CD28-B7 BLOCKADE IN ORGAN DYSFUNCTION SECONDARY TO COLD ISCHEMIA REPERFUSION INJURY - RAPID COMMUNICATION/

Ischemic injury to cadaver organs is a major risk facto; for developme nt of chronic organ dysfunction. We have recently shown that the B7 co stimulatory pathway plays a critical role in early organ dysfunction d eveloping after renal cold ischemia/reperfusion injury. We extended th ese observations to investigate the role of this pathway in the develo pment and progression of chronic organ dysfunction following such inju ry. Uninephrectomized rats which underwent cold ischemia/reperfusion i njury developed progressive proteinuria as compared to uninephrectomiz ed controls. Animals treated with CTLA4Ig, which blocks B7 costimulati on, starting on the day of injury had significantly better long-term s urvival and developed significantly less proteinuria than control anim als treated with control Ig. RT-PCR analysis of kidney tissue showed s ignificant reduction in expression of activation and inflammatory cyto kines, chemoattractants, and growth factors, as compared to controls. Delaying administration of CTLA4Ig for one week, but not four weeks, a fter injury was still effective in ameliorating development of progres sive proteinuria. Interestingly, selective blockade of B7-1 by a mutan t form of CTLA4Ig had no effect on early or chronic organ dysfunction. These findings indicate the long-term functional and molecular conseq uences of experimental cold ischemia/reperfusion injury, and suggest t hat B7-2 is critical in the development of organ dysfunction following ischemic injury even in the absence of alloantigen.