Environmental toxicants with the ability to directly or indirectly modify the cellular thiols of lymphocytes can initiate immune dysfunctions resulting in increased incidence of infectious diseases, cancer and/or autoimmune diseases. The majority of our analyses will employ T cells, the regulators of the immune system; however, we will also compare the thiol characteristics and sensitivities of T and B cells; furthermore, we will evaluate the thiol-related biochemical differences between mouse and human lymphocytes. Preliminary data suggests that these species have differential thiol characteristics. The ability of exogenous and endogenous thiols, thiol-blockers, oxidants and anti-oxidants, as well as irradiation, to alter the subcellular mechanisms necessary for the activation and growth of lymphocytes will be assessed. In order to accomplish this objective we first must evaluate some thiol characteristics key to the biochemical activation of lymphocytes. The lymphoid subsets have different thiol sensitivities which we believe are due, in part, to variances in their exofacial thiols. Biochemical and cellular/molecular biology technics will be utilized to assess the influences of thiol modulation at various levels within the cell (exofacial, transmembranal, cytosolic, and nuclear). Novel thiol reactive chemicals and antibodies will be used to probe these cellular domains. Various cDNA probes, monoclonal antibodies, and anti-sense oligonucleotides will be used to assess the regulation of the mRNA expression, protein expression (and distribution) and need for thiol modulation of cellular cysteinyl proteins believed to be involved in lymphocyte activation. Some specific proteins to be assayed include protein kinase C, phospholipase C, calmodulin, and ornithine decarboxylase as well as some proto-oncogenes (c-myc; c-fos). The homogenous nature of cloned T cells, T cell hybridomas, and T cell tumor lines will aid in the analysis of the thiol-related sensitivities and activities of the subsets. Subcellular differences between the T cell subsets and cell lines will be compared. Evaluation of some biochemical changes involved in the stimulation of the different types of T cells will aid in the assessment of differences between non-proliferating and rapidly proliferating T cells and the processes involved in modulating their activation. The mechanism(s) of cell injury and modulation of activation and growth by toxicants with thiol reactivities will be further defined by our analyses. In addition, information may be obtained on numerous diseases which concomitantly have aberrant immune functions and redox states such as AIDS, Bloom's Syndrome, Ataxia Telangiectasia and Down's Syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003778-07
Application #
3251468
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1985-06-15
Project End
1995-05-31
Budget Start
1991-06-01
Budget End
1992-05-31
Support Year
7
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Albany Medical College
Department
Type
Schools of Medicine
DUNS #
City
Albany
State
NY
Country
United States
Zip Code
12208
Ault, Jeffrey G; Lawrence, David A (2003) Glutathione distribution in normal and oxidatively stressed cells. Exp Cell Res 285:9-14
Colinas, R J; Walsh, A C (1998) Cell separation based on the reversible interaction between calmodulin and a calmodulin-binding peptide. J Immunol Methods 212:69-78
Hall, M J; Lawrence, D A; Lansiedel, J C et al. (1997) Long-term exposure to methotrexate induces immunophenotypic changes, decreased methotrexate uptake and increased dihydrofolate gene copy number in Jurkat T cells. Int J Immunopharmacol 19:709-20
Lawrence, D A; Song, R; Weber, P (1996) Surface thiols of human lymphocytes and their changes after in vitro and in vivo activation. J Leukoc Biol 60:611-8
Krieger, J A; Landsiedel, J C; Lawrence, D A (1996) Differential in vitro effects of physiological and atmospheric oxygen tension on normal human peripheral blood mononuclear cell proliferation, cytokine and immunoglobulin production. Int J Immunopharmacol 18:545-52
Lawrence, D A; Colinas, R J; Walsh, A C (1996) Influence of oxygen partial pressure on human and mouse myeloid cell line characteristics. Fundam Appl Toxicol 29:287-93
Walsh, A C; Li, W; Rosen, D R et al. (1996) Genetic mapping of GLCLC, the human gene encoding the catalytic subunit of gamma-glutamyl-cysteine synthetase, to chromosome band 6p12 and characterization of a polymorphic trinucleotide repeat within its 5' untranslated region. Cytogenet Cell Genet 75:14-6
Walsh, A C; Michaud, S G; Malossi, J A et al. (1995) Glutathione depletion in human T lymphocytes: analysis of activation-associated gene expression and the stress response. Toxicol Appl Pharmacol 133:249-61
Tian, L; Noelle, R J; Lawrence, D A (1995) Activated T cells enhance nitric oxide production by murine splenic macrophages through gp39 and LFA-1. Eur J Immunol 25:306-9
Palace, G P; Lawrence, D A (1995) Nucleotide changes in oxidatively stressed lymphocytes. J Biochem Toxicol 10:137-42

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