Tolerance induction permits the development of graft-versus-host disease: donor-mediated attack following small bowel transplantation in mixed chimeras

The induction of tolerance to organ allografts would eliminate acute and ch ronic rejection as well as the need for nonspecific immunosuppression. We h ave shown that tolerance induced through the creation of mixed allogeneic b one marrow chimeras allows for the long-term engraftment of cardiac and sma ll bowel allografts across strong multiple major histocompatibility barrier s. The possibility that tolerance might render the host susceptible to graf t-versus-host disease (GVHD) has not been investigated in this or other mod els of tolerance. To test this possibility chimeras were created by transpl antation of T-cell depleted ACI and Lewis bone marrow into lethally irradia ted Lewis rats. Chimerism was determined post bone marrow transplant (BMTx) by flow cytometry of lymphocytes from reconstituted animals. ACI/Lew chime ras (ALC), Lewis/ACI F-1 (LACF(1)), and Lewis (LEW) rats all received heter otopic ACI vascularized small bowel grafts. A second group of chimeras rece ived small bowel grafts from ACI rats pretreated with low dose irradiation to eliminate T-cells from the graft. LEW-->LEW small bowel isografts were a lso performed. Animals were examined for evidence of GVHD by clinical signs and histologic examination of biopsied tissues. GVHD was quantified using the popliteal lymph node enlargement assay. All LACF(1) rats developed seve re lethal GVHD following ACI small bowel transplant. Bone marrow chimeras, ALC (n = 6), developed fatal GVHD in a similar fashion after receiving a sm all bowel transplant. LEW-->LEW isografts and chimeras receiving bowel from irradiated ACI rats survived long term without GVHD while ACI-->LEW alloge neic transplants all underwent acute rejection. GVHD or its absence was con firmed histologically. Popliteal lymph node enlargement indices reflected t he presence of GVHD in the chimeras (1.87) and LACF(1) (5.4) receiving allo grafts, but not in isografts or chimeras receiving irradiated allogeneic tr ansplants. Analysis of cytokines in the tongues of rats undergoing GVHD sho wed elaboration of Th1 type proinflammatory cytokines which was not seen in isografted rats or rats receiving preirradiated small bowel. These results demonstrate that tolerance induction through mixed chimerism results in su sceptibility to smalt bowel induced GVHD. Preirradiating the donor bowel pr ior to SBTx can prevent GVHD.