This proposal outlines studies designed to accomplish xenogeneic organ transplantation after establishing specific tolerance to these donors. Recently, an experimental system has been developed in which lethally irradiated mice have been reconstituted with syngeneic T-cell depleted bone marrow plus a larger inoculum of xenogeneic bone marrow. Evidence has been presented showing that these """"""""mixed"""""""" xenogeneic chimeras are generally immunocompetent but specifically hyporesponsive to the xenogeneic donor. This tolerance is not complete, however, and preliminary studies suggest that humoral mechanisms are responsible for chronic xenogeneic rejection in this system. The studies outlined here will develop further this transplantation model: first, to characterize the humoral mechanisms of rejection; second, to manipulate these humoral responses to accomplish more complete tolerance; and third, to modify the system to avoid the need for whole body irradiation in order to allow clinical application of these promising experiments. These studies will add to our understanding of the important biological and clinical problem of xenografting. They will also create a system for studying humoral rejection in both presensitized patients and those suffering chronic allograft rejection. Finally, they represent another effort to develop a clinically applicable method of accomplishing specific tolerance for organ transplantation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL036372-07
Application #
3351335
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1986-04-01
Project End
1994-11-30
Budget Start
1992-12-01
Budget End
1993-11-30
Support Year
7
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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Auchincloss Jr, H; Sultan, H (1996) Antigen processing and presentation in transplantation. Curr Opin Immunol 8:681-7
Steele, D J; Laufer, T M; Smiley, S T et al. (1996) Two levels of help for B cell alloantibody production. J Exp Med 183:699-703
Wecker, H; Grusby, M J; Auchincloss Jr, H (1995) Effector cells must recognize antigens expressed in the graft to cause efficient skin graft rejection in SCID mice. Transplantation 59:1223-7
Steele, D; Wallstrom, A; Bleier, K J et al. (1994) Transplantation of pancreatic islets in diabetic nonhuman primates. Transplant Proc 26:3317-8
Auchincloss Jr, H (1994) Cell-mediated xenoresponses: strong or weak? Clin Transplant 8:155-9
Lee, R S; Grusby, M J; Glimcher, L H et al. (1994) Indirect recognition by helper cells can induce donor-specific cytotoxic T lymphocytes in vivo. J Exp Med 179:865-72
Auchincloss Jr, H; Lee, R; Shea, S et al. (1993) The role of ""indirect"" recognition in initiating rejection of skin grafts from major histocompatibility complex class II-deficient mice. Proc Natl Acad Sci U S A 90:3373-7
Grusby, M J; Auchincloss Jr, H; Lee, R et al. (1993) Mice lacking major histocompatibility complex class I and class II molecules. Proc Natl Acad Sci U S A 90:3913-7
Lee, R; Glimcher, L H; Auchincloss Jr, H (1993) Evidence that a ""four-cell cluster"" may prime cytotoxic T-cells during graft rejection. Transplant Proc 25:847-9

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