T-CELLS REACTIVE TO AN INDUCIBLE HEAT-SHOCK PROTEIN INDUCE DISEASE INTOXIN-INDUCED INTERSTITIAL NEPHRITIS

T cells reactive against immunodominant regions of inducible heat shoc k proteins (HSPs) have been identified in the chronic inflammatory les ions of several experimental autoimmune diseases. Since HSPs are known to be induced by a number of renal tubular epithelial cell toxins ass ociated with chronic interstitial nephritis, we investigated the relev ance of HSP expression and T cell reactivity to HSP70 in a model of pr ogressive inflammatory interstitial nephritis. Chronic administration of cadmium chloride (CdCl2) to SJL/J mice induces HSP70 expression in renal tubular cells 4-5 wk before the development of interstitial mono nuclear cell infiltrates. CdCl2 also induces HSP70 expression in cultu red tubular epithelial cells from SJL/J mice. CD4(+), TCR-alpha/beta() T cell lines specific for an immunodominant HSP peptide are cytotoxi c to heat stressed or CdCl2-treated renal tubular cells. Such HSP-reac tive T cells mediate an inflammatory interstitial nephritis after adop tive transfer to CdCl2-treated mice at a time when immunoreactive HSP7 0 is detectable in the kidneys, but before the development of intersti tial mononuclear cell infiltrates. T cells isolated from the nephritic kidneys of mice treated with CdCl2 for 13 wk are also cytotoxic to he at shocked or cadmium-treated tubular cells. These kidney-derived T ce lls additionally induced interstitial nephritis after passive transfer , indicating their pathogenic significance. Our studies strongly suppo rt a role for HSP-reactive T cells in CdCl2-induced interstitial nephr itis and suggest that the induction of HSPs in the kidney by a multitu de of ''nonimmune'' events may initiate or facilitate inflammatory dam age by HSP-reactive lymphocytes.