H-Y and the transplanted mouse heart.
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Biomedical subjects
Publications and source records attributed to J Shelby.
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We assessed the effect of syngeneic and allogeneic exchange transfusion (XTF) on cell-mediated immunity in a murine burn model. Mice were given a 30% TBSA scald injury and lymphocyte function was monitored with the popliteal lymph node assay for host-versus-graft (HVG) or graft-versus-host (GVH) response. Nonexchanged burned animals exhibited suppression of GVH response on postburn days (PBD) 3 and 8 and suppression of HVG response on PBD 3, 8, 11, and 14. Syngeneic XTF stimulated GVH response on PBD 3, and significantly improved both GVH and HVG response to alloantigens on postburn days 3 and 8 compared to the response of burned controls. Allogeneic XTF significantly improved GVH response on PBD 3 and 8, but did not improve HVG response. Restoration of lymphocyte function in all experimental groups occurred between PBD 14 and 18 and coincided with wound healing.
Prostaglandin E (PGE) production is elevated in burn-injured individuals and has been implicated as a mechanism in thermal injury-induced immunosuppression. Profound depression of cell-mediated immune response (CMIR) is a characteristic effect of burn injury, and was evaluated using the popliteal lymph node assay for graft-versus-host and host-versus-graft responsiveness in mice. Preservation of CMIR after burn injury was observed in animals treated with 40 mg/kg ibuprofen and in mice given anti-PGE antibody. It appears that PGE is a central immunoregulatory mediator of suppressed CMIR following thermal injury and that treatment resulting in inhibition of PGE production or neutralization of PGE with anti-PGE antibody prevented burn-induced immunosuppression.
Transmission of infectious disease, including virus, by allogeneic tissue transplants is a major clinical concern. The present study provided evidence for the transfer of murine cytomegalovirus (MCMV) by syngeneic and allogeneic skin grafts transplanted immediately after harvest from acutely infected donor mice. Transfer of MCMV also occurred following skin grafting with cryopreserved syngeneic skin. Recipients of infected skin were first positive for MCMV between 9 and 15 days post transplant, and MCMV was continually detectable through day 30. These results suggest that fresh or banked skin may serve as a source for transmission of cytomegalovirus infections.
Skin allograft survival time has been prolonged in a variety of animal and human studies. Burn injury, histocompatibility matching, and cyclosporine administration each independently have been shown to increase skin allograft survival times. A mouse model was developed to study these relationships. Histocompatibility matching of mouse H-2 I showed a trend toward skin allograft prolongation when comparing nonburned and burned animals. When there was complete histocompatibility of mouse H-2 and H-4 allograft survival time was significantly prolonged. Cyclosporine administration to the optimally matched donor/recipient combination further enhanced allograft survival. This study demonstrated that histocompatibility matching for the entire H-2 locus correlated with prolonged allograft survival. Optimal histocompatibility and cyclosporine administration further enhanced skin allograft survival in burned mice.
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Following a severe thermal injury (30% TBSA), 50% of the burned mice died within 48 hours. The immune response of the survivors was evaluated in vivo using the popliteal lymph node assay (PLNA) for host versus graft (HVG) or graft versus host (GVH) response. Suppression of GVH reactivity was observed using isolated splenocytes from burned mice harvested on postburn days 3, 8, and 11. Lymphocyte response evaluated in the burn environment using the HVG assay was profoundly deficient on postburn days 3 and 11. Recovery of immune function as determined by measurements of both responses occurred by postburn days 14-21, and coincided with wound healing. The PLNA proved to be a sensitive measure of immune function, and allowed for the evaluation of isolated cell populations, as well as measurement of lymphocyte function in the burn environment in the presence of circulating suppressor factors.
Two models were used to examine the role of prostaglandin (PGE) in the inductive phase of transfusion-induced suppression. First, it was observed that post-operative allogeneic third-party blood transfusion resulted in prolonged major histocompatibility complex (MHC)-compatible rat heart allograft survival. Additionally, pretransplant antigen-specific allogeneic transfusion decreased graft-versus-host (GVH) reactivity in mice. An inhibitor of PGE synthesis, indomethacin, blocked transfusion-induced suppression when it was administered to either transfused rat heart recipients, or graft-versus-host responder mice. Neutralization of endogenous PGE by anti-PGE antibody also blocked allogeneic blood induced suppression. Allogeneic-blood-induced splenic suppressor cells down-regulated normal GVH responsiveness, and appeared to be generated via a prostaglandin-dependent pathway.
MHC-disparate recipients that have been sensitized intradermally or via a skin graft reject transplanted mouse hearts hyperacutely. However, transplant survival is prolonged after intraperitoneal or intravenous sensitization. These opposite in vivo events are not correlated with differences in serum antibody responses, but the correlation of hyperacute rejection with delayed-type hypersensitivity is fairly strong. Prolonged survival of heart transplants is probably related to suppressor cells, and adoptively transferable in MHC-compatible combinations. Intraperitoneal or intravenous sensitization, while prolonging survival of heart transplants, causes hyperacute rejection of skin grafts, indicating the importance of the target; it is probably related to differences in the establishment of a blood supply.
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