Alloimmunization-activated suppressor cells. II. In vitro activity of suppressor cells implicated in the abrogation of lethal graft-versus-host reaction

Abstract

Incompatibility for DBA/2 (D2) minor histocompatibility antigens (MiHA) alone leads to a severe lethal graft-versus-host reaction (GVHR) in irradiated (D2 X B10.D2)F1 mice receiving a bone-marrow-plus-spleen-cell graft from B10.D2 donors. This mortality is abrogated when the donors are preimmunized simultaneously against specific D2 MiHA and unrelated H-2 antigens three days before grafting. Results presented here demonstrate that spleen cells from such preimmunized donors, which are able to diminish the intensity of the GVHR developed by normal cells, exhibit the following properties: (1) reduced proliferative response to D2 MiHA in one-way MLC; (2) radioresistant suppressive effect on the proliferative responses of both normal and specifically primed B10.D2 cells; (3) inability to lyse D2 target cells even after in vitro boosting, implying that the suppressive effect detected in vitro is not due to removal of the stimulating antigens from the culture; and (4) inability to suppress the development of an anti-MiHA cytolytic response by specifically primed B10.D2 cells, despite a pronounced suppressive effect on their proliferation. Taken together with the GVHR observations, these results suggest that simultaneous immunization against specific MiHA and unrelated H-2 antigens activates, in the spleens of treated donors, suppressor cells that can inhibit the immune response at the recognition phase, and probably also at an afferent, but not efferent, stage of cytotoxic effector-cell differentiation.