Age-Specific Prolongation of Graft Survival in Recipients Treated With Rapamycin is Linked to CD4 + IFN-g + IL-10+ Cells

Abstract

Introduction: Although the elderly represent 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 aging using a fully MHC-mismatched (DBA/2 on B57BL/6) murine transplantation model. Results: Old untreated recipients displayed a prolonged skin graft survival compared to their young counterparts (median survival time 9 vs. 7 days, p = 0.006). Rapamycin led to a marked and significant prolongation of graft survival specifically in old but not 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, anti-proliferative 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. This shift in cytokine balance was linked to an emergence of IFN-γ/IL-10 double-positive regulatory type 1 cells during Th1-differentiation of old T helper cells in presence of Rapamycin, a process that was independent of regulatory T cells. Conclusion: These results demonstrate a novel pathway of age-dependent alloimmunity for an immunosuppressive drug currently in widespread clinical use and with relevance for an age-specific immunosuppression.FigureFigure