We are studying the cellular and molecular basis of autoimmune diseases with two purposes. First, we want to establish the pathogenic role and antigen-specificity of T cells that cause autoimmune diseases such as multiple sclerosis, clotting factor inhibition, insulin-dependent diabetes, among others. Second, we would like to determine the feasibility of specific antigen-induced apoptosis as a means of treating such autoimmune diseases. To these ends, we have made progress in the following areas: 1) we have reinitiated studies of recombinant molecules containing antigens potentially involved in multiple sclerosis with the goal of establishing a Cooperative research agreement to test such a form of therapy in a clinical trial. 2) we are studying sets of apoptosis-related genes for association with autoimmunity to establish genetic determinants of autoimmunity; and 3) we are initiating studies of antigen-specific therapy to prevent the formation of blocking antibodies following factor VIII administration to hemophiliacs. We will also be initiating studies of a new transgenic mouse model for autoimmune thyroiditis. As part of these studies we are also trying to understand the regulation of antigen-induced death by T cell receptor stimulation. These studies should yield important new insights into the pathogenesis and treatment of autoimmune diseases which is a widespread health problem in the U.S. particularly among working women. We have shown that a transgenic mouse model can be constructed for the autoimmune disease myasthenia gravis. This disease is due to an antibody that causes muscle damage and we would like to test whether immunological tolerance directed at T cells can influence this disease. We have found that there are a number of factors that influence antigen-specific disease induction and we plan to use our new mouse strain to characterize the factors that precipitate the autoimmune symptoms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000717-10
Application #
6986316
Study Section
(LI)
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2004
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Zheng, Lixin; Bidere, Nicolas; Staudt, David et al. (2006) Competitive control of independent programs of tumor necrosis factor receptor-induced cell death by TRADD and RIP1. