This is a competitive renewal for an RO1 to apply mixed bone marrow chimerism to induce tolerance for primarily vascularized allografts. The applicants propose to continue their studies to apply mixed chimerism, with all of its advantages, to induce donor specific transplantation tolerance for solid organ allografts and to identify factors that will enable clinical application of this model. They will focus on three specific aims.
The first aim i s to achieve mixed chimerism with a nonlethal conditioning approach, since their current approaches require lethal recipient ablation, which cannot be justified in efforts to induce tolerance for solid organ grafts.
The second aim i s to define and characterize the host cell populations that constitute space (hematopoietic niche) and those that comprise alloresistance to engraftment in order to allow a specific approach to achieve chimerism and tolerance by targeting specific cellular populations in the host. The third specific aim is to examine whether chronic rejection of primarily vascularized allografts occurs or is prevented in mixed chimerism.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Allegheny University of Health Sciences
Schools of Medicine
United States
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Brouha, P C; Ildstad, S T (2001) Mixed allogeneic chimerism. Past, present, and prospects for the future. Transplantation 72:S36-42
Neipp, M; Gammie, J S; Exner, B G et al. (1999) A partial conditioning approach to achieve mixed chimerism in the rat: depletion of host natural killer cells significantly reduces the amount of total body irradiation required for engraftment. Transplantation 68:369-78
Neipp, M; Exner, B G; Maru, D et al. (1999) T-cell depletion of allogeneic bone marrow using anti-alphabetaTCR monoclonal antibody: prevention of graft-versus-host disease without affecting engraftment potential in rats. Exp Hematol 27:860-7
Exner, B G; Acholonu, I N; Bergheim, M et al. (1999) Mixed allogeneic chimerism to induce tolerance to solid organ and cellular grafts. Acta Haematol 101:78-81
Exner, B G; Domenick, M A; Bergheim, M et al. (1999) Clinical applications of mixed chimerism. Ann N Y Acad Sci 872:377-85;discussion 385-6
Neipp, M; Exner, B G; Ildstad, S T (1998) A nonlethal conditioning approach to achieve engraftment of xenogeneic rat bone marrow in mice and to induce donor-specific tolerance. Transplantation 66:969-75
Colson, Y L; Li, H; Boggs, S S et al. (1996) Durable mixed allogeneic chimerism and tolerance by a nonlethal radiation-based cytoreductive approach. J Immunol 157:2820-9
Colson, Y L; Lange, J; Fowler, K et al. (1996) Mechanism for cotolerance in nonlethally conditioned mixed chimeras: negative selection of the Vbeta T-cell receptor repertoire by both host and donor bone marrow-derived cells. Blood 88:4601-10
Kaufman, C L; Chambers, W H; Ildstad, S T (1993) Coexpression of NKR-P1 and alpha beta-TCR on lymphoid cells in fully xenogeneic (rat-->mouse) chimeras and syngeneically reconstituted (A-->A) rats. J Immunol 151:6002-11
Cooper, M H; Nalesnik, M A; Watkins, S C et al. (1993) Cross-species graft-versus-host-disease is accompanied by a donor-derived cellular immune response. Transplantation 56:934-40

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