A major focus of our research is defining the molecular mechanisms by which pollutants adversely affect the immune response to respiratory infection. Specific focus is currently on the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) and the immune response to influenza A viruses. Dioxins bind and activate the aryl hydrocarbon receptor (AhR). The AhR is a ligand-activated transcription factor and is often considered an “orphan receptor,” because it has been difficult to identify an endogenous ligand. However, in addition to TCDD, many other pollutants activate the AhR, including coplanar polychlorinated biphenyls (PCBs) and polyaromatic hydrocarbons (PAH), such as benzo[a]pyrene and 7,12-dimethylbenzanthracene, which are found in cigarette smoke and diesel exhaust. In addition to pollutants, many plant-derived natural compounds and tryptophan metabolites bind to the AhR. Therefore, we are exposed to AhR ligands daily through ingestion and inhalation.

It has been known for quite some time that dioxins are very potent immune suppressants, and that their toxicity is mediated by the AhR; however, the molecular mechanism is not known. Nevertheless epidemiological data suggest that exposure to pollutants that contain AhR agonists correlates with diminished host resistance, altered immune function and an increased incidence of influenza and other respiratory infections. In animals, AhR activation impairs survival following infection with influenza virus, further illustrating the relationship between exposure to AhR ligands and altered host resistance to infection.

Our specific focus is currently on defining the molecular mechanisms by which AhR activation modulates the immune response to influenza virus infection. This work includes assessment of effects on innate and adaptive immune responses, and currently involves the following projects:

• Elucidating the role of the AhR in pulmonary inflammation and determining the role of the AhR in dioxin-mediated impairment of host resistance to infection
• Determining the mechanisms by which AhR activation impairs the activation, proliferation and differentiation of virus-specific T lymphocytes
• Characterizing the effects of exposure to TCDD on immunological memory.

A separate but related project involves studies to understand how developmental exposure to dioxins causes functional alterations in the immune system of the offspring. The changes observed following exposure to TCDD during development include suppressed lymphocyte expansion and differentiation, altered cytokine production, and increased inflammation in the lungs after influenza virus infection. These changes occur at developmental exposures to TCDD that cause no detectable change in hematopoiesis or the cellularity of immune organs, suggesting that inappropriate AhR activation during development interferes with the normal programming of the immune system via epigenetic mechanisms.

While studying the mechanism by which developmental exposure to low levels of TCDD impairs immune function later in life, we made a novel and unexpected discovery that exposure during pregnancy severely impairs mammary gland differentiation and lactogenesis. We have initiated studies to identify the mechanism by which inappropriate AhR activation affects mammary gland differentiation, and intend for these studies to become another major focus of our research program.

Selected Research Articles

Hogaboam JP, Moore AJ, Lawrence BP. 2007. The aryl hydrocarbon receptor affects distinct tissue compartments during ontogeny of the immune system. Toxicol Sci. Nov 17; [Epub ahead of print]

Teske S, Bohn AA, Hogaboam JP, Lawrence BP. 2007. Aryl hydrocarbon receptor targets pathways extrinsic to bone marrow cells to enhance neutrophil recruitment during influenza virus infection. Toxicol Sci. Nov 15; [Epub ahead of print]

Lawrence BP. 2007. Environmental toxins as modulators of antiviral immune responses. Viral Immunol. Summer;20(2):231-242. Review

Lawrence BP. 2007. Environmental toxins as modulators of antiviral immune responses. Viral Immunol. Summer;20(2):231-242.

Neff-LaFord H, Teske S, Bushnell TP, Lawrence BP. 2007. Aryl hydrocarbon receptor activation during influenza virus infection unveils a novel pathway of IFN-gamma production by phagocytic cells. J Immunol. Jul 1;179(1):247-255.

Lawrence BP, Roberts AD, Neumiller JJ, Cundiff JA, Woodland DL. 2006. Aryl hydrocarbon receptor activation impairs the priming but not the recall of influenza virus-specific CD8+ T cells in the lung. J Immunol. Nov 1;177(9):5819-5828.

Vorderstrasse BA, Lawrence BP. 2006. Protection against lethal challenge with Streptococcus pneumoniae is conferred by aryl hydrocarbon receptor activation but is not associated with an enhanced inflammatory response. Infect Immun. Oct;74(10):5679-5686.

Vorderstrasse BA, Cundiff JA, Lawrence BP. (2006) A dose-response study of the effects of prenatal and lactational exposure to TCDD on the immune response to influenza a virus. J Toxicol Environ Health A. Mar;69(6):445-463.

Bohn AA, Harrod KS, Teske S, Lawrence BP. (2005) Increased mortality associated with TCDD exposure in mice infected with influenza A virus is not due to severity of lung injury or alterations in Clara cell protein content. Chem Biol Interact. Aug 15;155(3):181-190.

Schmittgen TD, Gissel KA, Zakrajsek BA, Lawrence BP, Liu Q, Jupe ER, Lerner MR, Do SV, Brackett DJ. (2005) Diverse gene expression pattern during 5-fluorouridine-induced apoptosis. Int J Oncol. Aug;27(2):297-306

Teske S, Bohn AA, Regal JF, Neumiller JJ, Lawrence BP. (2005) Activation of the aryl hydrocarbon receptor increases pulmonary neutrophilia and diminishes host resistance to influenza A virus. Am J Physiol Lung Cell Mol Physiol. Jul;289(1):L111-124.

Lawrence BP, Vorderstrasse BA. (2004) Activation of the aryl hydrocarbon receptor diminishes the memory response to homotypic influenza virus infection but does not impair host resistance. Toxicol Sci. Jun;79(2):304-314.

Vorderstrasse BA, Fenton SE, Bohn AA, Cundiff JA, Lawrence BP. (2004) A novel effect of dioxin: exposure during pregnancy severely impairs mammary gland differentiation. Toxicol Sci. Apr;78(2):248-257.

Neff-LaFord HD, Vorderstrasse BA, Lawrence BP. 2003. Fewer CTL, not enhanced NK cells, are sufficient for viral clearance from the lungs of immunocompromised mice. Cell Immunol. Nov;226(1):54-64.

Mitchell KA, Lawrence BP. (2003) T cell receptor transgenic mice provide novel insights into understanding cellular targets of TCDD: suppression of antibody production, but not the response of CD8⁺ T cells, during infection with influenza virus. Toxicol Appl Pharmacol. Nov 1;192(3):275-286.

Mitchell KA, Lawrence BP. (2003) Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) renders influenza virus-specific CD8⁺ T cells hyporesponsive to antigen. Toxicol Sci. Jul;74(1):74-84.

Warren TK, Mitchell KA, Lawrence BP. (2000) Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses the humoral and cell-mediated immune responses to influenza A virus without affecting cytolytic activity in the lung. Toxicol Sci. Jul;56(1):114-123.