Environmental & Molecular Toxicology

The overall goals of my research program are to understand the mechanisms by which chemicals of environmental significance interact with the immune system. Such interactions may result in altered immune function leading to decreased resistance to infectious diseases and increased susceptibility to cancer. We are especially interested in chemicals that act as ligands for the Ah receptor (AhR). Such chemicals include the polychlorinated dioxins, of which 2,3,7,8-tetrachlorodobenzo-p-dioxin (TCDD) is the most toxic, and polychlorinated biphenyls (PCB), which represent widespread environmental contaminants. We are also interested in studying the immunomodulatory effects of natural, food-derived AhR ligands. The majority of our studies involve the use of animal models, including transgenic and gene knock-out mice, to understand how the immune system in altered after exposure to these chemicals. Our recent finding that TCDD prevents the development of Type-1 diabetes in NOD mice without any overt side-effects demonstrates the adage that “one man’s poison is another man’s cure” and we plan to use this model extensively in the future. Multi-color flow cytometry is used extensively in our studies to determine the effects of chemical exposure on the activation and differentiation of individual immune cells. We also use genomic approaches to determine changes in gene expression that are induced by these chemicals.

Projects:

Internal Advisor; Administration Core A. 

Selected Publishings:

• Funatake, Castle J., Marshall, Nikki B. and Kerkvliet, Nancy I. (2008) '2,3,7,8-Tetrachlorodibenzo-p-dioxin Alters the Differentiation of Alloreactive CD8+ T Cells Toward a Regulatory T Cell Phenotype by a Mechanism that is Dependent on Aryl Hydrocarbon Receptor in CD4+ T Cells', Journal of
  Immunotoxicology, 5:1, 81 - 91
• YU Z, LOEHR CV, FISCHER KA, LOUDERBACK MA, KRUEGER SK, DASHWOOD RH, KERKVLIET NI, PEREIRA CB, JENNINGS-GEE JE, DANCE ST, MILLER MS, BAILEY GS, AND WILLIAMS DE. (2006) In utero exposure of mice to dibenzo[a,l]pyrene produces lymphoma in the offspring: role of the aryl hydrocarbon receptor. Cancer Res. 66(2):755-62.
• FUNATAKE, C.J., MARSHALL, N.B., STEPPAN, L.B., MOURICH, D.V., KERKVLIET, N.I. (2005) Cutting edge: Activation of the aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin generates a population of CD4+ CD25+ cells with characteristics of regulatory T cells. J Immunol. 175(7):4184-8.
• MAHADEVAN, B., LUCH, A., BRAVO, C.F., ATKIN, J., STEPPAN, L.B., PEREIRA, C., KERKVLIET, N.I., and BAIRD, W.M. (2005). Dibenzo[a,l]pyrene induced DNA adduct formation in lung tissue in vivo. Cancer Lett. 227(1):25-32.
• FUNATAKE, C.J., DEARSTYNE, E.A., STEPPAN, L.B., SHEPHERD, D.M., SPANJAARD, E.S., MARSHAK-ROTHSTEIN, A., KERKVLIET, N.I. (2004). Early consequences of 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on the activation and survival of antigen-specific T cells. Toxicol Sci. 82(1):129-42.
• CHOI, J-Y, OUGHTON, J.A., and KERKVLIET, N.I. (2003) Functional alterations in CD11b(+)Gr-1(+) cells in mice injected with allogeneic tumor cells and treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Int Immunopharmacol. 3(4):553-570.
• VORDERSTRASSE, B.A., DEARSTYNE, E.A. and KERKVLIET, N.I. (2003). Influence of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the antigen-presenting activity of dendritic cells. Tox. Sci. 72, 103-112.
• KERKVLIET, N. I., SHEPHERD, D.M. and L. BAECHER-STEPPAN (2002) T lymphocytes are direct, aryl hydrocarbon receptor (AhR)-dependent targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD): AhR expression in both CD4+ and CD8+ T cell is necessary for full suppression of a cytotoxic T lymphocyte response by TCDD. Toxicol. Appl. Pharmacol. 185(2):146-152.
• RUBY, C.E., LEID, M.. and KERKVLIET, N. I. (2002). 2,3,7,8-Tetrachlorodibenzo-p-dioxin suppresses tumor necrosis factor-a and anti-CD40-induced activation of NF-κB/Rel in dendritic cells: p50 homodimer activation is not affected. Molec. Pharmacol. 62(3):722-728.
• DEARSTYNE, E.A. and KERKVLIET, N.I. (2002). Mechanism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced decrease in anti-CD3-activated CD4+ T cells: The roles of apoptosis, Fas and TNF. Toxicology. 170(1-2):139-151.
• MAXWELL, J.R., RUBY, C., KERKVLIET, N.I., and VELLA, AT. (2002). Contrasting the roles of costimulation and the natural adjuvant lipopolysaccharide during the induction of T cell immunity. J Immunol. 168(9):4372-81.
• KERKVLIET, N. I. (2002). Recent advances in understanding the mechanisms of TCDD immunotoxicity. Int Immunopharmacol. 2(2-3):277-91.
• VORDERSTRASSE, B.A. and KERKVLIET, N.I. (2001). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) affects the number and function of murine splenic dendritic cells and their expression of accessory molecules. Toxicol. Appl. Pharmacol. 171(2):117-25.
• VORDERSTRASSE, B.A., STEPPAN, L. B., SILVERSTONE, A.E., AND KERKVLIET, N. I. (2001). Aryl hydrocarbon receptor-deficient mice generate normal immune responses to model antigens and are resistant to TCDD-induced immune suppression. Toxicol Appl Pharmacol. 171(3):157-64.
• SHEPHERD, D., STEPPAN, L.B., HEDSTROM, O. R., and KERKVLIET, N.I. (2001). Anti-CD40 treatment of TCDD-exposed C57Bl/6 mice induces activation of antigen-presenting cells yet fails to overcome TCDD-induced suppression of allograft immunity. Toxicol. Appl. Pharmacol. 170: 10-22.
• LAWRENCE, B.P., WILL, Y., REED, D.J. AND KERKVLIET , N. I. (2000). Gamma-glutamyltranspeptidase knockout mice as a model for understanding the consequences of diminished glutathione on T cell-dependent immune responses. Euro. J. Immunol. 30(7):1902-1910.
• PRELL, R.A., DEARSTYNE, E. STEPPAN, L. B., VELLA, A.T. and KERKVLIET, N.I. (2000). CTL hyporesponsiveness induced by TCDD: role of cytokines and apoptosis. Toxicol. Appl. Pharmacol. 166(3):214-21.
• SHEPHERD, D. M., DEARSTYNE, E.A. and KERKVLIET, N. I. (2000). Effects of TCDD on the activation of ovalbumin (OVA)-specific D011.10 transgenic CD4+ T cells in adoptively-transferred mice. Tox. Sci. 56(2):340-50.