RESPONSE OF RENAL CELLS IN INTERSTITIAL NEPHRITIS

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DESCRIPTION (Adapted from investigator's abstract): The appearance of interstitial nephritis is an expected development in the natural history of all forms of progressive renal failure. The investigators have been studying this inflammatory process using an experimental model of immune-mediated interstitial nephritis in mice called anti-tubular basement membrane (alphaTBM) disease. Primary immune injury is produced in this model by T cells and antibodies (alphaTMB-Ab/alpha3M-1-Ab) which are directed at a tubular target antigen (3M-1) expressed by proximal tubular epithelium. Histologic damage occurs through the formation of interstitial mononuclear cell infiltrates that subsequently invoke a progressive fibrogenesis with tubular atrophy. The emergence of this autoimmune process rendering structural damage is a product of complex biochemical events that depend on two interactive components; one component is the development of a destructive nephritogenic immune response. The other component is the reaction of the tubulo- interstitium to mononuclear intrusion. The long term purpose and goals of this application have been focused on the latter issue. In their current renewal they have concentrated selectively on several fundamental, inflammation-relevant protein systems which modulate the immunologic visibility, tissue boundaries, cell size, and phenotype of target tubular epithelium and their associated fibroblasts. Over the course of the last few years their work can be distilled down and tracked into four critical areas: one area has been to determine how MHC class II genes are regulated in tubular epithelium; the second area has been to determine how type IV collagen genes are modulated during basement membrane remodelling; the third area has been to understand the molecular mechanisms of tubular hypertrophy and how cellular enlargement may influence the expression of nephritogenic antigens; and the fourth area has been to develop antibodies and molecular probes which can be used specifically to identify tubulo-interstitial fibroblasts. These four project themes collectively bridge the disciplines of genetics and biochemistry with basic pathophysiology in order to better discern major processes leading to aberrant structural change in interstitial tissue. The investigators' experiments rely on both in vitro and in vivo technologies in order to assemble a comprehensive database on this subject; these technologies include the use of cell culture, radioimmunoassay, cDNA cloning, chimeric reporter gene constructs, gel retardation assays, DNA footprinting, transgene replacement, eurkaryotic transfection, and antisense inhibition. They believe their approach and the level of their analysis will lead to a better comprehension of critical somatic cell responses to immune events that may offer new insights regarding the formation of rational strategies for improved treatment of interstitial injury.