SYNERGISTIC IMMUNOSUPPRESSIVE ACTIONS OF CYCLOSPORINE WITH A MOUSE ANTI-RAT ALPHA BETA-T-CELL RECEPTOR MONOCLONAL-ANTIBODY/

A mouse IgG(1) mAb (R73) directed against the rat alpha/beta-TCR was d ocumented not only to prolong the survival of allografts across major RT1 plus non-RT1 antigenic disparities, but also to display a synergis tic immunosuppressive interaction with CsA. Heterotopic cardiac transp lants from Buffalo (RT1(b)) rats survived significantly longer in Wist ar-Furth (RT1(u)) hosts treated immediately after the operation with 0 .25 mg/kg R73 i.v., with a mean survival time of 11.0 +/- 5.5 versus 6 .8 +/- 1.2 days in the untreated group (P<0.01). Administration of 0.5 or 5.0 mg/kg R73 displayed dose-dependent prolongation of survival to 17.0 +/- 8.3 days (P<0.05) or 28.6 +/- 14.0 days (P<0.01), respective ly. One 0.5 mg/kg i.v. dose of R73 delivered to normal Wistar-Furth ho sts produced peripheral T cell depletion that reversed after 16 days. Three injections of 0.5 mg/kg R73 on days 0, 2, and 4 prolonged allogr aft survival to 52.5 +/- 38.6 days compared with 17.0 +/- 8.3 days wit h a single dose (P<0.01). Addition of 3 daily doses of 5 or 10 mg/kg C sA administered per oral gavage to a single dose of 0.05, 0.25, or 0.5 mg/kg R73 injected on day 0 produced a synergistic effect to prolong allograft survival, as determined by the rigorous median-effect analys is. The synergistic interaction, which may be explained by the inhibit ory effect of CsA on Ca2+-dependent pathways triggered after activatio n of TCR, the target of R73, warrants clinical investigation in order to assess the potential impact of anti-alpha/beta-TCR mAb on CsA-based immunosuppressive regimens.