Immunosenescence is broadly affecting alloimmunity with major implications on immunosuppression. Older recipients have thus far been mostly excluded from clinical trials. Here, we dissected the effect of aging on the efficacy of Rapamycin and CTLA-4-Ig.

Skin grafts of young DBA/2 mice were transplanted onto young (2 months) and old (18 months) C57BL/6 mice. Mice received either Rapamycin (1 mg per kg per day, i.p.), CTLA-4-Ig (0,2 mg per day i.p.) or PBS. Grafts in older, untreated recipients survived significantly longer (7 vs. 9 days; p=0,01), indicating that immunosenescence promotes allograft survival. Treatment with the costimulatory blocker CTLA-4-Ig prolonged graft survival modestly in an age-independent fashion (10 vs. 11 days in young and old animals, resp.). In contrast, Rapamycin prolonged graft survival in an age-specific fashion: while the median graft survival was modestly extended in young recipients (12 days), graft survival was significantly prolonged in old recipients (19 days; p=0,008). Next, we dissected age-specific effects of CTLA-4-Ig and Rapamycin on alloimmunity. Subsequent to costimulatory blockade, both CD4⁺ and CD8⁺ T cells significantly declined in young recipients only (p=0,003 and P=0.02, respectively). However, Rapamycin treatment had been linked to a significantly more pronounced decrease of CD4+ T cells in old recipients (p=0.0005). Moreover, we observed a significant decline of CD11c⁺MHC class II⁺ cells in old Rapamycin treated recipients (p=0.01).

Our data demonstrate that aging is critically impacting the efficacy of Rapamycin and CTLA-4-Ig emphasizing on the necessity of age-adapted immunosuppression.

CITATION INFORMATION: Schuitenmaker J, Edtinger K, Seyda M, Uehara H, Quante M, ElKhal A, Tullius S. Aging Is Critically Impacting the Efficacy of Immunosuppressants. Am J Transplant. 2016;16 (suppl 3).

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