T cells reactive to an inducible heat shock protein induce disease in toxin-induced interstitial nephritis.

Abstract

SummaryT cells reactive against immunodominant regions of inducible heat shock proteins (HSPs) have been identified in the chronic inflammatory lesions of several experimental autoimmune diseases. Since HSPs are known to be induced by a number of renal tubular epithelial cell toxins associated with chronic interstitial nephritis, we investigated the relevance of HSP expression and T cell reactivity to HSP70 in a model of progressive inflammatory interstitial nephritis. Chronic administration of cadmium chloride (CdClz) to SJL/J mice induces HSP70 expression in renal tubular cells 4-5 wk before the development of interstitial mononuclear cell infiltrates. CdC12 also induces HSP70 expression in cultured tubular epithelial cells from SJL/J mice. CD4 +, TCR-od~ + T cell lines specific for an immunodominant HSP peptide are cytotoxic to heat stressed or CdClz-treated renal tubular cells. Such HSP-reactive T cells mediate an inflammatory interstitial nephritis after adoptive transfer to CdClz-treated mice at a time when immunoreactive HSPT0 is detectable in the kidneys, but before the development of interstitial mononuclear cell infiltrates. T cells isolated from the nephritic kidneys of mice treated with CdC12 for 13 wk are also cytotoxic to heat shocked or cadmium-treated tubular cells. These kidney-derived T cells additionally induced interstitial nephritis after passive transfer, indicating their pathogenic significance. Our studies strongly support a role for HSP-reactive T ceils in CdC12-induced interstitial nephritis and suggest that the induction of HSPs in the kidney by a multitude of "nonimmune" events may initiate or facilitate inflammatory damage by HSP-reactive lymphocytes.

Heat Shock Protein 60 Is Released in Immune-Mediated Glomerulonephritis and Aggravates Disease

“…Furthermore, Hsp60, unlike Hsp70 and gp96, does not seem to introduce chaperoned peptides into the cross-presentation pathway, which could recruit CD8 T cells as effectors. T cell responses against Hsp70 have been shown to be important in CdCl 2 -induced interstitial nephritis (37), and T cells specific for Hsp60 have been shown to contribute to colitis in immunocompromised mice (38). However, if this played a role in the present study, then it would be difficult to explain why pathology was confined to the kidney and why systemic administration of Hsp60 alone did not cause any pathology.…”

Oxidative stress, renal infiltration of immune cells, and salt-sensitive hypertension: all for one and one for all

“…HSPs themselves can be the cause of autoimmune disease. For example, Weiss et al (149) showed that T cells reactive against HSPs can induce interstitial nephritis. In addition, HSPs are known to bind peptides in damaged tissue to form HSP-peptide complexes with strong immunogenicity (27,142).…”

Molecular basis of renal fibrosis

“…The most compelling evidence comes from observing the sequence of events that follow cadmium-induced renal injury in mice. The tubules that have been damaged by cadmium express heat shock protein 70 de novo, which in turn activates T cells and results in interstitial nephritis [29]. Passive transfer of these sensitized T cells to normal mice induces interstitial nephritis.…”