The studies presented in this renewal application are aimed at the investigation of the hypothesis that a regulatory subset of lymphocytes is contained within the RT6+ T cell population. In this view, one of the primary events in mercury-induced renal autoimmunity of BN and MAXX rats is a relative decrease of RT6+ T lymphocytes, followed by a return to normal levels when the animals spontaneously recover and become resistant to further induction of the disease. We stress the point that autoimmunity does no simply result form a decrease in regulatory RT6+ T lymphocytes but other factors (presence of specific T cell receptors, changes in cytokine-lymphokine network, changes in idiotype-anti-idiotype network) are also required for autoimmune disease to arise. At this point, we propose to focus on phenotypic and functional analyses of T lymphocytes from rats at various stages of renal autoimmunity for the following Specific Aims: 1. Investigate changes in percentages and total numbers of RT6+ and other subsets of T lymphocytes in anti-GBM autoimmunity induced by mercury in BN rats. We will determine whether the decrease of RT6+ lymphocytes in mercury-treated rats is equally distributed in the CD4+ and CD8+ (or other) subclasses or is more prevalent in one of the two. 2. Modulate anti-GBM autoimmunity through manipulations of the RT6+ T cell subset. In this investigation, we will examine whether RT6+ cell depletion favors anti-GBM autoimmunity in BN rats not treated with mercury, and, if rt6+ cell depletion by itself does not induce renal autoimmunity, whether it increases the severity and/or protracts the duration of mercury-induced anti-GBM autoimmunity. 3. Perform reconstitution experiments by adoptive transfer of RT6+ T lymphocytes. In this study, we will determine whether adoptive transfer of purified RT6+ lymphocytes from normal, untreated BN rats inhibits ongoing autoimmune responses to GBM and whether adoptive transfer of RT6+ lymphocytes from rats that have recovered from anti-GBM disease causes more potent suppressive effects than similar cells from untreated rats. 4. Study mechanisms of mercury-induced changes in percentage of RT6+ cells (T cell activation, accelerated export of RT6- cells from the thymus, RT6+ cell death). The studies presented in this renewal application are motivated by the problem of chemically induced autoimmunity in human subjects, a recently recognized environmental hazard that may affect individuals genetically pre-disposed to autoimmune disease and chronically exposed to certain chemicals. The mercury-induced rat model is particularly valuable for studies of immune regulation because of its reproducible response at various dosages of mercuric chloride, an incidence that has reached 100% in most of our experiments, its occurrence in 2 inbred rat strains (BN and MAXX) and a self-limiting autoimmune response.

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National Institute of Environmental Health Sciences (NIEHS)
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Toxicology Subcommittee 2 (TOX)
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University of Connecticut
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Bigazzi, P E; Kosuda, L L; Hannigan, M O et al. (2003) Lack of graft-versus-host-like pathology in mercury-induced autoimmunity of Brown Norway rats. Clin Immunol 109:229-37
Bigazzi, P E (1999) Metals and kidney autoimmunity. Environ Health Perspect 107 Suppl 5:753-65
Bigazzi, P E (1997) Autoimmunity caused by xenobiotics. Toxicology 119:1-21
Kosuda, L L; Hannigan, M O; Bigazzi, P E et al. (1996) Thymus atrophy and changes in thymocyte subpopulations of BN rats with mercury-induced renal autoimmune disease. Autoimmunity 23:77-89
Kosuda, L L; Greiner, D L; Bigazzi, P E (1994) Mercury-induced renal autoimmunity in BN-->LEW.1N chimeric rats. Cell Immunol 155:77-94
Kosuda, L L; Hosseinzadeh, H; Greiner, D L et al. (1994) Role of RT6+ T lymphocytes in mercury-induced renal autoimmunity: experimental manipulations of ""susceptible"" and ""resistant"" rats. J Toxicol Environ Health 42:303-21
Bigazzi, P E (1994) Autoimmunity and heavy metals. Lupus 3:449-53
Kosuda, L L; Greiner, D L; Bigazzi, P E (1993) Mercury-induced renal autoimmunity: changes in RT6+ T-lymphocytes of susceptible and resistant rats. Environ Health Perspect 101:178-85
Contrino, J; Kosuda, L L; Marucha, P et al. (1992) The in vitro effects of mercury on peritoneal leukocytes (PMN and macrophages) from inbred brown Norway and Lewis rats. Int J Immunopharmacol 14:1051-9
Potter, N T; Bigazzi, P E (1992) Acute optic neuritis associated with immunization with the CNS myelin proteolipid protein. Invest Ophthalmol Vis Sci 33:1717-22

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