Analysis of retinoid-mediated immunosuppression in vivo. Effects of Ro23-6457 on cellular alloimmune responses

We have investigated the immunosuppressive effects of a synthetic retinoid, Ro23-6457, on the in vivo development of cellular alloimmunity. We initially observed that treatment of C57Bl/6 mice with 10 mg/kg/day Ro23-6457 drug could prolong the survival of DBA/2 cardiac allografts, thus verifying its immunosuppressive potential in murine experimental models. We next used the sponge matrix model of allograft rejection and limiting dilution analysis (LDA) of cytotoxic T lymphocyte (CTL) frequency to dissect this phenomenon further. In this experimental system we observed the following effects of Ro23-6457: (1) dose-dependent decrease in the number of LDA-detectable, donor-reactive CTL accumulating in sponge matrix allografts; (2) failure to interfere with in vitro assays of cellular alloimmunity, including LDA; and (3) antigen non-specific depression of LDA-detectable CTL in lymph nodes, spleen and especially in peripheral blood. For peripheral blood CTL, the drug eliminated LDA-detectable CTL, an effect that was reversible and could not be attributed to the activation of suppressor cells. Since Ro23-6457 has little effect on the number of peripheral blood Thy1.2+ cells, it appears that this drug does not physically eliminate CTL, but makes them temporarily hyporesponsive to antigen stimulation, and thus undetectable in functional assays like LDA.