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.

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.

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-g/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.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.

CITATION INFORMATION: Heinbokel T, Quante M, Minami K, Elkhal A, Tullius S. CD4⁺IFN-γ⁺IL-10⁺ Regulatory Type 1 Cells Facilitate Prolongation of Graft Survival in Old Recipient Mice Treated with Rapamycin. Am J Transplant. 2017;17 (suppl 3).

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