Imaging DTH, IFN-gamma Responses and GA in Human Arteries. Graft arteriosclerosis (GA) is the major cause of late graft failure in cardiac transplantation. Reliable non-invasive tools for the detection of GA, specifically in its early form, do not currently exist. Coronary angiography and myocardial perfusion imaging are routinely performed but have limited detection accuracy for early disease. However, the detected neointima is not predictive of the clinical course. The overall goal of this project is to develop non-invasive, nuclear imaging-based modalities for early GA detection, based upon the immunopathogenesis. Our approaches will be closely linked to the Project 1 and 2 hypotheses, that TH1 cells are potent stimulators of the GA response through the elaboration of IFN-gamma which in turn, induces chemokine production, growth factor receptor expression and smooth muscle cell (SMC) activation/proliferation. We have recently established small animal imaging models which target modulated membrane markers in pathologic states, including an arterial injury model in mice. Specific proposals now include: (1) to define expression levels of known, carefully chosen candidates target molecules, including CXCR3 and CCR5 (T cells), PDGFbeta-R, alphavbeta3 and VCAM-1 (endothelial cells and SMC), IP- 10 and Mig (secreted), on CD4+ TH1 cells, IFN-gamma activated SMC and EC, in (a) cell culture, (b) organ culture, (c) human-to-mouse vascular transplant segments in a SCID mouse model, and (d) human specimens of chronic vascular rejection; (2) to select novel potential imaging ligands using a peptide phage display library and biopanning, in vitro, ex vivo, and in vivo, directing the phage biopanning at the same spectrum of immune-activated cells/tissues; (3) to radiolabel chosen ligands (antibodies, peptides and other small molecules) and determine their pharmacologic properties both in vitro and in vivo, using radioimmunoassays and autoradiography; and (4) to perform gamma camera-based in vivo imaging in the human arterial transplant to SCID mouse model, using a limited number of radiotracers selected in 1-3, above. Defined targeted imaging approaches will be the foundation for patient-based studies in the future. Ultimately, the ability to detect early pathogenetic features of GA may provide prognostic data and generate a new paradigm for treatment of transplant patients.
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