Enhanced allograft survival via simultaneous blockade of transferrin receptor and interleukin-2 receptor

Background, Transferrin receptor (TfR) expression follows the induction of interleukin 2 receptor (IL-2R) expression in a sequence that is necessary t o initiate cell proliferation in quiescent T lymphocytes. Therefore,we test ed the hypothesis that simultaneous blockade of TfR and IL-2R would be more effective in prolonging allograft survival and suppressing T-cell response s to alloantigen than single receptor blockade by modifying T-cell effecter s to alloantigen. Methods. Neonatal C57BL/6 hearts were transplanted to CBA/J recipients in a heterotopic, nonvascularized cardiac allograft model. Anti-TfR and/or anti -IL-2R or isotype-matched control monoclonal antibodies (mAbs) were adminis tered at 100 mu g intravenously on days 0 and 1 of transplantation. Results. Anti-TfR mAb (25.7+/-0.9 days) significantly (P<0.01) prolonged ca rdiac allograft survival compared with anti-IL-2R mAb (12.5+/-0.9 days) or the isotype control (15.7+/-1.2 days, P<0.01, Wilcoxon rank-sum). Anti-TfR plus anti-IL-2R mAbs significantly (P<0.01) prolonged cardiac allograft sur vival to 50.7+/-2.0 days compared with the isotype control or either agent alone. These agents in combination downregulated the intragraft T helper (T h)-1 cytokines, IL-2, interferon-gamma, and IL-15, while up-regulating the Th2 cytokine, IL-4, and completely abrogating the antigen-presenting cell I L-12p40 mRNA expression. Conclusions, Anti-TfR and anti-IL-2R mAbs are potent immunosuppressants. Co mbined blockade of TfR and IL-2R at the time of antigen presentation seems to be the most effective by shifting the intragraft Th cytokine paradigm.