Transferrin receptor in T cell activation and transplantation

Transferrin receptor (TfR) expression is up-regulated during T cell activation after the interaction of the T cell receptor with the antigen-major histocompatibility complex and the expression of interleukin-2 (IL-2) receptor, We hypothesize that anti-TfR monoclonal antibody (mAb) will prolong allograft survival by altering T cell responses, In a murine heterotopic nonvascularized cardiac allograft model, CBA/J (H-2(k)) recipients were transplanted with neonatal C57BL/6 (H-2(b)) donor hearts. Anti-TfR or isotype-matched control mAbs (100 mu g) were administered at the time of transplantation and on the following day. Splenocytes from naive CBA/J mice were stimulated in vitro with C57BL/6 alloantigen, Anti-TfR mAb TI-as administered at 5 mu g/mL during the initiation of culture, Cytotoxic T lymphocyte (CTL) and mixed lymphocyte responses (MLR) were performed to assess T cell function, After 24 h in culture, cells were harvested, RNA isolated, and semi-quantitative reverse transcriptase-polymerase chain reaction performed. Anti-TfR mAb prolonged allograft survival to 25.7 +/- 0.9 days compared to the isotype control (10.7 +/- 0.4 days, P < 0.01, Wilcoxon rank sum). Anti-TfR mAb completely abrogated the CTL response and suppressed the MLR by 70-86% compared to the isotype controls. Anti-TfR mAb suppressed IL-2, interferon-gamma (IFN-gamma), IL-IO, and IL-12 p40 mRNA expression, but had no effect on IL-4, IL-12 p35, and IL-15 mRNA expression. In conclusion, anti-TfR mAb prolongs allograft survival, suppresses T cell function, and alters IL-2, IL-IO, IL-12 p40, and IFN-gamma mRNA expression. These data suggest that the down-regulation in IL-12 mRNA by anti-TfR mAb may prevent the development of T helper cells, thereby promoting graft survival and altering cell-mediated immune responses, The partial effect by anti-TfR mAb on cytokine mRNA expression may be due to other contributing factors such as costimulation.