Immunohistochemical Detection of Protein Adducts of 2,4-Dinitrochlorobenzene in Antigen Presenting Cells and Lymphocytes after Oral Administration to Mice: Lack of a Role of Kupffer Cells in Oral Tole
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- 作者：Cynthia Ju and Lance R. Pohl
- 刊名：Chemical Research in Toxicology
- 出版年：2001
- 出版时间：September 2001
- 年：2001
- 卷：14
- 期：9
- 页码：1209 - 1217
- 全文大小：2356K
- 年卷期：v.14,no.9(September 2001)
- ISSN：1520-5010
文摘
Although current studies suggest that most drug-induced allergic reactions (DIARS) arecaused by immunogenic conjugates formed from the reaction of a reactive metabolite of a drugwith cellular proteins, it is not clear why these reactions are relatively rare. One possiblepathway that may explain the low incidence of DIARS in many cases is oral tolerance, anantigen-specific immunological hyporesponsiveness induced by oral administration of antigens.The mechanism of oral tolerance, however, is not clearly understood and is difficult to studydirectly with drugs, because animal models of DIARS have been elusive. We chose 2,4-dinitrochlorobenzene (DNCB) as a model compound to circumvent this problem because animalmodels of allergic reactions have been established for this compound. DNCB forms immunogenic2,4-dinitrophenylated (DNP) protein conjugates that can induce immune reactions and it causesoral tolerance when it is fed to animals prior to sensitization. We hypothesized that DNP-protein conjugates may have a role in oral tolerance. To test this idea, we have begun to identifycells bearing these conjugates after the oral administration of DNCB. Female C57BL/6J micewere fed DNCB and tissues were examined after 6 and 24 h. Immunohistochemical analysisindicated the presence of DNP-protein conjugates in enterocytes of the small intestine, inmacrophages and lymphocytes of the mesenteric lymph nodes, in dendritic cells andlymphocytes of the spleen, and in Kupffer cells and other sinusoidal cells of the liver. It wasfound that Kupffer cell depletion did not affect oral tolerance to DNCB. The findings suggestthat the cells bearing DNP-protein conjugates, other than Kupffer cells, in the liver and othertissues may be important in the induction of oral tolerance against DNCB. Protein adducts ofdrugs administered orally may also be present in these cells, and they may have a role in thedownregulation of DIARS in many individuals.