The overall working hypothesis of this project is that there are multiple stages at which activation of complement (C) and evoked antibody (Ab) responses can contribute to the pathogenesis of AGA. The first specific aim is to investigate donor heart warm ischemia, which is an independent risk factor for C activation -- as well as AGA. Preliminary findings, which demonstrate that C deposition in perioperative endomyocardial biopsies correlates with ischemic damage, will be extended by yearly coronary angiography to identify potential associations with the subsequent development of AGA. The second specific aim focuses on those classes and subclasses of Ab that can activate C. Our passive transfer studies demonstrating that alloantisera can cause AGA in rats will be extended by using monoclonal Ab of different specificities to known MHC class I epitopes and Ab elicited to synthetic heat shock protein (HSP) peptides, or combinations of these (HSP peptides in autologous or allogeneic MHC), to identify their ability to augment AGA through C activation. These results will be correlated with studies inhibiting particular alloAb subclass production using CTLAR4Ig to block the development of AGA. Our recent finding that cardiac transplants in C6 deficient rats sustain profound, reversible endothelialitis which does not progress onto AGA indicates a potential critical role for the membrane attack complex (MAC) of C. Thus, our third specific aim is to assess the role of C components involved in this initial phase of AGA, while the fourth specific aim is to identify mediators between C6 deposition and smooth muscle proliferation in the subsequent phase of AGA. sCR1, which inhibits the C3 and C5 convertases, and inhibitory anti-C3a and C5a Ab, will be used to assess the contribution of specific C components to the first phase of AGA. Based on in vitro evidence that C5b-C9 (MAC) deposition on endothelial cells causes its release, platelet derived growth factor (PDGF) will be examined as a potential mediator in the second phase of AGA.
These aims are feasible in the highly interactive setting of this program project. Morphological analysis of different stages of AGA lesions will be augmented with physiological assessments by Dr. Flavahan (Project l). Studies on C mediated PDGF production will be extended to CMV induction of PDGF with Drs. Hayward (Project 2), and in vitro studies with Dr. Ballermann (Project 3). Studies of antibody responses to autoantigens (HSP) will be supplemented with studies of cellular autoimmunity by Dr. Hess (Project 5).
| Huang, Jie; Huffman, Jennifer E; Yamakuchi, Munekazu et al. (2014) Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2. Arterioscler Thromb Vasc Biol 34:1093-101 |
| Mammen, Andrew L; Mahoney, James A; St Germain, Amanda et al. (2011) A novel conserved isoform of the ubiquitin ligase UFD2a/UBE4B is expressed exclusively in mature striated muscle cells. PLoS One 6:e28861 |
| Wehner, Jennifer R; Fox-Talbot, Karen; Halushka, Marc K et al. (2010) B cells and plasma cells in coronaries of chronically rejected cardiac transplants. Transplantation 89:1141-8 |
| 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 |
| Soong, Thing Rinda; Pathak, Arvind P; Asano, Hiroshi et al. (2010) Lymphatic injury and regeneration in cardiac allografts. Transplantation 89:500-8 |
| 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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