Defining the mechanisms of graft rejection has important clinical implications for developing specific therapies aimed at treating or preventing graft rejection. T cell activation, a critical first step in graft rejection in vivo, is know to involve two signals: antigen and an inductive signal. In vitro, studies have shown that these signals need not be received simultaneously or even be provided by the same cell.
The aim of this project is to investigate, in vivo, the validity of these in vitro phenomena. The project investigates, in two parts, the requirements for T cell activation and effector function in the islet allograft model. The first study addresses whether the two signals required for T cell activation, antigen and an inductive signal, can be provided by different cells in vivo. To address this, lymphokines (the inductive signal) will be provided by inducing a graft versus host reaction at varying distances form an established islet allograft carrying recognizable antigen. The question is how close must the graft versus host reaction, and therefore the lymphokine production, be to the graft to result in rejection. Additionally, it will be possible to answer whether specifically sensitized cells are activated or whether a nonspecific mechanism is responsible for the graft rejection. A related study addresses which lympholines are involved in the expression of the effector function of class I MHO reactive T cells. T cells specifically sensitized to graft antigens will be treated with Cyclosporin A (CSA) to block endogenous lymphokine production. The animals, also treated with CSA for the same reason, will be transplanted with the sensitized T cells, and then infused with purified lymphokines (IL-2, IF, IL-3). Which lymphokine(s) is/are required to reconstitute the effector function of the T cells, and thereby facilitate graft rejection, can be examined.
| Babcock, S K; Appel, V B; Schiff, M et al. (1989) Genetic analysis of the imperfect association of H-2 haplotype with lupus-like autoimmune disease. Proc Natl Acad Sci U S A 86:7552-5 |
| Babcock, S K; Georgiu, H; Kotzin, B et al. (1989) Cyclosporin-induced autoimmunity: a role for marrow-derived cells presenting self antigens in the thymus. Transplant Proc 21:220-1 |
