The use of purified self-antigens can facilitate the further analysis of pathogenic mechanisms in autoimmunity (1, 2). This report describes the isolation of the nephritogenic antigen of anti-tubular basement membrane (a-TBM)l-induced interstitial nephritis.
Recent efforts in our laboratory have concentrated on autoimmune mechanisms producing an experimental interstitial nephritis called anti-tubular basement membrane (anti-TBM)' disease (1) . Anti-TBM disease is induced in rodents after an immunization with renal tubular antigen (RTA) in adjuvant . Susceptible animals expressing the endogenous antigen (2) develop antibodies to the tubular basement membrane (anti-TBM-Ab) (3), a complex nephritogenic T cell repertoire (4), active fibrogenesis (5), interstitial cell infiltrates, and progressive renal failure . Such renal lesions can also spontaneously develop in patients, resulting in progressive renal insufficiency (6-8) . Both the nephritogenic antigen (3M-1) in the experimental model and the target antigen of human disease are crossreactive moieties of similar size (48,000 Mr) (9) . This association is seemingly unique among immune-mediated renal lesions, and supports the notion that experimental anti-TBM disease may be analogous to the human condition .With the ability to now isolate the active nephritogenic moiety of anti-TBM disease, we have extended our previous observations to provide a detailed anal-
We examined the effects of daily cyclophosphamide administration on the development and extent of tubulointerstitial nephritis produced in rats injected with tubular basement membranes in adjuvant. 15 mg/kg/day of cyclophosphamide completely blocked the development of interstitial lesions, while 2 mg/kg/day enhanced the degree of interstitial injury. When cyclophosphamide in the higher dose was started early in disease, 12 days after immunization, protection from progression was also observed as well as significant reductive improvement. If cyclophosphamide was administered late in disease, 21 days after immunization, no further progression was demonstrable, but substantial injury remained. In the latter two experiments, the beneficial effects of cyclophosphamide could not be explained by a reduction in anti-tubular basement membrane antibodies bound to the kidney. In groups of immunized rats that were tested, however, cyclophosphamide was able to non-specifically impair the delayed-type hypersensitivity response to tubular antigen and PPD. We conclude, therefore, that cyclophosphamide, in high but not low dosage, if given before damage is extensive and prolonged, may successfully inhibit the cellular immune response producing primary interstitial nephritis.
The nephritogenic effector T cell response producing interstitial nephritis in mice can be largely inhibited by the adoptive transfer of suppressor T cells before or after the induction of disease. These suppressor T cells are harvested from donor mice primed with tubular antigen-derivatized syngeneic lymphocytes, and two subsets of suppressor cells can be characterized within this donor cell population. The first suppressor cell in this network is an L3T4+, I-J+, RE-Id+ cell (Ts-1). Ts-1 cells are antigen-binding suppressor cells that inhibit afferent phase immune responses and, in the presence of tubular antigen, specifically induce Lyt-2+, I-J+ cells (Ts-2) that are antiidiotypic (RE-Id-binding) suppressors. The Ts-2 cell is functionally restricted in its suppressive effect by I-J and Igh-V gene products, and acts on the effector limb of the cell-mediated anti-tubular basement membrane immune response. These studies provide an experimental basis for further efforts to use immunoregulatory modulation in the control of autoimmune renal disease.
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