Chronic allograft rejection is the single most common cause of allograft failure after the first year of transplantation. It is a significant cause of end stage renal disease (ESRD) in children and may be as frequent a cause of ESRD as any other disease entity. In the pediatric population 19.1% of children on dialysis have had at least one previous renal transplant. Further understanding and improved treatment of chronic rejection is of critical importance in pediatrics as it will decrease the number of children requiring dialysis therapy and will optimize transplantation as a successful treatment modality for children. Chronic rejection has all the hallmarks of a chronic inflammatory process defined as inflammation of prolonged duration in which active inflammation tissue destruction and attempts at healing proceed simultaneously. The vascular endothelium participates in all events that lead to chronic rejection, from the initial lymphocyte encounter to the angiogenesis of the healing process. Angiogenesis has been previously described in transplant rejection in association with lymphocytic infiltration of the graft, and has been noted within the proliferative intima of graft arteriosclerosis lesions. However, very little is known of the initiation or progression of angiogenesis in rejection. Moreover, no study has evaluated the functional consequences of angiogenesis for chronic rejection. Our hypotheses predict that 1) alloactivated CD4+ T cells promote angiogenesis, and 2) that angiogenesis facilitates leukocyte entry into allografts to promote the development of chronic allograft rejection. Our overall objective is to define a pathophysiologic function for angiogenesis in chronic rejection.
Specific aims are designed to: 1) explore interactions among the endothelium, alloreactive CD4+ T cells and angiogenesis factors such as vascular endothelial growth factor (VEGF); and 2) to explore the functional effect of inhibition of angiogenesis in acute and chronic rejection in the F344 into LEW rat renal allograft model. The proposed studies will provide valuable information regarding the role of angiogenesis in rejection. Such knowledge may be the basis for developing new therapeutic agents to modulate or dysregulate the angiogenesis reaction and chronic allograft rejection.
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