This continuation application is based on our novel finding that a deficiency of C6, which prevents assembly of the membrane attack complex (MAC), can delay acute allograft rejection from 7-10 days to greater than 6 weeks. This finding is of potential importance for 4 reasons. First, it demonstrates that complement (C), which is not suppressed adequately by conventional immunosuppressive agents used clinically, can play a significant role in acute allograft rejection. Second, this does not appear to be a strain-specific or anecdotal effect, because acute rejection is inhibited in all of the high responder strains into which we have now bred the C6 deficiency. Third, the effects C6 deficiency are not limited to one type of vascularized allografts, but affects transplants of both heart and lung. Fourth, C6 deficiency delays both acute rejection and chronic graft vasculopathy. Preliminary data indicate that donor and recipient sources of C6 can contribute to graft injury and rejection. Our hypothesis is that C from donor and recipient sources contribute to early tissue injury initiated by physiological stress as well as antibody deposition.
The specific aims are to test mechanisms that control C6 production and activation in allografts. We will use an interrelated series of in vivo experiments that take advantage of congenic C6 deficient rat strains that we have bred to determine: 1) the source of C6 in acute injury cardiac and lung transplants, 2) the source of C6 in chronic vasculopathy and obliterative bronchiolitis, and 3) the role of altered expression of membrane-associated C regulators. The experimental approach will utilize the novel C6 deficient strains of rats that we developed in the first funding period of this project for both in vivo cardiac transplant studies and as sources of C6 deficient cells for in vitro studies. Most importantly, we will use our extensive clinical material to verify the relevance of our experimental findings to humans.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Bridges, Nancy D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
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
Soong, Thing Rinda; Pathak, Arvind P; Asano, Hiroshi et al. (2010) Lymphatic injury and regeneration in cardiac allografts. Transplantation 89:500-8
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
Morrell, Craig N; Murata, Kazunori; Swaim, Anne Marie et al. (2008) In vivo platelet-endothelial cell interactions in response to major histocompatibility complex alloantibody. Circ Res 102:777-85
Lee, Maria Teresa; Parwani, Anil; Humphrey, Richard et al. (2008) Gamma heavy chain disease in a patient with diabetes and chronic renal insufficiency: diagnostic assessment of the heavy chain fragment. J Clin Lab Anal 22:146-50
Murata, Kazunori; Iwata, Takekazu; Nakashima, Shinji et al. (2008) C4d deposition and cellular infiltrates as markers of acute rejection in rat models of orthotopic lung transplantation. Transplantation 86:123-9
Lee, Chih-Yuan; Lotfi-Emran, Sahar; Erdinc, Melek et al. (2007) The involvement of FcR mechanisms in antibody-mediated rejection. Transplantation 84:1324-34
Wasowska, Barbara A; Lee, Chih-Yuan; Halushka, Marc K et al. (2007) New concepts of complement in allorecognition and graft rejection. Cell Immunol 248:18-30
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

Showing the most recent 10 out of 31 publications