The goal of this research project is to analyze the mechanisms of antibody induced glomerulonephritis (GN) in rats when the target antigenic determinant is a single well-defined structure, by using monoclonal (hybridoma) antibodies as specific probes. We will produce mouse hybridomas against rat glomerular basement membrane (GBM) proteins and cultured glomerular cells, and initially define the properties of the resultant monoclonal antibodies (class and subclass of immunoglobulin, ability to fix complement and fine specificity). Different monoclonal antibody preparations will be passively administered to rats to produce functional and morphologic glomerular abnormalities. Nephritogenic and non-nephritogenic antibodies will be compared with respect to quantity of binding to kidneys, turnover rates, localization of binding and ability to fix complement with a view to defining the properties of heterologous antibodies that are critical for the induction of passive GN. The target antigens for nephritogenic and non-nephritogenic antibodies will be purified from solubilized GBM preparations, using the antibodies as specific immunoabsorbents. These antigens will be characterized, and their localization in the kidneys determined by antibody binding. Finally, attempts will be made to induce an active, auto-immune form of GN by immunizing animals with purified autologous antigens, and the immune mechanisms involved in the pathogenesis of this anto-immune GN will be analyzed by in vitro tests and adoptive transfer experiments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK035931-02
Application #
3234226
Study Section
Pathology A Study Section (PTHA)
Project Start
1985-01-01
Project End
1989-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Pagtalunan, M E; Rasch, R; Rennke, H G et al. (1995) Morphometric analysis of effects of angiotensin II on glomerular structure in rats. Am J Physiol 268:F82-8
Rennke, H G; Klein, P S; Sandstrom, D J et al. (1994) Cell-mediated immune injury in the kidney: acute nephritis induced in the rat by azobenzenearsonate. Kidney Int 45:1044-56
Allan, C H; Mendrick, D L; Trier, J S (1993) Rat intestinal M cells contain acidic endosomal-lysosomal compartments and express class II major histocompatibility complex determinants. Gastroenterology 104:698-708
Mendrick, D L; Kelly, D M; Rennke, H G (1991) Antigen processing and presentation by glomerular visceral epithelium in vitro. Kidney Int 39:71-8
Mendrick, D L; Chung, D C; Rennke, H G (1990) Heymann antigen GP330 demonstrates affinity for fibronectin, laminin, and type I collagen and mediates rat proximal tubule epithelial cell adherence to such matrices in vitro. Exp Cell Res 188:23-35
Miller, P L; Scholey, J W; Rennke, H G et al. (1990) Glomerular hypertrophy aggravates epithelial cell injury in nephrotic rats. J Clin Invest 85:1119-26
Fries, J W; Sandstrom, D J; Meyer, T W et al. (1989) Glomerular hypertrophy and epithelial cell injury modulate progressive glomerulosclerosis in the rat. Lab Invest 60:205-18
Mendrick, D L; Rennke, H G (1988) Induction of proteinuria in the rat by a monoclonal antibody against SGP-115/107. Kidney Int 33:818-30
Fries, J W; Mendrick, D L; Rennke, H G (1988) Determinants of immune complex-mediated glomerulonephritis. Kidney Int 34:333-45
Mendrick, D L; Rennke, H G (1988) Epitope specific induction of proteinuria by monoclonal antibodies. Kidney Int 33:831-42