Paul J. Martin

A variety of malignancies can be cured by high dose chemotherapy and radiotherapy followed by hematopoietic reconstitution with allogeneic marrow or peripheral blood stem cells. Donor T lymphocytes present in the graft help to prevent rejection, initiate immune reconstitution, and eliminate residual malignant cells, but they also cause graft-versus-host disease (GVHD).

Previous studies have focused on characterizing the donor cells that prevent rejection. Results showed that donor T cells prevent marrow graft rejection in mice most effectively when they recognize antigens expressed by host effector populations that cause rejection. Results also showed that donor T cells must have a cytotoxic mechanism mediated either by Fas ligand or by granule exocytosis in order to prevent marrow graft rejection.

Donor T cells that recognize recipient alloantigens not only prevent rejection but also cause GVHD. We have developed a model system for studies of GVHD in mice by using T cell receptor-transgenic donor CD8 cells that recognize a recipient alloantigen with low, intermediate, or high avidity. This system makes it feasible to assess the effects of these cells in recipients and to determine the function and fate of the donor cells.

Results have shown that donor CD8 cells cause sustained GVHD when the T cell receptor has intermediate avidity for a recipient alloantigen, but not when the T cell receptor has high or low avidity for a recipient alloantigen. The goals of current studies are (1) to define the mechanisms that lead to tolerance when the T cell receptor has high avidity for a recipient alloantigen and (2) to determine the mechanisms of tissue injury when the T cell receptor has intermediate avidity for a recipient alloantigen.