RAT STEM-CELLS DEVELOPING IN IRRADIATED SCID MICE FAIL TO BECOME TOLERIZED AND CAUSE LETHAL GRAFT-VERSUS-HOST DISEASE

Graft-versus-host disease (GVHD) is prominent in irradiated hosts give n whole allogeneic bone marrow cells but is generally undetectable whe n T-depleted stem cells are transferred; under these conditions, the m ature T cells arising from the donor stem cells become tolerant to hos t antigens and fail to cause GVHD, We show here that a radically diffe rent situation can occur when hosts are reconstituted with xenogeneic stem cells, When Lightly irradiated, adult C.B-17 SCID mice injected w ith Lewis rat fetal Liver (FL) cells show near-total repopulation with rat-derived lymphohemopoietic cells, including T and B cells, However , in marked contrast to chimeras prepared with allogeneic mouse FL cel ls, rat FL --> SCID chimeras develop severe and often lethal chronic G VHD, In these rat --> mouse chimeras, the rat T cells show limited tol erance to host mouse antigens as determined by various parameters incl uding mixed lymphocyte reaction and cytotoxic T lymphocyte assays in v itro, adoptive transfer of T cells to secondary SCID hosts, and the la ck of VP deletion to endogenous host mtv antigens. GVHD in irradiated rat --> SCID chimeras is most prominent with Lewis FL but also applies to Fisher 344 and Wistar Furth FL cells, The failure of newly formed rat T cells in rat --> SCID chimeras to become fully tolerant to host mouse antigens appears to be due to depletion of host antigen-presenti ng cells by irradiation, Thus, rat --> SCID chimeras generated by tran splanting rat FL cells into unirradiated neonatal SCID mice fail to de velop GVHD, and the rat T cells display self-tolerance, As allogeneic H-2-different mouse FL --> irradiated SCID chimeras display strong sel f-tolerance, presumably through recognition of host antigens on thymic epithelial cells, the implication is that mouse thymic epithelial cel ls are tolerogenic only for mouse and not for rat immature T cells.