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

2012; National Academy of Sciences; Volume: 109; Issue: 31 Linguagem: Inglês

10.1073/pnas.1203795109

1091-6490

Li‐Fen Lee, Kathryn Logronio, Guang Huan Tu, Wenwu Zhai, Irene Ni, Mei Li, Jeanette Dilley, Jessica Yu, Arvind Rajpal, Colleen Brown, Charles Takeshi Appah, Sherman M. Chin, Bora Han, Timothy Affolter, John Lin,

T-cell and B-cell Immunology

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 IL-7Rα 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-7Rα antibody therapy. Furthermore, IL-7Rα antibody therapy increases the frequency of regulatory T cells without affecting their suppressor activity. The durable efficacy and the multipronged tolerogenic mechanisms of IL-7Rα antibody therapy suggest a unique disease-modifying approach to T1D.