Transplantation has become widely accepted as the treatment of choice for end-stage organ failure. Unfortunately, transplanted organs eventually fail as a result of immunologic reactions resulting in two distinct processes called acute and chronic rejection. Acute rejection typically occurs early within the first few months following transplantation. In contrast, chronic rejection is more insidious and takes years to develop. Current treatments for rejection involve immunosuppressive medications and have been most successful at preventing acute rejection. There is currently no treatment for chronic rejection. In this research proposal, we have identified a molecule called vascular endothelial growth factor (VEGF) as a mediator of inflammation in the transplanted organ. VEGF is induced in tissues when there is a lack of oxygen and it promotes signals that result in immune cells being recruited into the tissue. Since transplantation characteristically involves organs that have been without oxygen for a period of time, we suggest that VEGF expression will also be a characteristic feature of transplantation. If VEGF is expressed, it may function to mediate immune rejection of the organ. However, this is entirely unexplored. We will first test whether VEGF is expressed and whether it is functional in organs as a result of a lack of oxygen or whether other factors associated with rejection mediate its expression. To block VEGF, we plan to administer an anti-VEGF antibody to mice following transplantation. We will also use this antibody with conventional immunosuppressive medications to determine whether it improves outcomes. We have several mice and reagents that will enable us to determine how VEGF promotes inflammation in the transplanted organ. Together, we believe these studies have the potential to identify VEGF as a therapeutic target for the future.
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