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 given whole allogeneic bone marrow cells but is generally undetectable when T-depleted stem cells are transferred; under these conditions, the mature T cells arising from the donor stem cells become tolerant to host antigens and fall to cause GVHD. We show here that a radically different situation can occur when hosts are reconstituted with xenogeneic stem cells. When lightly irradiated, adult C.B-17 SCID mice injected with 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 cells, rat FL-->SCID chimeras develop severe and often lethal chronic GVHD. In these rat-->mouse chimeras, the rat T cells show limited tolerance to host mouse antigens as determined by various parameters including mixed lymphocyte reaction and cytotoxic T lymphocyte assays in vitro, adoptive transfer of T cells to secondary SCID hosts, and the lack of V beta 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-presenting cells by irradiation. Thus, rat-->SCID chimeras generated by transplanting rat FL cells into unirradiated neonatal SCID mice fail to develop GVHD, and the rat T cells display self-tolerance. As allogeneic H-2-different mouse FL-->irradiated SCID chimeras display strong self-tolerance, presumably through recognition of host antigens on thymic epithelial cells, the implication is that mouse thymic epithelial cells are tolerogenic only for mouse and not for rat immature T cells.
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Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA.
Kosaka
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Sprent
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D019264:Adoptive Transfer; D000818:Animals; D005260:Female; D016332:Fetal Tissue Transplantation; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D007108:Immune Tolerance; D007111:Immunity, Cellular; D008099:Liver / Q000166:cytology* / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D011247:Pregnancy; D051381:Rats; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D018183:Transplantation Chimera; D014916:Whole-Body Irradiation