This project is designed to be a systematic assessment of major factors that contribute to the pathogenesis of cardiac transplant arteriopathy. The investigators will employ an experimental system of our design in which mouse hearts, transplanted between defined strains, develop advanced obstructive coronary atherosclerotic lesions while the remainder of the heart is relatively free of rejection activity. They have shown that coronary lesions can be the result of cellular or humoral immune responses in isolation from one another. They will now determine the relative importance of the """"""""direct"""""""" and """"""""indirect"""""""" pathways of cellular activation in causing this process by employing newly created """"""""knockout"""""""" mice in which these pathways can be isolated. The investigators will also establish the relative importance of Th1 versus Th2 cell activation systems and will seek to influence the predominance of one or the other by appropriate cytokine treatment. The mechanism by which humoral immunity incites lesion formation will be pursued using fractions of an antiserum known to produce arteriopathy on transfer to scid recipients bearing surviving heart transplants. The involvement of complement in this process will also be ascertained and the potential for blocking the development of vascular lesions by inactivating certain cell adhesion processes, such as ICAM 1/LFA 1, VCAM 1/VLA 4, and fibronectin systems, will be explored. The potential for the late appearance of coronary lesions after a transplanted heart has been fully protected for an extended period by profound immunosuppression and the susceptibility of lesions to reversal at various times after transplantation will also be investigated. The possibility that """"""""organ specific"""""""" antigens contribute to the immune events that lead to arteriopathy will be approached using recipients fully tolerant of donor- specific histocompatibility antigens delivered on spleen cells by neonatal injection. The results derived from these studies are expected to suggest fruitful approaches to the control of the important process of transplant arteriopathy.
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