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Diabetologia

Erschienen in:

01.10.2012 | Article

Low doses of anti-CD3, ciclosporin A and the vitamin D analogue, TX527, synergise to delay recurrence of autoimmune diabetes in an islet-transplanted NOD mouse model of diabetes

verfasst von: F. Baeke, T. L. Van Belle, T. Takiishi, L. Ding, H. Korf, J. Laureys, C. Gysemans, C. Mathieu

Erschienen in: Diabetologia | Ausgabe 10/2012

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Abstract

Aims/hypothesis

Anti-CD3 monoclonal antibodies remain the most promising immune therapy for reversing recent-onset type 1 diabetes. However, current clinical trials have revealed their major drawback, namely the narrow therapeutic window in which low doses are ineffective and higher doses that preserve functional beta cell mass cause side effects. Strategies that sidestep these limitations while preserving or improving anti-CD3’s therapeutic efficiency are essential. We hypothesised that combining a potent vitamin D₃ analogue (TX527), ciclosporin A (CsA) and anti-CD3 would act to lower the dose while maintaining or even boosting therapeutic efficacy to counteract autoimmune destruction of transplanted islets.

Methods

This study involved the use of syngeneic islet transplantation, immunofluorescence microscopy, immune phenotyping by flow cytometry, RT-PCR analysis, and in vitro and in vivo suppression assays.

Results

Combination therapy with TX527, CsA and anti-CD3 was well tolerated on the basis of weight, bone and calcium variables. Remarkably, combining all three agents at sub-therapeutic doses greatly reduced recurrent autoimmune responses to a grafted islet mass (mean ± SEM: 79.5 ± 18.6 days; p < 0.01), by far exceeding the therapeutic efficacy of monotherapy (24.8 ± 7.3 days for anti-CD3) and dual therapy (25.5 ± 12.4 days for anti-CD3+CsA). Combination therapy surpassed anti-CD3 monotherapy in reducing islet infiltration by effector/memory phenotype CD8⁺ T cells, as well as by reducing proinflammatory cytokine responses and increasing the frequency of T regulatory cells that were functional in vitro and in vivo, and acted in a cytotoxic T lymphocyte antigen 4-dependent manner.

Conclusions/interpretation

Combining the immunomodulatory actions of anti-CD3 mAb with CsA and the vitamin D₃ analogue, TX527, delivers therapeutic efficacy in an islet-transplanted NOD mouse model of diabetes.

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Titel: Low doses of anti-CD3, ciclosporin A and the vitamin D analogue, TX527, synergise to delay recurrence of autoimmune diabetes in an islet-transplanted NOD mouse model of diabetes
verfasst von: F. Baeke
T. L. Van Belle
T. Takiishi
L. Ding
H. Korf
J. Laureys
C. Gysemans
C. Mathieu
Publikationsdatum: 01.10.2012
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 10/2012
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-012-2630-1

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