Acute transplant rejection can be construed as consisting of an afferent limb, the recognition of the transplanted kidney as foreign and the subsequent stimulation and recruitment of host immune-competent cells, and an efferent limb resulting from the consequences of such stimulation and recruitment. The cells participating in the effector limb of acute rejection contribute to the ultimate loss of the graft in two major ways: (1) mediation of the acute derangements in glomerular function (depressed GFR and increased protein excretion) and (2) mediation of the proliferative inflammatory response leading to replacement of functional renal tissue by fibrotic scarring. In this proposal, we direct our attention to the functional impairment and tissue destruction which characterize this efferent limb. Thus, although we employ the model of renal transplantation, we are not proposing classic transplant studies; rather, we are using allograft rejection as a model of immune-mediated glomerular dysfunction and destruction. Our proposed studies derive their justification from the observation that, in the initial phases of rejection, glomerular structure is intact while glomerular function is dramatically impaired. Hence, a role is proposed for infiltrating and endogenous activated leukocytes in elaborating a number of potent biologically active products that mediate the observed glomerular dysfunction. In this regard, we focus our attention on vasocative lipid-derived mediators including end-products of cyclooxygenase and lipoxygenase metabolism of arachidonic acid and platelet activating factor (PAF). By utilizing glomerular micropuncture and permselectivity studies, analytic techniques of eicosanoid and PAF identification and quantitation, cellular separation and flow cytometry, and glomerular and cell culture methodology, we will attempt an elucidation of the roles of these lipid mediators in the functional aspects of acute allograft rejection. In regard to the mitogenic proliferative response which accompanies tissue destruction, we intend to investigate the expression of peptide growth factors in the rejecting allograft. These studies become particularly relevant in view of our demonstration of potent glomerular functional effects for one of these peptides (EGF), raising the possibility that their increased expression during rejection may contribute to the functional changes as well. Finally, the involvement of lipid mediators in the vasoconstrictor component of cyclosporin A nephrotoxicity will be examined. Evidence for such an involvement is abundant, rendering its further investigation potentially rewarding.

Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37203
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