Anti–IL-7 Receptor-Α Reverses Established Type 1 Diabetes In
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Correction IMMUNOLOGY Correction for “Anti–IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function,” by Li-Fen Lee, Kathryn Logronio, Guang Huan Tu, Wenwu Zhai, Irene Ni, Li Mei, Jeanette Dilley, Jessica Yu, Arvind Rajpal, Colleen Brown, Charles Appah, Sherman Mi- chael Chin, Bora Han, Timothy Affolter, and John C. Lin, which appeared in issue 31, July 31, 2012, of Proc Natl Acad Sci USA (109:12674–12679; first published June 25, 2012; 10.1073/ pnas.1203795109). The authors note that their conflict of interest statement was omitted during publication. The authors declare that all the authors are full-time employees of Pfizer Inc. Pfizer Inc. filed a patent application, with L.F.-L., J.C.L., and W.Z. as co- inventors: US Application Serial No. 13/033,491, entitled “Antagonist Anti-IL-7 Receptor Antibodies and Methods.” www.pnas.org/cgi/doi/10.1073/pnas.1214896109 CORRECTION www.pnas.org PNAS | October 2, 2012 | vol. 109 | no. 40 | 16393 Downloaded by guest on September 23, 2021 Anti–IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function Li-Fen Leea,1, Kathryn Logronioa, Guang Huan Tua, Wenwu Zhaia, Irene Nia, Li Meia, Jeanette Dilleya, Jessica Yua, Arvind Rajpala, Colleen Browna, Charles Appaha, Sherman Michael Chin a, Bora Hanb,TimothyAffolterb, and John C. Lina,1 aRinat, Pfizer Inc., South San Francisco, CA 94080; and bDrug Safety R and D, Pfizer Inc., La Jolla, CA 92121 Edited by Lewis L. Lanier, University of California, San Francisco, CA, and approved May 28, 2012 (received for review March 7, 2012) Genetic variation in the IL-7 receptor-α (IL-7R) gene is associated influence the development of the IFN-γ–expressing CD8+ with susceptibility to human type 1 diabetes (T1D). Here we in- TC1 cells. vestigate the therapeutic efficacy and mechanism of IL-7Rα anti- The activities of CD4+ and CD8+ T effector cells (Teffs) are body in a mouse model of T1D. IL-7Rα antibody induces durable, normally under stringent control by a number of negative regu- complete remission in newly onset diabetic mice after only two lators expressed on their surface. One major negative regulator, to three injections. IL-7 increases, whereas IL-7Rα antibody therapy Programmed Death 1 (PD-1) interacts with its ligand (PD-L1) + + reduces, the IFN-γ–producing CD4 (TH1) and IFN-γ–producing CD8 (27) to maintain the robust long-term tolerance of Teffs in the T cells. Conversely, IL-7 decreases and IL-7Rα antibody enhances the inflamed tissue (28–30). IL-7 was recently shown to down-regu- inhibitory receptor Programmed Death 1 (PD-1) expression in the late PD-1 in a murine viral infection model (31). It is thus per- effector T cells. Programmed Death 1 blockade reversed the immune tinent to ask whether IL-7 may contribute to the PD-1 down- tolerance mediated by the IL-7Rα antibody therapy. Furthermore, IL- regulation in the NOD mice. α 7Rα antibody therapy increases the frequency of regulatory T cells In this study we investigate how the IL-7/IL-7R pathway contributes to the development of T1D in the NOD mouse without affecting their suppressor activity. The durable efficacy and α IMMUNOLOGY the multipronged tolerogenic mechanisms of IL-7Rα antibody ther- model by using IL-7R blocking antibodies. We also elucidate apy suggest a unique disease-modifying approach to T1D. the cellular and molecular mechanisms that underlie the prom- ising therapeutic efficacy of IL-7Rα antibody therapy. T cell depletion | programmed death ligand 1 | biologics | adoptive transfer Results IL-7Rα Antibody Treatment Showed Efficacy in the Prevention of ype I diabetes (T1D) in both humans and animal models, Diabetes. To study the role of IL-7/IL-7Rα pathway in T1D, fe- Tsuch as nonobese diabetic (NOD) mice, is a complex, mul- male NOD mice were given either 10 mg/kg of control IgG tifactorial autoimmune disease in which the islet-specific T-cell (mIgG2a or rat IgG1) or an anti–IL-7Rα, 28G9 (of rat IgG1 immune response destroys insulin-producing β-cells in the islets isotype or rIgG1), or 28G9-mIgG2a in which the Fc portion of of Langerhans (1–4). At the clinical onset of diabetes, some the original rIgG1 clone is replaced with that of mouse IgG2a residual β-cells still produce