Involvement of drug-specific T cells in acute drug-induced interstitial nephritis.
Drug-induced interstitial nephritis can be caused by a plethora of drugs and is characterized by a sudden impairment of renal function, mild proteinuria, and sterile pyuria. For investigation of the possible pathomechanism of this disease, drug-specific T cells were analyzed, their function was characterized, and these in vitro findings were correlated to histopathologic changes that were observed in kidney biopsy specimens. Peripheral blood mononuclear cells from three patients showed a proliferative response to only one of the administered drugs, namely flucloxacillin, penicillin G, and disulfiram, respectively. The in vitro analysis of the flucloxacillin-reactive cells showed an oligoclonal immune response with an outgrowth of T cells bearing the T cell receptor Vbeta9 and Vbeta21.3. Moreover, flucloxacillin-specific T cell clones could be generated from peripheral blood, they expressed CD4 and the alphabeta-T cell receptor, and showed a heterogeneous cytokine secretion pattern with no clear commitment to either a Th1- or Th2-type response. The immunohistochemistry of kidney biopsies of these patients revealed cell infiltrations that consisted mostly of T cells (CD4+ and/or CD8+). An augmented presence of IL-5, eosinophils, neutrophils, CD68+ cells, and IL-12 was observed. In agreement with negative cytotoxicity assays, no cytotoxicity-related molecules such as Fas and perforin were detected by immunohistochemistry. The data indicate that drug-specific T cells are activated locally and orchestrate a local inflammation via secretion of various cytokines, the type of which depends on the cytokine pattern secreted and which probably is responsible for the renal damage.
Spanou
Zoi
Z
Division of Allergology, Clinic of Rheumatology and Clinical Immunology/Allergology, PKT2, D572, Inselspital, CH-3010 Bern, Switzerland.
Keller
Monika
M
Britschgi
Markus
M
Yawalkar
Nikhil
N
Fehr
Thomas
T
Neuweiler
Jörg
J
Gugger
Mathias
M
Mohaupt
Markus
M
Pichler
Werner J
WJ
D000368:Aged; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D016207:Cytokines / Q000378:metabolism; D004221:Disulfiram / Q000009:adverse effects; D003875:Drug Eruptions / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000009:adverse effects*; D005436:Floxacillin / Q000009:adverse effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009395:Nephritis, Interstitial / Q000139:chemically induced* / Q000473:pathology; D010400:Penicillin G / Q000009:adverse effects; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D000900:Anti-Bacterial Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D011948:Receptors, Antigen, T-Cell; D005436:Floxacillin; D010400:Penicillin G; D004221:Disulfiram