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...
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...
The effect of pyridoxine (PN) supplementation on lymphocyte
responsiveness was investigated in 15 elderly volunteers (aged
65-81 years) by measuring lymphocyte proliferation to T and B cell
mitogens, lymphocyte subpopulations with monoclonal antibodies
(T3, T4, T8) and plasma pyridoxal 5'-phosphate (PLP) concentration
at pre-supplementation and after 1 and 2 months...
In vivo generation of cytotoxic T cell activity
against alloantigen is suppressed by the aromatic
hydrocarbon (Ah) receptor binding 3,3',4,4',5,5'-
hexachlorobiphenyl isomer (HxCB). Previous studies in
this laboratory suggest that HxCB may alter early
event(s) in the activation of cytotoxic T lymphocytes
(CTL). Production of and response to interleukins 1...
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent immunosuppressant and a prototypic ligand for the aryl hydrocarbon receptor (AhR). In a graft versus host (GvH) response, treatment with TCDD suppresses a cytotoxic T-lymphocyte (CTL) response by Day 10, concurrent with a T-regulatory (Treg) like phenotype in the donor CD4+ T-cells, observed on Day...
The AhR is a ligand-activated transcription factor that mediates the potent immunosuppressive effects of TCDD. AhR-dependent changes in gene expression appear to alter the differentiation of CD4+ T cells to induce a population of CD4+CD25+ T regulatory cells (Tregs) that suppress the immune response. Ascertaining if and how the AhR...
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...
The aryl hydrocarbon receptor (AhR) has recently been described as a novel therapeutic target, given the potent suppression of multiple immune-mediated diseases following activation by the prototypic ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In the parent-into-F1 graft-versus-host (GVH) model, suppression of the cytotoxic T-lymphocyte (CTL) response is associated with the presence of CD25⁺CTLA-4⁺IL-10⁺Foxp3[superscript...
Monocrotaline (MCT) is a member of a class of naturally occurring
phytotoxins known as pyrrolizidine alkaloids (PAs). Exposure to PAs can result
in liver and cardiopulmonary lesions as well as lymphoid organ atrophy. In the
present study C57BI/6 (B6) mice received MCT (0-150 mg/kg/day, po) for 14
days. Overt toxicity...
In experimentally exposed mice, the environmental contaminant 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) produces significant suppression of adaptive immune responses at low doses. However, the underlying biochemical and cellular mechanisms of TCDD-induced immunotoxicity have remained elusive since the identification of these effects nearly 30 years ago. Antigen-presenting cells (APC) constitute various populations of...