Effect of cyclosporin A on human lymphocyte responses in vitro. II. Induction of specific alloantigen unresponsiveness mediated by a nylon wool adherent suppressor cell

Cyclosporin A (CsA) was assessed for its ability to induce immunologic unresponsiveness to alloantigens in the in vitro model of the primary and secondary mixed lymphocyte reactions (MLR). CsA added in graded amounts to primary MLR resulted in a dose-dependent inhibition of the proliferative response as well as inhibited the induction of cytotoxic effector cells. At the highest doses of CsA tested in primary MLR, cytotoxic lymphocyte (CTL) generation was completely abolished whereas alloantigen-activated suppressor cells were found in substantial levels. After 12 days of incubation with alloantigen in primary MLR, primed lymphocytes were thoroughly washed to remove CsA and rechallenged in secondary MLR with the original sensitizing lymphocytes. Rechallenged lymphocytes from primary control cultures without CsA responded in a second set fashion with peak proliferation occurring on day 4 and a concomitant enhancement of cytotoxic lymphocyte activity. In contrast, lymphocytes from primary MLR cultures with CsA when rechallenged with the original sensitizing alloantigen exhibited very low levels of proliferation peaking on day 4 but without the induction of CTL activity. Associated with the low levels of proliferation was a 2- to 5-fold increase of suppressor cell activity. The lymphocytes from CsA-treated cultures remained fully responsive to PHA stimulation and were able to respond to challenge with third party, unrelated alloantigens, which resulted in the induction of cytotoxic effector lymphocytes. Nylon wool fractionation of the primed lymphocytes from CsA-treated cultures restored the capacity to generate cytolytic effector cells in response to challenge with the original sensitizing alloantigen. These results indicate that CsA treatment in primary MLR leads to specific alloantigen unresponsiveness that is maintained, at least in part, by a nylon wool-adherent suppressor cell.