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

• Published in: Transplantation Vol. 68; no. 9; p. 1369
• Main Authors: Woodward, J E, Bayer, A L, Baliga, P
• Format: Journal Article
• Language: English
• Published: United States 15.11.1999
• Subjects: Animals; Antibodies, Monoclonal - therapeutic use; Cytokines - genetics; Female; Graft Survival; Heart Transplantation; Immunosuppressive Agents - therapeutic use; Isoantigens - immunology; Killer Cells, Natural - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred CBA; Receptors, Interleukin-2 - antagonists & inhibitors; Receptors, Transferrin - antagonists & inhibitors; RNA, Messenger - analysis; T-Lymphocytes - immunology; Transplantation, Homologous
• ISSN: 0041-1337
• DOI: 10.1097/00007890-199911150-00025

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. 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. 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. 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.