An mAb directed to the α/β-heterodimer of the rat T cell receptor was used to prevent rejection of cardiac allografts in sensitized (accelerated rejection) recipients. Over a wide dose range, α/β-TCR-directed therapy abrogated accelerated rejection at 24–36 hr and extended cardiac allograft survival in a dosedependent fashion, both when given after heart transplantation as well as during or before the sensitizing skin transplants (8.9±1.0 days, 12.7±0.6 days, or 8.7±1.5 days, respectively). Pretreatment with R73 completely abrogated host sensitization induced by skin grafting. As a result, post-heart transplant cyclosporine course (15 mg/kg for 7 day) has led to long-term graft acceptance (> 90 days vs. 15.2±1.6 days with postoperative CsA therapy alone). Administration of R73 mAb produced incomplete depletion (CD5+ cells) and partial modulation (α/β-TCR/CD5 double-positive cells) in the peripheral blood. It suppressed in situ protein expression of many cytokines to background levels, in particular that of IL-2 and IFN-γ, both when given after as well as before cardiac transplantation. However, only pretransplant mAb application was associated with augmented in situ elaboration of IL-4. α/β-TCR-directed therapy induced strong host antiidiotypic and, to a lesser degree, anti-isotypic antibody responses. Taken together, these results provide the rationale for a novel immunosuppressive strategy involving induction of hyporesponsiveness by α/β-TCR-directed therapy before the alloantigenic exposure.
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