Differential effects of transferrin receptor blockade on the cellular mechanisms involved in graft rejection

Since transferrin receptor (TfR) appears on activated T cells following the interaction of the antigen-major histocompatibility complex (MHC) with the T cen receptor (TCR) and the appearance of interleukin (IL)-2R, we therefo re hypothesize that in vivo blockade of TfR prolongs allograft survival by altering the cellular mechanisms involved in graft rejection. Previous resu lts in our laboratory have demonstrated that anti-TfR monoclonal antibody ( mAb) at 100 mu g on days 0 and 1 of transplantation significantly prolonged allograft survival to 25.7 +/- 0.9 days in a murine heterotopic, nonvascul arized cardiac allograft model. In the current studies, administration of a nti-TfR mAb at the time of maximal TfR expression, on days 2 and 3 post-tra nsplantation, failed to prolong allograft survival (13.0 +/- 0.0 days) comp ared to the isotype controls (10.5 +/- 0.5 and 10.7 +/- 0.4 days) (p < 0.01 , Wilcoxon rank sum). A 4-day course of anti-TfR mAb significantly prolonge d allograft survival compared to the isotype controls, but was no more effe ctive than a 2-day course of the mAb. Anti-TfR mAb suppressed the mixed lym phocyte response to donor-specific and third-party alloantigen by 78.7% (p < 0.05) and 80.8% (p < 0.05), respectively, while stimulating the CTL respo nse to donor-specific (16.3%, p < 0.05) and third party (49.3%, p < 0.01) a lloantigen. Anti-TfR mAb suppressed IL-15 and increased IL-4 intragraft mRN A expression when compared to the isotype controls. Examination of cell sur face receptors important during T cell activation revealed alterations in e xpression following anti-TfR mAb treatment. Anti-TfR mAb is an effective im munosuppressant prolonging allograft survival by altering cell-mediated imm une responses and the intragraft cytokine micro-environment.