The effect of cyclosporin on murine autoreactive delayed type hypersensitivity induced with syngeneic lymphoblasts

The effect of cyclosporin on an immunological autoreactive experimental model was analyzed. The experimental system consisted of X-irradiated A mice injected with syngeneic concanavalin A-induced lymphoblasts and footpad-challenged 7 days later with syngeneic lipopolysaccharide-induced lymphoblasts. 24-72 h after challenge, the footpads of these mice responded with significant swelling, accumulation of 125I-UdR or massive cellular infiltration revealed by histological examination. Since the immunological activity was transferred by Lyt-1+ T cells from the sensitized donors to naive recipients, we designated it 'syngeneic delayed-type hypersensitivity' (syn-DTH). This DTH was induced and elicited mostly by antigens of the syngeneic lymphoblasts and not by contaminants attached to them, indicating the immunological autoreactive nature of this system. Multiple doses of 60 mg/kg cyclosporin, given daily in the time interval between immunization and challenge, or on the last four days before challenge, inhibited the syn-DTH. Multiple injections of cyclosporin Before or close to the induction phase of the syn-DTH was ineffective, whereas single or multiple injections of cyclosporin close to the effector phase (the challenge time) markedly reduced the syn-DTH. Even a single injection of cyclosporin 24 h after the challenge efficiently reduced the 48-h syn-DTH. Adoptive transfer experiments revealed that T cells from X-irradiated mice immunized with concanavalin A-induced lymphoblasts and injected with cyclosporin, failed to efficiently transfer the syn-DTH response to naive recipients. Similarly, the syn-DTH response of naive X-irradiated recipient mice injected with cyclosporin, failed to be reconstituted with primed T cells derived from X-irradiated mice immunized with concanavalin A-induced lymphoblasts. Since the nonspecific footpad swelling response of X-irradiated mice challenged with lymphoblasts alone is resistant to the standard protocol of the cyclosporin treatment, we suggest that cyclosporin inhibits the ability of T cells to produce or release lymphokines at the effector phase of DTH, while phagocytic cells involved in the DTH response are not affected by it. The practical and the theoretical implications of this research are discussed.