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,
Departments of
*
Immunology,
Pediatrics, and
Surgery, Duke University Medical Center, Durham, NC 27710
Many obstacles still prevent successful xenotransplantation of
porcine donor organs. When hyperacute rejection is averted,
transplanted pig organs are subject to acute vascular and cellular
rejection. In autologous systems, leukocyte recruitment into inflamed
tissues involves selectins, integrins, and Ig family members. To
determine whether these mechanisms allow human leukocytes to
effectively enter porcine grafts, the pathways by which human
leukocytes adhere to TNF-
-stimulated porcine aortic endothelium were
examined under static and physiologic flow conditions. L-selectin and
E-selectin had overlapping functions in neutrophil capture and rolling,
whereas Ab blockade of E-selectin and the ß2 integrins
inhibited firm arrest of rolling neutrophils. Combined blockade of
selectins and ß2 integrins resulted in negligible human
neutrophil attachment to pig endothelium. Lymphocyte attachment to
porcine endothelium was primarily L-selectin mediated, whereas
ß2 integrin and VCAM-1/very late Ag-4 (VLA-4)
interactions promoted static adhesion. Concurrent ß2
integrin, VLA-4, VCAM-1, and L-selectin blockade completely inhibited
lymphocyte attachment. Thus, interactions between leukocyte-endothelial
cell adhesion receptor pairs remained remarkably intact across the
human-porcine species barrier. Moreover, disrupting the adhesion
cascade may impair the ability of human leukocytes to infiltrate a
transplanted porcine organ during rejection.
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