Rapamycin prolongs graft survival and induces CD4+IFN-[gamma]+IL-10+ regulatory type 1 cells in old recipient mice.

Background: Although the elderly represents a rapidly growing population among transplant recipients, age-specific aspects have not been considered sufficiently in clinical trials. Moreover, age-specific effects of immunosuppressive therapies remain poorly understood. Methods: Here, we assessed the impact of Rapamycin on alloimmune responses in old recipients using a fully MHC-mismatched murine transplantation model. Results: Old untreated recipients displayed a prolonged skin graft survival compared to their young counterparts, an observation that confirmed data of our previous experiments. Rapamycin led to a significant prolongation of graft survival in both, young and old recipients. However, graft survival was age-dependent and extended in old vs. young recipients (19 days vs. 12 days, p=0.004). This age-specific effect was not linked to changes in frequencies or subset composition of either CD8+ or CD4+ T cells. Moreover, antiproliferative effects of Rapamycin on CD8+ and CD4+ T cells as assessed by in vivo BrdU-incorporation were comparable and age-independent. In contrast, the systemic production of IL-10 was markedly elevated in old recipients treated with Rapamycin. In parallel to this shift in cytokine balance, IFN-[gamma]/IL-10 double-positive regulatory type 1 cells emerged during Th1-differentiation of old T helper cells in presence of Rapamycin. Similarly, CD4+IFN-[gamma]+IL-10+ cells expanded among Foxp3-negative cells after in vivo treatment of old recipients with Rapamycin. Conclusions: Our results highlight novel aspects of age-dependent immunosuppressive effects of Rapamycin, with relevance for age-specific immunosuppressive regimens. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2fh0tPT