P. Kwiatkowski et al., IMPORTANCE OF CD49D-VCAM INTERACTIONS IN HUMAN MONOCYTE ADHESION TO PORCINE ENDOTHELIUM, Xenotransplantation, 5(1), 1998, pp. 67-74
Citations number
21
Categorie Soggetti
Transplantation,"Medicine, Research & Experimental
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.