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Rapamycin and Interleukin-10 Treatment Induces T Regulatory Type 1 Cells That Mediate Antigen-Specific Transplantation Tolerance

¹ San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy
² Immunology of Diabetes Unit, San Raffaele Scientific Institute, Milan, Italy
³ Vita Salute San Raffaele University, Milan, Italy

Address correspondence and reprint requests to Prof. Maria-Grazia Roncarolo, HSR-TIGET, Via Olgettina 58, 20132 Milano, Italy. E-mail: m.roncarolo{at}hsr.it

Abbreviations: CFSE, carboxyfluorescein diacetate succinimidyl ester; FACS, fluorescence-activated cell sorting; FoxP3, transcription factor Forkhead box P3; GvHD, graft versus host disease; IL, interleukin; mAb, monoclonal antibody; OVA, ovalbumin peptide 323–339; TCR, T-cell receptor; TGF-ß, transforming growth factor-ß; Th cell, T helper cell; Tr cell, T regulatory cell; Tr1 cell, Tr type 1 cell

Islet transplantation is a cure for type 1 diabetes, but its potential is limited by the need for constant immunosuppression. One solution to this problem is the induction of transplantation tolerance mediated by T regulatory cells. T regulatory type 1 (Tr1) cells are characterized by their production of high levels of interleukin (IL)-10, which is crucial for their differentiation and suppressive function. We investigated the effects of IL-10 administered in combination with rapamycin on the induction of Tr1 cells that could mediate a state of tolerance in diabetic mice after pancreatic islet transplantation. The efficacy of this treatment was compared with IL-10 alone and standard immunosuppression. Stable long-term tolerance that was not reversible by alloantigen rechallenge was achieved only in mice treated with rapamycin plus IL-10. Tr1 cells that produced high levels of IL-10 and suppressed T-cell proliferation were isolated from splenocytes of rapamycin plus IL-10–treated mice after treatment withdrawal. In rapamycin plus IL-10–treated mice, endogenous IL-10 mediated an active state of tolerance, as was observed when the blockade of IL-10 activity rapidly induced graft rejection >100 days after transplantation. CD4⁺ T-cells from rapamycin plus IL-10–treated mice transferred antigen-specific tolerance in mice that received new transplants. Thus rapamycin plus IL-10 not only prevented allograft rejection but also induced Tr1 cells that mediated stable antigen-specific, long-term tolerance in vivo.

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