Monocyte-endothelial interactions in the pathogenesis of delayed xenograft rejection.
Published: 2005
Language: eng
Number of pages: 192
Description: Hallmarks of delayed xenograft rejection include monocyte infiltration, endothelial cell activation and disruption of the endothelial barrier. The monocyte is an important initiator of this type of rejection because monocytes accumulate within hours after xenografting and prior monocyte depletion suppresses the development of this type of rejection. However, the mechanisms that mediate monocyte-induced xenograft injury are unclear at present. In Chapter 2 we report that human monocytes activate xenogeneic endothelial cells through calcium signals. Monocyte contact with porcine but not human endothelium leads to an endothelial calcium transient mediated via a G-protein coupled receptor that results in upregulation of porcine VCAM-1 and E-selectin. Although human monocyte adhesion was greater to porcine than to human endothelium, especially when studied under laminar flow, blockade of the xeno-specific endothelial calcium signals did not reduce adhesion of human monocytes to porcine endothelium. Human monocyte contact to porcine endothelium also resulted in reorganization of the F-actin cytoskeleton with a concomitant increase in endothelial monolayer permeability. In contrast to the effect on adhesion, these changes appear to be regulated through endothelial calcium signals. Taken together, these data suggest that human monocytes are capable of activating xenogeneic endothelial cells through calcium transients, as well as other distinct pathways.In Chapter 3, we further define the mechanism of human monocyte adhesion to xenogeneic endothelial cells under conditions of physiological flow. In contrast to allogeneic leukocytes that require upregulation of endothelial adhesion molecules and chemokines in order to adhere and emigrate into effector tissues, we demonstrate that human monocytes adhere rapidly to unstimulated xenogeneic endothelial cells. The major xenoantigen Galalpha(1,3)Galbeta(1,4)GlcNAc-R (alpha-gal) is abundantly expressed on xenogeneic endothelium. We have identified a putative receptor for alpha-gal on human monocytes that is a member of the C-type family of lectin receptors. Monocyte arrest under conditions of laminar flow is regulated by alpha-gal, since alpha-gal cleavage or blockade results in a dramatic reduction in monocyte adhesion. Recruitment of human monocytes to unactivated xenogeneic endothelial cells requires both alpha4 and beta2 integrins on the monocyte. Binding of alpha-gal to monocytes results in rapid activation of beta2 but not alpha4 integrins. Thus, activation of monocyte beta2 integrins by alpha-gal expressed on xenogeneic endothelium provides a mechanistic link that may explain the dramatic accumulation of monocytes in xenografts in vivo.
Notes: Source: Dissertation Abstracts International, Volume: 66-10, Section: B, page: 5311.

Thesis (Ph.D.)--University of Toronto, 2005.

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