Synergistic immunosuppressive actions of cyclosporine with a mouse anti-rat ⍺/β-T cell receptor monoclonal antibody

A mouse IgG₁ mAb (R73) directed against the rat α/β-TCR was documented not only to prolong the survival of allografts across major RT1 plus non-RT1 antigenic disparities, but also to display a synergistic immunosuppressive interaction with CsA. Heterotopic cardiac transplants from Buffalo (RT1^b) rats survived significantly longer in Wistar-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), respectively. One 0.5 mg/kg i.v. dose of R73 delivered to normal Wistar-Furth hosts 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 allograft survival to 52.5±38.6 days compared with 17.0±8.3 days with a single dose (P<0.01). Addition of 3 daily doses of 5 or 10 mg/kg CsA 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 analysis. The synergistic interaction, which may be explained by the inhibitory effect of CsA on Ca²⁺-dependent pathways triggered after activation of TCR, the target of R73, warrants clinical investigation in order to assess the potential impact of anti-α/β-TCR mAb on CsA-based immunosuppressive regimens.