Immune tolerance to combined organ and bone marrow transplants after fractionated lymphoid irradiation involves regulatory NK T cells and clonal deletion.
Immune tolerance to organ transplants has been reported in laboratory animals and in humans after nonmyeloablative conditioning of the host and infusion of donor bone marrow cells. We examined the mechanisms of immune tolerance to mouse cardiac allografts in MHC-mismatched hosts that developed mixed chimerism after posttransplant conditioning with a 2-wk course of multiple doses of lymphoid tissue irradiation, depletive anti-T cell Abs, and an infusion of donor bone marrow cells. When CD1(-/-) or J(alpha)281(-/-) hosts with markedly reduced NK T cells were used instead of wild-type hosts, then the conditioning regimen failed to induce tolerance to the heart allografts despite the development of mixed chimerism. Tolerance could be restored to the CD1(-/-) hosts by infusing enriched T cells from the bone marrow of wild-type mice containing CD1-reactive T cells but not from CD1(-/-) host-type mice. Tolerance could not be induced in either IL-4(-/-) or IL-10(-/-) hosts given the regimen despite the development of chimerism and clonal deletion of host T cells to donor MHC-Ags in the IL-10(-/-) hosts. We conclude that immune tolerance to bone marrow transplants involves clonal deletion, and tolerance to heart allografts in this model also involves regulatory CD1-reactive NK T cells.
Higuchi
Masanori
M
Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Center for Clinical Science Research Building, 300 Pasteur Drive, Stanford, CA 94305, USA.
Zeng
Defu
D
Shizuru
Judith
J
Gworek
Jennifer
J
Dejbakhsh-Jones
Sussan
S
Taniguchi
Masaru
M
Strober
Samuel
S
D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics / Q000276:immunology; D000961:Antilymphocyte Serum / Q000008:administration & dosage; D016026:Bone Marrow Transplantation / Q000276:immunology*; D017637:Clonal Deletion / Q000235:genetics / Q000528:radiation effects; D016207:Cytokines / Q000502:physiology; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D007274:Injections, Intraperitoneal; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology* / Q000528:radiation effects; D015182:Lymphatic Irradiation / Q000379:methods; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011828:Radiation Chimera / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000528:radiation effects; D019172:Transplantation Conditioning / Q000379:methods
D018949:Antigens, CD1; D000961:Antilymphocyte Serum; D016207:Cytokines; D016753:Interleukin-10