompanied by a shift from T helper (Th) 1 towards a predominant Th2 profile. In the Phase II trial, GAD-alum-treated patients responded with an early GAD65-specific Th2 skewed cytokine secretion, with highest IL-5 and IL-13 secretion in clinical responders. Also, the CCR4/CCR5 ratio indicating balance between Th2/Tc2 and Th1/Tc1 responses, increased in treated patients. The recall response to GAD65 was characterized by a wide range of cytokines, but the relative contribution of each cytokine suggests a shift towards a more pronounced Th2-associated profile over time. Induction of a CD4+ cell subset upon GAD65-stimulation 4 years after treatment, suggesting clonal expansion of the memory T-cell compartment upon antigen re-challenge, was seen in parallel to a persistent GAD65-specific cytokine response. Finally, even if the phase III trial failed to reach the primary endpoint at 15 months, a subgroup analysis showed that the treatment had an effect on preservation of residual insulin secretion, but the effect was not seen until after 30 months. Taken together, these results suggest that GAD-alum treatment might exert its effect through induction of an early Th2 skewed immune response which tends to deviate away from a destructive Th1/Tc1 response upon GAD65 re-challenge, and generation of GAD65-specific memory T cells that produce cytokines and exert effector responses which may be important for regulating GAD65 immunity. Continued research to better understand how immunomodulation with autoantigen modifies T-cell responses and also which patients are suitable for treatment, is crucial for optimizing future intervention trials using ² -cell antigens.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2012. s. 81
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1310
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-77747 (URN)978-91-7519-888-0 (ISBN)
Disputas
2012-06-01, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2012-05-28 Laget: 2012-05-28 Sist oppdatert: 2019-12-10bibliografisk kontrollert

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