Immunosenescence has broad consequences on alloimmunity and immunosuppression in the elderly may require age-adaptation. Here, we investigated the influence of aging on the effectivity of Tacrolimus by performing a fully MHC-mismatch skin transplants (DBA) in young (6 wks.; C57BL/6) and old recipient mice (18 month; C57BL/6). Transplant outcomes were monitored and mechanisms of immune responses were dissected in detail.

Tacrolimus dosed in a weight-adjusted fashion, resulted into a highly significantly prolonged survival in old recipients (26.3 vs. 11.3 d; n = 7; p=0.001). Of note, trough levels were significantly higher in older animals. Next, we adjusted Tacrolimus dose by trough levels; mean graft survival remained to be prolonged in old recipients (15.4 vs. 11 d. in young recipients; n=7) n = 7; p=0.003). Detailed immune monitoring revealed declining CD4+ T cells in old recipients (2.9 x 106 vs. 5.4 x 106, p<0.001). Proliferation of CD4+ T cells was inhibited in an age-specific manner (x1.7 in old mice; p<0.05). Similarly, cytokine production was affected in an age specific fashion with reduced productions for IL-2+, IL-17A+ and IL-4+ in old mice (p<0.05). When naïve CD4+ T-cells were cultured under TH1 polarizing conditions, as present subsequent to transplantation, old naïve CD4+ T cells produced more IL10+ and IL4+ (p< 0.01). Strikingly, this effect was significantly enhanced, when Tacrolimus was added to the cell culture.

In summary, older mice demonstrated a significantly prolonged graft survival under adjusted trough levels for Tacrolimus. Moreover, CD4+ T-cell function is more suppressed in old recipient mice. Of note, old naïve CD+ T cells produced more IL-10+ and IL4+ under Th1 polarizing conditions. Those data indicate an age-specific effectivity of Tacrolimus supporting that older organ recipients may require reduced Tacrolimus doses.

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