Elderly patients constitute the fastest growing proportion of organ transplant recipients. Whether immunosuppression needs to be adapted in an age-dependent manner or if immunosuppressants have an age-specific mode of action remains unclear and yet, clinically, of critical importance.

We explored the effects of rapamycin and CTLA4-Ig on immune responses and transplant outcome in an experimental model.

Fully mismatched cardiac allografts from young (3 months) DBA donor mice were transplanted into either young (3 months) or old (18 months) C57BL/6 recipients; animals were treated with either CTLA4-Ig (0,2 mg/day, days 0, 2, 4, 6), rapamycin (1 mg/KG/day, days 0, 1, 2, 4, 6, 8, 10, 12, 14) or PBS (n=5/group). Animals were followed for > 100 d.

Following co-stimulatory blockade with CTLA4-Ig cardiac allografts were accepted indefinitely in young animals. In sharp contrast, old mice treated with CTLA4-Ig rejected their graft after a MST of 34 days. Of note, recipient age promoted the immunosuppressive effects of rapamycin: while allograft survival in old recipients treated with rapamycin was indefinite, allografts survival in young animals was limited to a MST of 29 d.

Next, we assessed age-specific systemic immune response to CTLA4-Ig and rapamycin by fluorescence-activated cell sorting (FACS) analysis and mixed lymphocyte reaction (MLR). Interestingly, FACS-analysis of splenocytes from young recipient mice treated with either CTLA4-Ig or rapamycin demonstrated a significant increase in naive CD4+ T cells (p = 0,0018 and 0,0172, respectively) while a significant decrease in CD4+ central memory T cells was observed (p

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