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

Graduation date: 1998

Graduation date: 1999

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds are well-recognized for their immunosuppressive activity, which is mediated through an intracellular receptor and transcription factor, aryl hydrocarbon receptor (AhR). Laboratory animals exposed to TCDD are less resistant to infection and have severely impaired humoral and cell-mediated immune responses. This dissertation addressed the hypothesis that exposure to TCDD disrupts early events during the activation of CD4⁺ T cells, leading to their premature loss from the spleen. Initially, ovalbumin (OVA)-specific CD4⁺ T cells from transgenic DO11.10 mice were used to monitor the effects of TCDD on activated antigen-specific T cells. A graft-versus-host (GVH) model, in which T cells from C57B1/6 (B6) mice are injected into C57B1/6 x DBA/2 Fl (Fl) mice, was used to study the role of AhR specifically in the T cells in response to TCDD. B6 donor T cells (from AhR[superscript +/+] or AhR[superscript -/-] mice) respond to DBA/2 antigens in Fl mice and a CD4-dependent CTL response is generated. In both models, exposure to TCDD significantly decreased the number of responding CD4⁺ T cells in the spleen beginning on day 4 after initiation of the response. Exposure to TCDD altered the phenotype of OVA-specific CD4⁺ T cells beginning on day 2 after immunization with OVA. These studies also suggested that apoptosis was not the primary mechanism responsible for the loss of CD4⁺ T cells from the spleen in TCDD-treated mice. Exposure to TCDD induced AhR-dependent changes in the phenotype of B6 donor CD4⁺ T cells such that a subpopulation of CD25⁺ cells was increased in TCDD-treated Fl mice, and these cells had in vitro functional characteristics consistent with regulatory T (Treg) cells. Exposure to TCDD increased the frequency of donor CD4⁺ T cells producing interleukin (IL)-2. In addition, increased expression of CD25 in TCDD-treated mice was correlated with increased signaling through the IL-2 receptor. However, IL-2 alone was not sufficient to mimic the potent immunosuppressive effects of TCDD. These results suggest that TCDD suppresses T cell immunity in part by inducing and/or expanding a subpopulation of Treg cells by a mechanism that may involve IL-2. / Graduation date: 2006

This thesis reviews the scientific, litigatory, policy parameters of the Agent Orange controversy. Agent Orange, an herbicide used by the United States during the Viet Nam War, is the subject of continuing conflict involving its possible deleterious effects on veterans who may have been exposed to the herbicide. Central to this controversy are various legal issues. Many of these issues are a result of the governmental philosophy that defines government’s role vis-a-vis citizens, its employees, and the private enterprise sector.This study critically reviews the areas which are of major influence in this subject area and makes a proposal for action involving the legal issue of the burden of proof.