ENDOTHELIAL ACTIVATION AND CYTOKINE EXPRESSION IN HUMAN ACUTE CARDIACALLOGRAFT-REJECTION

By extrapolation from the responses of cultured human umbilical vein e ndothelial cells (EC) and bovine aortic EC to short-term cytokine stim ulation, EC activation is postulated as a likely component of the host response in acute allograft rejection and cardiac transplant-associat ed accelerated arteriosclerosis, To investigate the extent to which EC activation occurs in vivo in humans and to identify potential targets for therapeutic interventions, we compared the phenotypic characteris tics of vascular EC as seen during clinicopathologically significant v s non-significant acute cardiac allograft rejection. We used monoclona l and monospecific polyclonal antibodies to coagulation molecules [tis sue factor, thrombomodulin (TM), antithrombin III fibrinogen/fibrin, c ross-linked fibrin and von Willebrand factor (vWF)], adhesion molecule s (P-selectin, ICAM-1) and major histocompatibility complex (MHC) clas s I and II molecules, In addition we sought evidence of local cytokine production (IL-l, IL-2R, IL-4, IL-6, IL-7, IL-8, TNF-alpha, PDGF-AA, PDGF-BB), which might mediate alterations in expression of these prote ins. We found that in clinically significant grades of cardiac allogra ft rejection requiring increased immunosuppression, in contrast to les ser grades of rejection not requiring clinical intervention, there was increased microvascular EC activation and differential expression of cytokines. EC changes associated with more extensive cardiac allograft rejection requiring treatment included: (i) disruption of the normal anticoagulant state with downregulation of TM and AT-III, upregulation of tissue factor and vWF expression, and associated extensive fibrin deposition; (ii) upregulation of MHC class I antigens, which are poten tial targets for host cytotoxic T lymphocytes; (iii) increased express ion of the leucocyte adhesion molecules P-selectin and ICAM-1; (iv) ex pression of the pro-inflammatory cytokines IL-1 beta and TNF-alpha; an d (v) increased expression of PDGF-AA and BE, which are known to promo te migration and proliferation of intimal cells, and hence may contrib ute to development of transplant-associated atherosclerosis. Collectiv ely these findings suggest that im mune events resulting in EC surface changes and/or production of key cytokines play a role in the pathoge nesis of acute transplant rejection and may contribute to the long-ter m complication of accelerated arteriosclerosis in allograft coronary a rteries.