Rapamycin Prolongs Graft Survival and Induces CD4+IFN-γ+IL-10+ Regulatory Type 1 Cells in Old Recipient Mice

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.

Here, we assessed the impact of rapamycin on alloimmune responses in old recipients using a fully major histocompatibility complex-mismatched murine transplantation model.

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 versus 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 cluster of differentiation (CD)8 or CD4 T cells. Moreover, antiproliferative effects of rapamycin on CD8 and CD4 T cells as assessed by in vivo bromdesoxyuridine 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-γ/IL-10 double-positive regulatory type 1 cells emerged during T helper type 1 differentiation of old T helper cells in presence of rapamycin. Similarly, CD4IFN-γIL-10 cells expanded among Foxp3-negative cells after in vivo treatment of old recipients with rapamycin.

Our results highlight novel aspects of age-dependent immunosuppressive effects of rapamycin, with relevance for age-specific immunosuppressive regimens.