Leukocyte endothelial cell interactions in pig to human organ xenograft rejection

Abstract

In cases where antibody- and complement-mediated hyperacute rejection (HAR) of vascularized organ xenografts has been prevented, acute vascular rejection (AVR) and acute T cell-mediated rejection (ACR) cause graft destruction. Infiltration of leukocytes (innate and graft-primed T cells) into the graft execute the latter two rejection modalities. The leukocyte extravasation process, which is a prerequisite for graft infiltration, is governed by adhesion molecules, including the selectin, integrin and immunoglobulin protein families, and the chemokine protein family. The compatibility between porcine endothelial cell and human leukocyte adhesion molecules was investigated in dynamic adhesion and static transendothelial migration assays. The effect of human anti-pig antibodies on human leukocyte adhesion to, and transendothelial migration across, porcine endothelium was assessed under dynamic and static conditions, respectively. In contrast to previously published results, no difference in the ability of neutrophils to adhere to pig and human endothelium was observed. Furthermore, no evident quantitative or qualitative differences in the capacity of human and porcine endothelium to support transendothelial migration of human leukocytes (T, B and natural killer (NK) cells, monocytes, and neutrophils) could be detected. The presence of human anti-pig antibodies (Abs) modulated the migration of leukocytes across porcine endothelium, as well as neutrophil adhesion to porcine endothelium under conditions of flow. Antibodies specific for pig endothelial adhesion molecules can potentially be used as species (graft)-specific immunosuppressive reagents in order to prevent cellular organ xenograft rejection.