EXPRESSION OF VASCULAR CELL-ADHESION MOLECULE-1 IN KIDNEY ALLOGRAFT-REJECTION

VCAM-1, a leukocyte adhesion molecule expressed by cytokine-activated endothelial cells in culture, may mediate mononuclear leukocyte infilt ration in vessels and interstitium in solid organ allograft rejection. Using the avidin-biotin immunoperoxidase technique and an affinity-pu rified rabbit polyclonal antisera to recombinant human VCAM (rVCAM Ab) which works in methyl Carnoy's fixed tissues, we studied the expressi on of this molecule in biopsies of transplanted kidneys (N = 34) with and without features of rejection and allograft nephrectomies (N = 17) as well as nontransplanted control tissues (N = 26). The rVCAM Ab sho wed a population of reactive endothelial cells limited to sites of pro minent subendothelial leukocytic cell infiltration in arteries and vei ns, and occasional peritubular capillaries ( PTC) in rejecting allogra fts. Endothelial expression of VCAM was rarely identified in biopsies showing interstitial rejection only or cyclosporine toxicity, usually in PTC, and was only rarely encountered in nontransplanted control tis sues. Apparent de novo expression of VCAM-1 by arterial smooth muscle cells and mesangial cells was present in cases of severe rejection. In addition, a population of cells (DC) with dendritic morphology was id entified by rVCAM Ab within sites of lymphoid cell aggregation in reje cting allografts. Further evidence that these cells represent true DC was obtained by identification of VCAM-1 positive, morphologically sim ilar cells in both germinal centers and interfollicular areas of all s even reactive lymph nodes tested; and by similar staining of these cel ls in the allografts and lymph nodes by antibodies to nerve growth fac tor receptor and the complement receptor CRI, previously shown to reco gnize DC. DCs were generally not seen in uninflamed normal control org ans or portions of allografts uninvolved by lymphoid aggregates. Enhan ced tubular epithelial cell expression of VCAM-1 was also present in r ejecting allografts. All staining could be abolished by absorption of the antisera with VCAM-1 transfected, but not ICAM-1 or ELAM-1 transfe cted, CHO cells. In situ hybridization studies utilizing a cDNA probe to human VCAM-1 demonstrated mRNA production by glomerular, tubular an d vascular cells corresponding to sites where the protein was immunohi stochemically localized. This study provides evidence that: (1) endoth elial cell expression of VCAM-1 may define sites of acute vascular inf lammation in renal transplant rejection; (2) VCAM-1 is expressed by so me arterial smooth muscle cells during vascular rejection; (3) VCAM-1 expression by mesangial cells and tubular cells may be upregulated in transplant rejection; and (4) there is probably a population of VCAM-1 expressing DC that migrates into host kidneys. and participates in th e cellular rejection process.