Thesis (M.S.)--University of Wisconsin--Madison. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 52-56).

Thesis (Ph. D.)--University of Canterbury, 2008. / Typescript (photocopy). Includes bibliographical references (leaves 218-239). Also available via the World Wide Web.

Thesis (Ph. D.)--University of Missouri--Columbia, 1998. / Typescript. Vita. Includes bibliographical references (leaves : 129-152). Also available on the Internet.

No description available.

T cell-dependent immune responses are highly sensitive to suppression by exposure to the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), yet direct effects of TCDD on T cells have been difficult to demonstrate. Because the activation of naive T cells is initiated by dendritic cells (DC), the studies presented in this dissertation were designed to test the hypothesis that TCDD affects these antigen-presenting cells in a manner which ultimately results in suppressed T cell activation. The expression of numerous cell surface proteins known to be important in signaling T cells to proliferate and differentiate was evaluated on splenic DC from C57B1/6 and Balb/c mice. The production of IL-12 and the ability of DC to activate allogeneic and antigen-specific T cells were also tested. Contrary to expectation, exposure to TCDD resulted in enhanced expression of several accessory molecules including B7-2, CD40, ICAM-1, CD24 and the major histocompatibility complex (MHCII). In contrast, expression of LFA-1 was significantly decreased on DC from TCDD-treated mice. These effects were dose-dependent, persisted for at least 14 days, and did not occur in aryl hydrocarbon receptor (AhR)-deficient mice. Interestingly, TCDD treatment also decreased the numbers of DC recovered from the spleen by day 7 following exposure in C57B1/6 mice and by day 3 in Balb/c animals. When T cells were cultured with DC from TCDD-treated mice, the proliferative response of the T cells and the production of IL-2, IL-4, and IFN-�� was not suppressed but instead tended to be increased. DC production of IL-12 was also enhanced. Furthermore, TCDD did not interfere with the ability of DC to internalize latex beads or to activate antigen-specific T cells, suggesting that uptake and processing of antigen by DC is not impaired by TCDD. AhR message was detected in splenic DC and AhR protein was found in two DC cell lines, indicating that DC may be directly affected by TCDD. Taken together, these results suggest that TCDD provides an activation stimulus to DC and may lead to their premature deletion. The relationship between these effects and TCDD-induced immune suppression remains to be determined. / Graduation date: 2001

The immune system has been identified as a very sensitive target for the toxic effects of 2,3,7,S-tetrachlorodibenzo-p-dioxin (TCDD). Exposure to TCDD has been shown to disrupt the generation of both cell-mediated and humoral T cell-dependent immunity in laboratory animals; however, the mechanism remains unknown. In this dissertation, the hypothesis is tested that TCDD exposure alters T cell activation and differentiation either directly or by inhibiting the activation of antigen presenting cells (APC). Previous studies from our laboratory using the PSI5 tumor allograft model suggest that TCDD inhibited T cell activation by suppressing the induction of the costimulatory molecule CDS6 on B220+ and Mac-1+ cells. To address the effects of TCDD on APC, we further characterized the activation of splenic APC in the PSI5 model and found that TCDD suppressed the induction of the accessory molecules CDS6, CD54 and MHC II on APC as well as their production of IL-12. Although it was determined that the induction of these costimulatory molecules following PSI5 immunization was CD40independent, their in vivo expression could be enhanced by administering an agonistic antibody to CD40 to mice. APC from anti-CD40 treated mice expressed significantly higher levels of these accessory molecules and IL-12, and this enhanced APC activation was largely unaffected by TCDD. However, TCDD-treated mice receiving both P815 and anti-CD40 were unable to generate T cell-dependent allograft immunity suggesting that suppression of APC activation may not be underlying TCDD immunosuppression. To address the direct effects of TCDD on T cell activation, we adoptively-transferred DO11.10 TCR transgenic T cells into syngeneic recipients and monitored their activation in vivo following exposure to antigen. Although treatment of adoptively-transferred mice had no effect on the expansion or activation of the OVA-specific CD4+ T cells, the production of the T cell-derived cytokines IL-2, IFN-��, IL-4 and IL-10 was suppressed. These data suggest that TCDD may suppress the differentiation of OVA-specific T cells into effector T helper cells which are capable of driving T cell-dependent immune responses. / Graduation date: 2000

Graduation date: 1997

Thesis (Ph. D.)--University of Missouri--Columbia, 1998. / "December 1998" Typescript. Vita. Includes bibliographical references (l. 129-152). Also available on the Internet.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1982. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

No description available.