Anti-IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function.
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.
Rinat, Pfizer Inc, South San Francisco, CA 94080, USA. Li-Fen.Lee@pfizer.com
Li-Fen
LF
Lee
Kathryn
K
Logronio
Guang Huan
GH
Tu
Wenwu
W
Zhai
Irene
I
Ni
Li
L
Mei
Jeanette
J
Dilley
Jessica
J
Yu
Arvind
A
Rajpal
Colleen
C
Brown
Charles
C
Appah
Sherman Michael
SM
Chin
Bora
B
Han
Timothy
T
Affolter
John C
JC
Lin
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D015851:Interleukin-7 / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D061026:Programmed Cell Death 1 Receptor; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology
D000906:Antibodies; D000943:Antigens, Differentiation; D015851:Interleukin-7; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D007371:Interferon-gamma