Mechanisms of donor-specific transfusion tolerance: preemptive induction of clonal T-cell exhaustion via indirect presentation.
Induction of transplantation tolerance to alloantigens without general immunosuppression remains an enduring challenge. Injecting a donor-specific transfusion (DST) of spleen cells together with blocking alphaCD154 antibody prior to graft transplantation is an effective way to induce long-lived graft acceptance. Using a novel T-cell receptor (TCR) transgenic (Tg) model of CD4+ T-cell-mediated rejection, this study sheds new insights into the cellular basis for enhanced graft survival induced by DST and alphaCD154. The study shows that DST and alphaCD154 induce an early, robust, abortive expansion of the Tg T cells that results in profound anergy. This is contrasted with the more delayed, regional, productive response elicited by an allogeneic graft. Studies show that the induction of tolerance to the allograft induced by DST is mediated by indirect presentation by host antigen-presenting cells. Based on these observations, we conclude that DST and alphaCD154 preemptively tolerize the alloreactive T-cell compartment to prohibit subsequent responses to the immunogenic allograft.
Department of Microbiology & Immunology, Dartmouth Medical School, 1 Medical Center Dr, Lebanon, NH 03756, USA.
Sergio A
SA
Quezada
Bruce
B
Fuller
Lamis Z
LZ
Jarvinen
Mercedes
M
Gonzalez
Bruce R
BR
Blazar
Alexander Y
AY
Rudensky
Terry B
TB
Strom
Randolph J
RJ
Noelle
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017951:Antigen Presentation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism; D002999:Clone Cells; D016654:Genes, RAG-1 / Q000235:genetics*; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016038:Skin Transplantation / Q000276:immunology*; D013154:Spleen / Q000166:cytology; D014019:Tissue Donors
D000906:Antibodies; D007519:Isoantigens; D023201:CD40 Ligand