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Anti-IL-7 receptor-? reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function.

ABSTRACT: Genetic variation in the IL-7 receptor-? (IL-7R) gene is associated with susceptibility to human type 1 diabetes (T1D). Here we investigate the therapeutic efficacy and mechanism of IL-7R? antibody in a mouse model of T1D. IL-7R? antibody induces durable, complete remission in newly onset diabetic mice after only two to three injections. IL-7 increases, whereas IL-7R? antibody therapy reduces, the IFN-?-producing CD4(+) (T(H)1) and IFN-?-producing CD8(+) T cells. Conversely, IL-7 decreases and IL-7R? antibody enhances the inhibitory receptor Programmed Death 1 (PD-1) expression in the effector T cells. Programmed Death 1 blockade reversed the immune tolerance mediated by the IL-7R? antibody therapy. Furthermore, IL-7R? antibody therapy increases the frequency of regulatory T cells without affecting their suppressor activity. The durable efficacy and the multipronged tolerogenic mechanisms of IL-7R? antibody therapy suggest a unique disease-modifying approach to T1D.

SUBMITTER: Lee LF

PROVIDER: S-EPMC3412026 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Anti-IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function.

Lee Li-Fen LF Logronio Kathryn K Tu Guang Huan GH Zhai Wenwu W Ni Irene I Mei Li L Dilley Jeanette J Yu Jessica J Rajpal Arvind A Brown Colleen C Appah Charles C Chin Sherman Michael SM Han Bora B Affolter Timothy T Lin John C JC

Proceedings of the National Academy of Sciences of the United States of America 20120625 31

Genetic variation in the IL-7 receptor-α (IL-7R) gene is associated with susceptibility to human type 1 diabetes (T1D). Here we investigate the therapeutic efficacy and mechanism of IL-7Rα antibody in a mouse model of T1D. IL-7Rα antibody induces durable, complete remission in newly onset diabetic mice after only two to three injections. IL-7 increases, whereas IL-7Rα antibody therapy reduces, the IFN-γ-producing CD4(+) (T(H)1) and IFN-γ-producing CD8(+) T cells. Conversely, IL-7 decreases and I ...[more]

PMID: 22733769

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Project description:Background: Epigenetic alteration of the genome has been shown to provide palliative effects in mouse models of certain human autoimmune disorders. We have investigated whether chromatin remodeling could provide protection against autoimmune diabetes in nonobese diabetic (NOD) mice. Treatment of female mice during the transition from prediabetic to diabetic stage (18-24 weeks of age) with the well-characterized histone deacetylase inhibitor, Trichostatin A (TSA) effectively reduced the incidence of diabetes and abrogated the ability of splenocytes to adoptively transfer the disease into immunodeficient NOD.scid mice. Protection against diabetes was accompanied by histone hyperacetylation in pancreas and spleen, increased frequency of CD4+ CD62L+ cells in the spleen, reduction in cellular infiltration of islets, restoration of normoglycemia and glucose-induced insulin release by beta cells. In vitro activation of splenic T lymphocytes derived from protected mice resulted in enhanced expression of IFN-gamma mRNA and protein without altering the expression of Il4, Il17, Il18, Inos, and Tnfa genes nor the secretion of IL-2, IL-4, IL-17 and TNF-alpha proteins. Consistently, expression of the transcription factor involved in Ifng transcription, Tbet/Tbx21 but not Gata3 and Rorgt, respectively required for the transcription of Il4 and Il17, was upregulated in activated splenocytes of protected mice. These data indicate that abrogation of autoimmune diabetes is associated with the selective upregulation of certain inducible genes in T lymphocytes. Microarray analysis was performed to determine the changes in global gene expression underlying abrogation of autoimmune diabetes by TSA-mediated epigenetic modulation and identified a distinct group of genes down-regulated during this process. Female NOD mice were treated subcutaneously with TSA (500 µg/Kg body weight) during the transition from prediabetic to diabetic stage (18-24 weeks of age), at weekly intervals. Since we sought to determine the modulation of global gene expression associated with long-term protection against diabetes, TSA treated mice were killed between 32 and 36 weeks of age and total RNA was extracted from uninduced splenocytes. RNA was also extracted from splenocytes of untreated mice that became diabetic and those that did not develop diabetes till 36 weeks of age. Blood glucose levels were determined weekly to monitor the glycemic condition in untreated and TSA-treated mice. To minimize the variability in gene expression among individual mice, RNA was extracted from splenocytes of 3 to 5 mice per group and pooled. Each sample was hybridized to microchips in duplicate. Female NOD mice were treated with Trichostatin A (500 µg/Kg body weight) between 18-24 weeks of age or left untreated.

Dataset Information

Anti-IL-7 receptor-? reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function.

Publications

Anti-IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function.

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