The long-term objective of the applicant's research is to develop clinically applicable methods to attain durable function of porcine lung in man. In order to achieve this goal, specific mechanisms mediating hyperacute lung rejection of pig lungs perfused with human blood must be elucidated and controlled. Complement activation is an important mechanism mediating hyperacute rejection in porcine-to-primate xenotransplantation. We hypothesize that expression of human decay-accelerating factor (hDAF) in pig lung will inhibit complement activation in the lung and subsequently inhibit hyperacute rejection of the lung by human blood. We will evaluate the efficacy of transgenic hDAF expression on porcine endothelium in deterring the vasoconstrictive and cytotoxic events identified during hyperacute pulmonary rejection. We will also apply pharmacologic and biochemical studies to elucidate relative contributions of complement-dependent and - independent mechanisms of injury in our model of hDAF transgenic pulmonary xenotransplantation. With these studies we propose to determine whether complement inhibition, likely in conjunction with modulation of complement- independent mechanisms, will prove important in preventing hyperacute rejection of pulmonary xenografts.
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