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-2k) recipients were transplanted with neonatal C57BL/6 (H-2b) donor hearts. Anti-TfR or isotype-matched control mAbs (100 microg) 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 was administered at 5 microg/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-10, 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-10, 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.
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, USA.
A L
AL
Bayer
P
P
Baliga
J E
JE
Woodward
D000818:Animals; D000911:Antibodies, Monoclonal; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D016027:Heart Transplantation / Q000276:immunology; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D012333:RNA, Messenger / Q000378:metabolism; D011990:Receptors, Transferrin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014181:Transplantation Immunology; D014182:Transplantation, Autologous; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D016207:Cytokines; D012333:RNA, Messenger; D011990:Receptors, Transferrin