The Fibrosis-Immunity Interface in Corneal Transplantation

PROJECT SUMMARY/ABSTRACT Corneal transplantation is the most commonly performed type of solid-tissue transplantation in the world and T cell-mediated alloimmune rejection is the most common cause of corneal transplant failure. We have recently demonstrated that immune rejection leads to myofibroblast formation and the novel finding that myofibroblasts are capable of suppressing T cell alloimmunity. This preliminary data has laid the foundation for the present comprehensive research program in which we investigate the mechanisms by which myofibroblasts regulate effector T cell function and trafficking in corneal transplantation. In Specific Aim 1 we will define the precise mechanisms by which myofibroblasts regulate alloreactive effector T cell function. To complete this Aim, we will utilize a corneal myofibroblast and T cell co-culture system to identify and modulate candidate factors regulating T cell activation, proliferation, function and survival. We will then use a murine model of corneal transplantation to demonstrate the critical role of myofibroblast-derived factors in suppressing T cell alloimmunity, thereby improving corneal transplant survival in vivo. In Specific Aim 2, we will define the precise mechanisms by which myofibroblasts regulate alloreactive effector T cell trafficking to the transplanted corneal graft. To complete this Aim, we will utilize in vitro migration assays to determine how myofibroblasts regulate T cell chemotaxis and a corneal myofibroblast and vascular endothelial cell co-culture system to define how myofibroblasts regulate T cell extravasation. We will then modulate select myofibroblast-derived factors in our in vivo model of corneal transplantation to demonstrate their critical role in suppressing T cell infiltration of the transplanted corneal graft and graft rejection. The overarching goal of this research program is to investigate the relationship between myofibroblasts and alloreactive T cells in corneal transplantation, providing fundamental insights in a previously unexplored area. Ultimately, through this work we hope to leverage the immunosuppressive properties of myofibroblasts to identify and develop novel therapeutic strategies for the prevention and/or treatment of T cell-mediated immune rejection in corneal transplantation and other forms of solid-tissue organ transplantation.