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Involvement of Drug-Specific T Cells in Acute Drug-Induced Interstitial Nephritis

Zoi Spanou^*, Monika Keller^*, Markus Britschgi^*, Nikhil Yawalkar, Thomas Fehr, Jörg Neuweiler, Mathias Gugger^||, Markus Mohaupt^¶ and Werner J. Pichler^*

^* Division of Allergology, Clinic of Rheumatology and Clinical Immunology/Allergology, Department of Dermatology, and ^¶ Division of Nephrology/Hypertension, Inselspital, and ^|| Institute of Pathology, University of Bern, Bern, and Department of Nephrology; and Institute of Pathology, Kantonsspital, St. Gallen, Switzerland

Address correspondence to: Dr. Werner J. Pichler, Division of Allergology, Clinic of Rheumatology and Clinical Immunology/Allergology, PKT2, D572, Inselspital, CH-3010 Bern, Switzerland. Phone: +41-31-632-2264; Fax: +41-31-632-2747; E-mail: werner.pichler{at}insel.ch

Received for publication May 1, 2006. Accepted for publication July 17, 2006.

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 V9 and V21.3. Moreover, flucloxacillin-specific T cell clones could be generated from peripheral blood, they expressed CD4 and the -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.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673