Induction of adhesion molecules on the endothelia of rejecting cardiac allografts

Adhesion of leukocytes to vascular endothelium and their migration from the circulation into underlying tissue is regulated by an array of inducible cell adhesion molecules. We determined the kinetics and expression patterns of adhesion molecules expressed by the endothelia of rat cardiac allografts including the following: major histocompatibility complex class II (OX6), intercellular adhesion molecule-1 (1A29), vascular cell adhesion molecule-1 (5F10), leukocyte function-associated antigen-1 alpha-chain (WT.1), the common beta-chain of beta 2 integrins (WT.3), and very late activation antigen-4 (HP2.1) on inflammatory cells.

Intraabdominal heterotopic cardiac allografts (n = 12) were transplanted from the dark agouti (DA) rats (AG-B4, RT1a) to the Wistar-Furth (WF) rats (AG-B2, RT1v) strain and syngeneic controls (n = 12) were transplanted from dark agouti rat donors to dark agouti rat recipients. The grafts were removed 1, 3, and 5 days after transplantation, and cryostat sections were prepared for indirect immunoperoxidase staining with monoclonal antibodies. The intensity of adhesion molecule expression was scored from 0 to 3 in a blind review.

In nontransplanted dark agouti rat hearts, intercellular adhesion molecule-1 was constitutively expressed at a low level on capillary (0.5 +/- 0.5) and postcapillary venular (0.5 +/- 0.2) endothelia. In syngeneic controls, the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 was also faint and not induced, but a clear induction of class II expression was found on capillary endothelia. Large vessels stained negative for adhesion molecules. In allografts, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, but not class II, were significantly upregulated on capillary endothelia (p < 0.05). On postcapillary venular endothelia, a distinct induction (p < 0.05) of all three molecules was observed during acute rejection 5 days after transplantation. Concomitantly, the inflammatory leukocytes expressed high levels of leukocyte function-associated antigen-1 alpha-chain and beta-chain in the perivascular space. The expression of very late activation antigen-4 by lymphocytes was, however, nonexistent. In allograft arteries and arterioles, class II and vascular cell adhesion molecule-1, but not intercellular adhesion molecule-1, were weakly expressed during acute rejection.

Our results suggest that postcapillary venular endothelia may be the major site for leukocyte extravasation during acute cardiac allograft rejection in the rat model.