IMPORTANCE OF CD49D-VCAM INTERACTIONS IN HUMAN MONOCYTE ADHESION TO PORCINE ENDOTHELIUM

By using a primate model of natural antibody depletion, we have previo usly shown that delayed rejection of porcine cardiac xenografts in unm odified primate recipients resulted from xenograft infiltration with m onocyte/macrophage lineage cells. In the present study, we initially s howed that human monocytes/macrophages demonstrated significantly grea ter adherence to unstimulated pig aortic endothelial cells (PAEC) than to human umbilical vein endothelial cells (HUVEC). Human TNF-alpha au gmented monocyte adhesion to HUVEC by 5-fold higher levels than to PAE C. This effect could not be explained on the basis of incompatibility between human TNF-alpha and its receptor on PAEC since porcine VCAM ex pression increased by 75-85% after stimulation with TNF-alpha. TNF-aug mented monocyte adherence was abrogated by either treatment of PAEC wi th an anti-VCAM Mab or monocytes with an anti-CD49d Mab. These results suggest that VCAM-CD49d interactions are important in adhesion of hum an monocytes to PAEC but may not be as effective as those between huma n monocytes and allogeneic endothelium, perhaps because of structural differences across species. Other interactions, as yet undefined, must explain the relative increase in adhesiveness of human monocytes for unstimulated PAEC versus HUVEC. In experiments investigating the funct ional consequences of this enhanced monocyte adherence, PAEC stimulati on induced 10-fold higher levels of macrophage-derived IL-1 beta and 3 -fold higher levels of T cell proliferation compared with HUVEC. Using an anti-DR Mab to interrupt antigen presentation by autologous macrop hages markedly reduced the T cell proliferative response to PAEC. Toge ther, these results indicate that the enhanced adherence of human mono cytes to PAEC contributes to xenograft rejection beyond the hyperacute period by leading to tissue infiltration, elaboration of cytokines, a nd an augmented indirect pathway of T cell xenoantigen recognition.