The long term objectives of this project are to understand the factors that contribute to corneal graft allogenicity, and identify potential mechanisms whereby graft survival can be enhanced by immunologic manipulation of the host or donor cornea. Although corneal transplantation is a common and highly successful means of treating blindness due to corneal incompetence, it is estimated that over 2500 corneal grafts are rejected in the U.S. annually. In addition, the mechanisms of immunologic host sensitization and responsiveness to corneal tissue remain unclear. Using PVG.R1 and PVG.1A congenic rat strains which differ from the PVG strain only at the major class I MHC locus (RT1.A) and the entire rat MHC respectively, we have recently characterized: the nature of humoral and cellular responsiveness to intact allogeneic cornea as well as its separate components; the expression of MHC antigen expression in rat corneas; and the relative influence of class I and class II MHC antigens expression in the cornea on inducing allogeneic responses. Experiments are proposed to determine whether MHC antigen expression and corneal immunogenicity can be affected in this model by treatments with known MHC antigen modulators such as hyperbaric oxygen, anti-donor class I and class II MHC monoclonal antibodies, and allogeneic lymphocytes. Similarly, the potential effects of recipient therapy using donor blood transfusions and anti-donor MHC antisera will be examined in terms of enhancing graft survival by reducing host responsiveness or donor cornea immunogenicity. Finally, we will employ a combination of in vivo adoptive transfer and in vitro third party MLC/CML studies to examine the cellular and molecular mechanisms involved in these models of corneal allograft rejection and enhancement.
