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Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12674-9. doi: 10.1073/pnas.1203795109. Epub 2012 Jun 25.

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

Author information

1
Rinat, Pfizer Inc, South San Francisco, CA 94080, USA. Li-Fen.Lee@pfizer.com

Erratum in

  • Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):16393.

Abstract

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.

PMID:
22733769
PMCID:
PMC3412026
DOI:
10.1073/pnas.1203795109
[Indexed for MEDLINE]
Free PMC Article

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