Tolerogenic Role of Kupffer Cells in Allergic Reactions

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• 作者：Cynthia Ju ; J. Philip McCoy ; Christine J. Chung ; Mary Louise M. Graf ; and Lance R. Pohl
• 刊名：Chemical Research in Toxicology
• 出版年：2003
• 出版时间：December 2003
• 年：2003
• 卷：16
• 期：12
• 页码：1514 - 1519
• 全文大小：306K
• 年卷期：v.16,no.12(December 2003)
• ISSN：1520-5010

文摘

Drug-induced allergic reactions (DIARs), including allergic hepatitis, cutaneous reactions,and blood dyscrasias, are unpredictable and can be life threatening. Although current studiessuggest that DIARs are caused by immunogenic drug-protein adducts, it remains unclearwhat factors determine the susceptibility to DIARs. We hypothesized that most individualsmay be resistant to DIARs in part because they become immunologically tolerant to drug-protein adducts in the liver, an organ with tolerogenic properties. Because animal models ofDIARs are elusive, we tested this hypothesis using a murine model of 2,4-dinitrochlorobenzene(DNCB)-induced delayed type hypersensitivity reaction that is mediated by immunogenic 2,4-dinitrophenylated (DNP)-protein adducts. Intravenous pretreatment of mice with DNP-BSAled to its accumulation in hepatic Kupffer cells (KC) and induced immunological tolerance tosubsequent DNCB sensitization. Tolerance could be abrogated by prior depletion of KC orinduced in naïve mice by transferring a T cell-depleted, KC-enriched fraction of livernonparenchymal cells from mice tolerized 1 month earlier by DNP-BSA pretreatment. Thesefindings implicate KC as a primary and sustained inducer of tolerance against DNP-proteinadducts and suggest a similar role in modulating allergic reactions against drug-proteinadducts. Perhaps genetic and/or environmental factors affecting the activities of these cellsmay play a role in determining individual susceptibility to DIARs.