T cells reactive to an inducible heat shock protein induce disease in toxin-induced interstitial nephritis.
T 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 (CdCl2) to SJL/J mice induces HSP70 expression in renal tubular cells 4-5 wk before the development of interstitial mononuclear cell infiltrates. CdCl2 also induces HSP70 expression in cultured tubular epithelial cells from SJL/J mice. CD4+, TCR-alpha/beta+ T cell lines specific for an immunodominant HSP peptide are cytotoxic to heat stressed or CdCl2-treated renal tubular cells. Such HSP-reactive T cells mediate an inflammatory interstitial nephritis after adoptive transfer to CdCl2-treated mice at a time when immunoreactive HSP70 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 CdCl2 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 cells in CdCl2-induced interstitial nephritis and suggest that the induction of HSPs in the kidney by a multitude of "non-immune" events may initiate or facilitate inflammatory damage by HSP-reactive lymphocytes.
Penn Center for Molecular Studies of Kidney Diseases, Department of Medicine, University of Pennsylvania, Philadelphia 19104-6144.
R A
RA
Weiss
M P
MP
Madaio
J E
JE
Tomaszewski
C J
CJ
Kelly
D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D001426:Bacterial Proteins; D001427:Bacterial Toxins / Q000276:immunology*; D002104:Cadmium / Q000494:pharmacology; D019256:Cadmium Chloride; D002460:Cell Line; D018834:Chaperonin 60; D018833:Chaperonins / Q000276:immunology*; D002712:Chlorides / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis*; D006360:Heat-Shock Proteins / Q000276:immunology*; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D007687:Kidney Tubules, Proximal; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009163:Mycobacterium bovis / Q000276:immunology; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D018834:Chaperonin 60; D002712:Chlorides; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D010446:Peptide Fragments; C074119:heat-shock protein 65, Mycobacterium; D002104:Cadmium; D018833:Chaperonins; D019256:Cadmium Chloride