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.
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|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|
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