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

作者：Lee Li Fen^*; Logronio Kathryn; Tu Guang Huan; Zhai Wenwu; Ni Irene; Mei Li; Dilley Jeanette; Yu Jessica; Rajpal Arvind; Brown Colleen; Appah Charles; Chin Sherman Michael; Han Bora; Affolter Timothy; Lin John C

来源：Proceedings of the National Academy of Sciences, 2012, 109(31): 12674-12679.

DOI：10.1073/pnas.1203795109

• T cell depletion
• programmed death ligand 1
• biologics
• adoptive transfer

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

• 出版日期2012-7-31