THE ROLE OF THE B7 COSTIMULATORY PATHWAY IN EXPERIMENTAL COLD ISCHEMIA REPERFUSION INJURY/

Ischemia/reperfusion injury associated with organ retrieval and storag e influences the development of chronic graft dysfunction, the major c linical problem in solid organ transplantation. The potential role of mononuclear cells (T cells and monocyte/macrophages) in this type of i njury is unknown. Inbred male Lewis rats were uninephrectomized and th e left kidney perfused in situ with 10 ml of iced University of Wiscon sin solution. Immunohistological studies showed mononuclear cell infil tration of the ischemic organs associated with the upregulation of MHC class II antigen expression. Reverse transcriptase-PCR indicated that T cell associated cytokines and monocyte/macrophage activation marker s/products are upregulated early after the ischemic insult. B7 express ion occurred within 24 h and peaked at 3 d. Plasma creatinine levels r ose transiently with complete recovery of renal function by 5 d. Anima ls began to develop progressive proteinuria after 8-12 wk, indicative of the long-term functional consequences of early ischemia/reperfusion injury. Blockade of T cell CD28-B7 costimulation with CTLA4Ig resulte d in significant inhibition of T cell and macrophage infiltration and activation in situ. Treated animals did not exhibit transient renal dy sfunction, nor developed proteinuria over time. This is the first demo nstration that blocking T cell costimulatory activation in the absence of alloantigen can prevent the early and late consequences of ischemi a/reperfusion injury.