Mechanisms of long-term donor-specific allograft survival induced by pretransplant infusion of lymphocytes.
Pretransplantation donor-specific transfusion (DST) can enhance allograft survival in man and animals. However, due to the lack of a specific marker to identify donor-reactive cells in vivo in man and normal (nontransgenic) animals, the underlying mechanism remains unknown. In this study, we use 2CF1 transgenic mice expressing a transgenic T-cell receptor (TCR) specifically recognizing Ld, a major histocompatibility complex (MHC) class I molecule, to delineate the role of DST in long-term skin allograft survival and its underlying mechanisms. Our main findings include: (1) in the absence of any other immunosuppressive treatment, a single dose pretransplantation infusion of viable splenocytes from an Ld+ donor is sufficient to induce permanent donor-specific skin allograft survival in 2CF1 anti-Ld TCR transgenic mice; (2) DST leads to a deletion of the majority (>60%) of donor-reactive T cells in the periphery of the recipient. However, deletion does not necessarily result in tolerance; (3) remaining donor-reactive T cells from DST-treated mice are fully responsive to Ld in vitro, and can suppress the antidonor response of naive T cells in vitro only when exogenous interleukin (IL)-4 is provided; and (4) the sera level of IL-4 in DST-treated tolerant mice is significantly increased. These results suggest that the generation of a subset of T cells with the potential to specifically inhibit antidonor responses, together with promotion of IL-4 production in recipients, may be important mechanisms for the induction and maintenance of antigen-specific tolerance.
Yang
L
L
Department of Cellular and Molecular Pathology, Multi Organ Transplantation Program, The Toronto Hospital Research Institute, University of Toronto, Toronto, Canada.
Du Temple
B
B
Khan
Q
Q
Zhang
L
L
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D017637:Clonal Deletion; D005260:Female; D006082:Graft Enhancement, Immunologic; D006085:Graft Survival / Q000276:immunology; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology*; D064532:Histocompatibility Antigen H-2D; D007108:Immune Tolerance; D015847:Interleukin-4 / Q000096:biosynthesis / Q000097:blood; D017710:Lymphocyte Transfusion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014019:Tissue Donors; D014184:Transplantation, Homologous / Q000276:immunology
D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins; D015847:Interleukin-4