In the first four years of this project, the investigators have shown that rat ACI vascularized heart allografts are accepted by Lewis hosts with a combination of TLI, ATG, and intravenous injections of donor cells. With one model, the results showed that donor cells, such as monocytes and dendritic cell precursors, with surface expression of class II MHC molecules but with incomplete expression of co-stimulatory molecules such as B7-1 and B7-2, were potent facilitators of nonchimeric tolerance, based on immune deviation rather than on clonal anergy or clonal deletion. In a second model, donor cell infusions containing hematopoietic stem cells, such as bone marrow, were potent facilitators of chimeric tolerance, which was best explained by clonal anergy or deletion. Tolerance required both an alteration of the host immune system by the preparatory regimen and the injection of an appropriate donor cell population in both models. Additional data show that NK1.1+ T-cells are an important component of the host tolerance response. In particular, these cells seem to be important for the production of IL-4 that is required for tolerance. The studies proposed here will test the hypothesis that TLI causes an increase in NK1.1+ T-cells, such that they become the predominant subset of T-cells in the spleen; that activation of the host NK1.1+ T-cells, and their secretion of IL-4, is required for the induction of tolerance; and that donor cells that facilitate tolerance activate host NK1.1+ T-cells by donor cell expression of CD1. In order to test the hypothesis further, they will use mice that lack NK1.1+ T-cells (CD1 or Jalpha281 KO) or lack specific cytokines (IL-4 KO, IL-10 KO, IFNgamma KO). In addition, they will use donor mice that lack specific antigen presenting molecules (CD1 KO, MHC Class II KO). They propose to study the role of NK1.1+ T-cells and their IL-4 secretion in tolerance by TLI, TLI plus ATG, and a depleting anti-CD4 mAb in a heart transplant model. They will also study GVHD using similar hypotheses and models. Mice tolerant of their allografts will be observed for evidence of immune deviation, clonal anergy or deletion, chimerism, and allograft expression of cytokine mRNA.
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