Available information indicates that antibody mechanisms initiate most experimental and human glomerulonephritis. Much less is known about the immune mechanisms, humoral or cellular, responsible for tubulointerstitial nephritis (TIN). Even with the information available and the use of aggressive therapeutic maneuvers to modulate nephritogenic antibody responses, damage often progresses relentlessly to renal failure necessitating costly and only partially satisfactory measures such as dialysis. Studies herein will quantitate the humoral and cellular mechanisms leading to initiation, evolution, progression, and/or regression of immunologically-induced autoimmune models of TIN in the rat using nephritogenic anti-tubular basement membrane (TBM) antibodies and effector T cell lines and clones. Assessment of the contributions of antibody and immune cells and their clones will be defined during the evolutionary stages of sequential antibody deposition, polymorphonuclear leukocyte accumulation, and subsequent lymphocyte and monocyte/macrophage dominated stages of TIN in the Brown Norway (BN) rat induced with heterologous TBM in adjuvants. A new model of cell-mediated and transferrable nodular TIN produced in the Lewis (LEW) rat by immunization with BN renal basement membrane (RBM) will be studied using similar techniques for comparison to the antibody related BN TIN. The factors controlling the nephritogenic autoimmune responses including their induction and modulation will be elucidated. These studies entail modulation of cell surface receptors and study of the mechanisms of induction of disease resistance using attenuated T cell lines. It will be necessary to identify the antigens reactive with the humoral and cellular immune elements involved. The LEW rat, with proper immunization, develops anti-basement membrane antibodies similar to those seen in human Goodpasture's syndrome. This serious human disease is currently lacking a model to examine the poorly understood immunopathogenesis of the not infrequent episodic and sometimes fatal pulmonary hemorrhage of these patients. The immunized LEW rat will be explored as a potential model for detailed investigation of the pathogenesis of this immunologically-induced lung injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK032353-06
Application #
3230800
Study Section
Pathology A Study Section (PTHA)
Project Start
1983-04-01
Project End
1991-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
6
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92037
Wilson, C B (1991) Nephritogenic tubulointerstitial antigens. Kidney Int 39:501-17
Wilson, C B (1989) Study of the immunopathogenesis of tubulointerstitial nephritis using model systems. Kidney Int 35:938-53
Blantz, R C; Peterson, O W; Blantz, E R et al. (1988) Sexual differences in glomerular ultrafiltration: effect of androgen administration in ovariectomized rats. Endocrinology 122:767-73
Blantz, R C; Gabbai, F; Gushwa, L C et al. (1987) The influence of concomitant experimental hypertension and glomerulonephritis. Kidney Int 32:652-63
Yamamoto, T; Wilson, C B (1987) Quantitative and qualitative studies of antibody-induced mesangial cell damage in the rat. Kidney Int 32:514-25