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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29AI033054-01A3
Application #
2068022
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1995-01-01
Project End
1999-12-31
Budget Start
1995-01-01
Budget End
1995-12-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Rochester
Department
Surgery
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
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