Lymphocyte Loss and Immunosuppression Following Acetaminophen-Induced Hepatotoxicity in Mice as a Potential Mechanism of Tolerance

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• 作者：Mary Jane Masson ; Richard A. Peterson ; Christine J. Chung ; Mary L. Graf ; Leah D. Carpenter ; Jeffrey L. Ambroso ; David L. Krull ; Janeice Sciarrotta ; Lance R. Pohl
• 刊名：Chemical Research in Toxicology
• 出版年：2007
• 出版时间：January 2007
• 年：2007
• 卷：20
• 期：1
• 页码：20 - 26
• 全文大小：570K
• 年卷期：v.20,no.1(January 2007)
• ISSN：1520-5010

文摘

Current evidence suggests that drug-induced liver disease can be caused by an allergic response (drug-induced allergic hepatitis, DIAH) induced by hepatic drug-protein adducts. The relatively low incidenceof these reactions has led us to hypothesize that tolerogenic mechanisms prevent DIAH from occurringin most people. Here, we present evidence for the existence of one of these regulatory pathways. Followinga hepatotoxic dose of acetaminophen in C57Bl/6 mice, lymphocyte loss that appeared to be due at leastin part to apoptosis was noted in the spleen, thymus, and draining lymph nodes of the liver. There wasno observable lymphocyte loss in the absence of hepatotoxicity. Acetaminophen-induced liver injury(AILI) also led to a functional suppression of the immune system as determined by the inhibition of adelayed-type hypersensitivity response to dinitrochlorobenzene. Further studies with adrenalectomizedmice suggested a role for corticosterone in the depletion of lymphocytes following APAP-induced liverinjury. In conclusion, these findings suggest that lymphocyte loss and immunosuppression followingAILI may prevent subsequent occurrences of allergic hepatitis and possibly other forms of APAP-inducedallergies induced by hepatic drug-protein adducts. Similar regulatory pathways may inhibit otherhepatotoxic drugs from causing allergic reactions.