This project will use clinical and experimental approaches to advance the hypothesis that activation of complement causes vascular injury in allografts and promotes AGA. The clinical finding that is most relevant to the renewal is that complement is deposited and can be detected in human heart transplants. Diffuse pericapillary deposits of complement were found in the first posttransplant endomyocardial biopsy from 25 of the 86 (29%) patients who received cardiac transplants at Johns Hopkins. Complement deposition correlated with early macrophage infiltration and subsequently with a higher incidence of AGA. In addition, complement deposition was more frequent in hearts transplanted to female recipients and in hearts from female and older donors. The animal model revealed that release of von Willebrand factor and p-selectin from endothelial cells and platelets is a primary feature of complement-mediated arterial injury. Based on these data, we have generated the hypothesis that complement and antibody mediate activation of macrophages and b cells in transplants. We will focus on the following testable model: (1) antibodies (elicited by previous pregnancies in women) bind endothelial cells and activate complement, (2) the complement split product C3b stimulates macrophage activation, (3) its end product C3d augments b cell production of antibodies to HLA and auto-antigens, (4) these elicited antibodies activate additional complement, and (5) arteries in hearts from female and older donors are more susceptible to complement mediated injury due to expressing lower levels of regulators complement activation. Each of these specific aims will be tested both in clinical material and experimental models. The clinical studies will validate data from the more easily manipulated experimental models in rats. We will make effective use of the Clinical/Pathology core for human specimens and the Animal Core for cardiac allografts in rats.
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Harris, Tamia A; Yamakuchi, Munekazu; Kondo, Maiko et al. (2010) Ets-1 and Ets-2 regulate the expression of microRNA-126 in endothelial cells. Arterioscler Thromb Vasc Biol 30:1990-7 |
Lowenstein, Charles J; Cameron, Scott J (2010) High-density lipoprotein metabolism and endothelial function. Curr Opin Endocrinol Diabetes Obes 17:166-70 |
Ferlito, Marcella; Fulton, William B; Zauher, Mohamed A et al. (2010) VAMP-1, VAMP-2, and syntaxin-4 regulate ANP release from cardiac myocytes. J Mol Cell Cardiol 49:791-800 |
Jeong, Youngtae; Chaupin, Damian F; Matsushita, Kenji et al. (2009) Aldosterone activates endothelial exocytosis. Proc Natl Acad Sci U S A 106:3782-7 |
Kirk, A D; Morrell, C N; Baldwin 3rd, W M (2009) Platelets influence vascularized organ transplants from start to finish. Am J Transplant 9:14-22 |
Murata, Kazunori; Baldwin 3rd, William M (2009) Mechanisms of complement activation, C4d deposition, and their contribution to the pathogenesis of antibody-mediated rejection. Transplant Rev (Orlando) 23:139-50 |
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