insulin, offering a potential window (Table S1). In the prophylactic treatment paradigm, we admin- for therapeutic intervention to stop the autoimmune destruction istered these different antibodies to NOD mice once weekly and preserve β-cell function (5). from 9 wk of age till the end of the study. We found that 100% of MHC class II genes are the major genetic loci determining the NOD mice were prevented from diabetes by 28G9-mIgG2a, 67% susceptibility of T1D in human and NOD mice, although MHC (six of nine) by 28G9-rIgG1 compared with 0–20% of mice class II genes alone cannot fully account for genetic pre- treated with rat IgG1 isotype or mouse IgG2a isotype controls, disposition to T1D (6, 7). Recently, a SNP in the IL-7 receptor respectively (Fig. 1A). We also observed a pronounced dose- (IL-7Rα) gene was identified as one of the non-MHC–linked loci dependent effect of 28G9-rIgG1 in the prophylactic paradigm associated with risk of multiple sclerosis (8–10) and T1D (11, (Fig. S1 A–C). 12). IL-7 is a major survival factor implicated in mouse and Histological examination of mice at the end of the pro- human immune homeostasis and disorders (13). IL-7 is essential phylactic experiment revealed that pancreatic islets were heavily for the homeostatic proliferation of naïve T cells and also con- infiltrated by T cells in control IgG-treated mice, but less in those + tributes to that of CD8 memory T cells in mice (14, 15). Pro- treated with 28G9-mIgG2a or with 28G9-rIgG1 (Fig. 1 B and C). vision of exogenous IL-7 or lymphopenia-induced production of Moreover, insulin staining in the islets of the 28G9-mIgG2a– IL-7 can promote the expansion of self-reactive T-cell clones treated mice was significantly higher than that in the control IgG- (16). The IL-7 receptor is composed of two subunits: the com- treated group (Fig. 1D). mon γ-chain and the IL-7Rα chain. In humans, IL-7Rα de- In the spleen of NOD mice, CD4+ and CD8+ T cells ficiency results in the absence of T cells but B-cell counts remain expressed high levels of IL-7Rα, B cells expressed low levels of normal (17), whereas the IL-7Rα KO mice are essentially devoid IL-7Rα, but regulatory T cells (Tregs), NK, and CD11b+ cells of T and B cells (18), suggesting that the effect of IL-7/IL-7Rα signaling in T-cell development is shared between humans and mice. + + Author contributions: L.-F.L. and J.C.L. designed research; L.-F.L., K.L., G.H.T., and T.A. The islet autoreactive CD4 helper T (TH) cells and CD8 performed research; W.Z., I.N., L.M., J.D., J.Y., A.R., C.B., C.A., and S.M.C. contributed cytotoxic T (TC) cells are involved in the immune pathogenesis new reagents/analytic tools; L.-F.L., K.L., G.H.T., B.H., and J.C.L. analyzed data; and L.-F.L. of human T1D and NOD mice (19–25). Recently we showed that and J.C.L. wrote the paper. fl IL-7 can promote the development of IFN-γ–producing TH1 The authors declare no con ict of interest. cells, but not IL-17–producing TH17 cells, from the naïve T cells This article is a PNAS Direct Submission. fi of humans and of the C57BL/6 mice (26). This nding raises an 1To whom correspondence may be addressed. E-mail: Li-Fen.Lee@pfizer.com or John.Lin@ intriguing possibility that IL-7/IL-7Rα pathway may be linked to pfizer.com. T1D risk at least in part through the regulation of TH1 de- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. velopment. In addition, it was not known whether IL-7 could 1073/pnas.1203795109/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1203795109 PNAS Early Edition | 1of6 A B a bcCD3 CD4 d CD8 100 28G9-mIgG2a 80 28G9-mIgG2a (10 mg/kg) 60 28G9-rIgG1 (10 mg/kg) e fhg 40 Ctrl mIgG2a (10mg/kg) 28G9-rIgG1 Ctrl rIgG1 (10 mg/kg) Diabetes free (%) 20 0 i jkl Days after birth Ctrl rIgG1 C E F 100 1.0 2.5 1.5 PLN 1.5 PLN SPL SPL ) ) ) 4 ) - 7 7 80 4 - 0.8 - 2.0 3 - 60 2 0.6 1.5 1.0 1.0 40 0.4 1.0 1 ** ** 0.5 *** 0.5 20 ** 0.5 % of NOD islets % 0 0.2 ** Cell Counts (10 Counts Cell IL-17+ CD4+ CD8+ cells(x10 CD8+ 0 cells(x10 CD4+ 0 0 IFN CD4+ + (10 Counts Cell 0 0 D ** 6.0 1.5 MLN MLN 4 10.0 2.0 ) PLN PLN ) ) ) 6 4 - 6 4 - - 8.0 - 1.5 3 4.0 1.0 6.0 1.0 2 4.0 ** 2.0 ** 5.0 * * 0.5 1 2.0 ** ** * ** CD4+ cells (x10 cells CD4+ IL-17+ CD4+ IFN CD4+ + (10 Counts Cell Cell Counts (10 Counts Cell 0 cells(x10 CD8+ 0 0 Insulin staining score 0 0 Fig.