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The Role of Haptic Macrophages in Regulation of Idiosyncratic Drug Reactions

Department of Pharmaceutical Sciences and Integrated Department of Immunology, University of Colorado Health Sciences Center, Denver, Colorado, USA

Correspondence: Cynthia Ju, Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, 4200 East 9^th Avenue, Denver, CO 80262, USA; e-mail:cynthia.ju{at}uchsc.edu.

Idiosyncratic drug reactions (IDR) account for approximately 6%–10% of all adverse drug reactions. The unpredictable and serious nature of these reactions makes them a significant economic burden and safety concern to the health care community and the pharmaceutical industry. Clinical and laboratory evidence suggests that adverse immune responses against drug–protein adducts play a role in the pathogenesis of IDR. However, it remains unclear why only a small percentage of patients are susceptible to developing these reactions. We hypothesized that most patients develop immunological tolerance against drug–protein adducts as a default mechanism, and that IDRs can only occur when this tolerance is deficient or abrogated in susceptible individuals. Using a murine model of 2,4-dinitrochlorobenzene (DNCB)–induced delayed type hypersensitivity (DTH) reaction, our previously published data demonstrated that intravenous pretreatment of mice with dinitrophenyl-bovine serum albumin (DNP-BSA) induced immunological tolerance to subsequent DNCB sensitization, and that hepatic macrophages (Kupffer cells, KC) played an important role in mediating such tolerance. Further mechanistic investigation revealed that KC, acting as incompetent antigen-presenting cells, cannot elicit strong T cell reactions, and that they actively suppress T cell activation through production of prostaglandins. These findings suggest that KCs may play a critical role in regulating immune reactions within the liver and contributing to liver-mediated systemic immune tolerance.

Key Words: Kupffer cells • immune tolerance • delayed-type hypersensitivity

Abbreviations: APC, antigen-presenting cells • DC, dendritic cells • DNCB, 2,4-dinitrochlorobenzene • DNP-BSA, dinitrophenyl-bovine serum albumin • DTH, delayed-type hypersensitivity • IDRs, idiosyncratic drug reactions • KC, Kupffer cells • L-NMMA, N-monomethyl-L-arginine • MHC, major histocompatibility complex • NO, nitric oxide • PG, prostaglandin • PM, peritoneal macrophages • TFA, trifloroacetyl chloride • TCR, T-cell receptor

This version was published on January 1, 2009

Toxicologic Pathology, Vol. 37, No. 1, 12-17 (2009)
DOI: 10.1177/0192623308329475


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