This project seeks to utilize didactic and research experiences to provide a program for the development of an effective independent investigator in the field of renal immunology. Phase 1 will establish an educational foundation as well as create a formulative research and methodologic experience. the former will be accomplished through seminars in the Immunology Graduate Group, lectures, conferences, and journal clubs. The latter will evolve from the further study of an already operational model of anti-tubular basement membrane (AlphaTBM) disease producing interstitial nephritis in mice. This project will initially examine the qualitative and quantitative aspects of the AlphaTBM B cell repertoire. Such an analysis will require the generation of a library of monoclonal AlphaTMB antibodies (AlphaTBM-Ab), as well as an evaluation of B cell precursor frequencies. The immunogenetics of the B cell response will be examined utilizing congenic mice to assess the relationship between heavy-chain allotype, haplotype, paratypic and idiotypic composition of AlphaTBM-Ab, and disease susceptibility. Further analysis of the immunoregulation of AlphaTBM disease will examine both the humoral and cellular arms of the idiotypic network and will employ anti-idiotypic antisera to polymorphic and broadly cross-reactive idiotypes. Solid phase radioimmunoassay will be used extensively to allow a fine analysis of the AlphaTBM serology. Finally, the further purification of nephritogenic TBM antigens will utilize monoclonal AlphaTBM-Ab affinity columns and an intensive analytical biochemical approach to isolate distinct epitopes. At the conclusion of Phase 1, it is anticipated that a more independent effort will be undertaken. This will consist of a detailed analysis of the afferent and immunoregulatory phase of experimental membranous nephritis, a model analogous to one of the most common causes of adult nephrotic syndrome. Since the relevant antigen can be readily isolated, and because the antibody response is critical to the nephritogenic immune response, many of the studies outlined for Phase 1 should be both feasible and easily applicable. A detailed immunogenetic analysis will be undertaken utilizing congenic rodents and variables described for AlphaTBM disease above. In sum, it is felt that Phase 2 has great potential to further understanding regarding induction and control of this experimental form of membranous glomerulonephritis.
| Clayman, M D; Raymond, A; Colen, D et al. (1987) The Limulus amebocyte lysate assay. A rapid and sensitive method for diagnosing early gram-negative peritonitis in patients undergoing continuous ambulatory peritoneal dialysis. Arch Intern Med 147:337-40 |
