Donor specific tolerance has the potential to prolong solid organ allograft survival and avoid the complications associated with non- specific immunosuppression. We created mixed allogeneic chimeras through transplantation of allogeneic and syngeneic T cell-depleted (TCD) bone marrows, and demonstrated that this chimerism effectively produces long- term tolerance to vascularized heart allografts across major and minor histocompatibility barriers. This approach has recently been extended to transplantation of the highly immunogenic small bowel allograft across these same barriers. Preliminary studies demonstrate bone marrow cells share sufficient antigens with small bowel grafts to prevent rejection by chimeras. The extent to which this tolerance depends upon peripheral chimerism, its resistance to breakage and graft-versus-host disease (GVHD) will be examined in the experiments of Specific Aim # 1. We will test the hypothesis: central tolerance depends upon an intrathymic persistence and sharing of alloantigens between donor bone marrow-derived thymic cells and the allograft.
Specific Aim #2 will examine presence of donor-derived intrathymic alloantigenic cells, the dependence of tolerance upon persistence of this alloantigen, and the ability of tolerant thymuses to transfer tolerance. Initial investigations into deletion-, and suppressor-based mechanisms will be made. Attempts to further separate the role of peripheral alloantigen from central alloantigen in tolerance induction will be made in Specific Aim #3 by looking at the effects on tolerance of chimeric cells maturing in syngeneic thymi, and elimination of chimerism after established tolerance. Tolerance will be stringently defined by the ability to cross highly incompatible full MHC barriers to the highly small bowel allograft. These experiments will lay the necessary groundwork for more detailed cellular and molecular investigations into the mechanisms of tolerance in bone marrow chimeras.
| Blom, D; Morrissey, N; Mesonero, C et al. (1998) Tolerance induction by intrathymic inoculation prevents chronic renal allograft rejection. Transplantation 65:272-5 |
| Blom, D; Morrissey, N J; Mesonero, C et al. (1996) Induction of specific tolerance through mixed hematopoietic chimerism prevents chronic renal allograft rejection in a rat model. Surgery 120:213-9;discussion 219-20 |
| Orloff, M S; DeMara, E M; Coppage, M L et al. (1995) Alterations of the interleukin-4 pathway in production of tolerance by mixed hematopoietic chimerism. Surgery 118:212-9 |
