Involvement of inflammation and associated Mac-1⁺Gr-1⁺ cells in the immune suppression induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/qv33s175d

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  • Exposure to TCDD suppresses the generation of immune responses through unknown mechanisms. Interestingly, TCDD enhances inflammatory responses to various stimuli. The goal of the studies presented in this thesis was to examine the role of hyperinflammation in TCDD-induced immunotoxicity. Previously we observed an increase in Mac-1⁺ cells in the spleen that coincided with the suppressed CTL response in TCDD-treated C57B1/6 mice following injection of allogeneic P815 tumor cells. We hypothesized that these Mac-1⁺ cells represented a systemic inflammatory response and were an immunomodulatory population that suppressed the development of the CTL response. In order to test the hypothesis, we characterized the phenotype and function of Mac-1⁺ cells in addition to investigating inflammatory components, such as TNF and SAA. Mac-1⁺ cells were found to co-express Gr-1 antigen and were identified morphologically as neutrophils. The Mac-1⁺ cells increased in the spleen, blood as well as bone marrow during the development of an allogeneic immune response. In mice treated with TCDD, the increase in Mac-1⁺ Gr-1⁺ cells was enhanced. However, plasma levels of TNF and SAA were not increased in TCDD-treated mice. Mac-1⁺ Gr-1⁺ + cells from TCDD-treated mice expressed lower levels of Gr-1⁺ and a number of surface molecules, such as ICAM-1, F4/80, LFA-1, and CD40 relative to cells from vehicle treated-mice. CD62L was shed on Mac-1⁺ Or-1⁺ cells in the blood from TCDD-treated mice suggesting that Mac-1⁺ Gr-1⁺ cells were highly activated. Indeed, the oxidative burst was significantly enhanced in Mac-1⁺ Gr-1⁺ cells from TCDD-treated mice. When immunomodulatory functions of Mac-1⁺ Gr-1⁺ cells were examined, splenic Mac-1⁺ Gr-1⁺ cells from TCDD-treated mice did not inhibit cytotoxic activity of in vivo activated CTL, but suppressed the in vitro generation of allo-reactive CTL in a cell number-and cell contact-dependent manner. Although these cells appeared to have immunomodulatory properties in vitro, in vivo depletion of Mac-1⁺ Gr-1⁺ cells did not restore the CTL response in TCDD-treated mice. Furthermore, immunohistochemical staining of spleens showed that Mac-1⁺ Gr-1⁺ cells were located in the red pulp and separated from T cells, suggesting that direct interaction between the cells was unlikely. Therefore, although the increase in Mac-1⁺ Gr-1⁺ cells in TCDD-treated mice coincided temporally with the failure to develop CTL activity, we conclude that Mac-1⁺ Or-1⁺ cells do not contribute to the immune suppression induced by TCDD in P815-injected mice and that enhanced inflammation is independent from TCDD-induced immunotoxicity.
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