Numerous clinical observations indicate that in certain patients alloantibodies probably contribute to rejection. Although some investigators have attributed a causal relationship to this association, there are still insufficient data to evaluate critically the mechanisms of such antibody-mediated acute allograft injury. Presently, the availability of inbred """"""""knock out"""""""" mice, monoclonal antibodies to critical mediators, and soluble recombinant receptors provide the means to establish a causative role of antibody in the in vivo pathogenesis of acute graft rejection. Recent in vitro studies have demonstrated that antibodies and complement can initiate dynamic interactions among endothelial cells, macrophages and platelets that are mediated by adhesion molecules and their ligands. The potential role of these receptors and their ligands has not been examined in acute alloantibody-mediated rejection. The hypothesis to be tested in this proposal is that alloantibody and complement mediate acute cardiac rejection by activating endothelial cells, macrophages and platelets through ,expression of P-selectin and von Willebrand factor. The proposed studies are based upon our extensive preliminary data from cardiac allograft models in complement deficient rats as well as immunoglobulin knock out (IgKO), C4, C3 and CR2 KO mice.
The specific aims of this project will test our hypothesis by demonstrating that: 1. Passive transfer of complement-activating classes and subclasses of mAbs specific for donor MHC antigens can reconstitute cardiac allograft rejection in IgKO mice and cause the upregulation of P- selectin, von Willebrand factor, and MCP-l in endothelial cells. 2. Passive transfer of non-complement-fixing subclasses of mAbs specific for donor MHC antigens will modulate in a dose-dependent manner cardiac allograft rejection induced in IgKO mice by complement-activating subclasses of mAbs with the same specificity. 3. Activation of endothelial cells, B-cells, platelets and macrophages by antibody mediated acute rejection is inhibited in C4, C3 and CR2 KO mice resulting in prolonged cardiac allograft survival. 4. P-selectin augments activation of endothelial cells, platelets and macrophages in allograft rejection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063948-02
Application #
6390579
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Massicot-Fisher, Judith
Project Start
2000-07-24
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$327,000
Indirect Cost
Name
Johns Hopkins University
Department
Pathology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Lee, Chih-Yuan; Lotfi-Emran, Sahar; Erdinc, Melek et al. (2007) The involvement of FcR mechanisms in antibody-mediated rejection. Transplantation 84:1324-34
Murata, K; Fox-Talbot, K; Qian, Z et al. (2007) Synergistic deposition of C4d by complement-activating and non-activating antibodies in cardiac transplants. Am J Transplant 7:2605-14
Yamakuchi, Munekazu; Kirkiles-Smith, Nancy C; Ferlito, Marcella et al. (2007) Antibody to human leukocyte antigen triggers endothelial exocytosis. Proc Natl Acad Sci U S A 104:1301-6
Qian, Zhiping; Lee, Chih-Yuan; Murata, Kazunori et al. (2006) Antibody and complement mediated injury in transplants following sensitization by allogeneic blood transfusion. Transplantation 82:857-64
Minami, K; Murata, K; Lee, C-Y et al. (2006) C4d deposition and clearance in cardiac transplants correlates with alloantibody levels and rejection in rats. Am J Transplant 6:923-32
Qian, Z; Liu, J; Fox-Talbot, K et al. (2005) A rat model of pregnancy-induced sensitization to transplants. Transplant Proc 37:96-7
Qian, Z; Bieler, J G; Baldwin 3rd, W M et al. (2005) Expression of CR1/2 receptor on alloantigen-stimulated mouse T cells. Transplant Proc 37:32-4
Nakashima, Shinji; Soong, T Rinda; Fox-Talbot, Karen et al. (2005) Impact of MHC class II incompatibility on localization of mononuclear cell infiltrates to the bronchiolar compartment of orthotopic lung allografts. Am J Transplant 5:694-701
Baldwin 3rd, William M; Kasper, Edward K; Zachary, Andrea A et al. (2004) Beyond C4d: other complement-related diagnostic approaches to antibody-mediated rejection. Am J Transplant 4:311-8

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