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 to initiate cell proliferation in quiescent T lymphocytes. Therefore, we tested the hypothesis that simultaneous blockade of TfR and IL-2R would be more effective in prolonging allograft survival and suppressing T-cell responses to alloantigen than single receptor blockade by modifying T-cell effectors 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 administered at 100 microg intravenously on days 0 and 1 of transplantation.


RESULTS
Anti-TfR mAb (25.7+/-0.9 days) significantly (P<0.01) prolonged cardiac 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 survival to 50.7+/-2.0 days compared with the isotype control or either agent alone. These agents in combination down-regulated the intragraft T helper (Th)-1 cytokines, IL-2, interferon-gamma, and IL-15, while up-regulating the Th2 cytokine, IL-4, and completely abrogating the antigen-presenting cell IL-12p40 mRNA expression.


CONCLUSIONS
Anti-TfR and anti-IL-2R mAbs are potent immunosuppressants. Combined 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.
Woodward
J E
JE
Department of Surgery, Medical University of South Carolina, Charleston 29425, USA. woodwardje@msx.upmc.edu
Bayer
A L
AL
Baliga
P
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics; D005260:Female; D006085:Graft Survival; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007519:Isoantigens / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D012333:RNA, Messenger / Q000032:analysis; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors*; D011990:Receptors, Transferrin / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D016207:Cytokines; D007166:Immunosuppressive Agents; D007519:Isoantigens; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D011990:Receptors, Transferrin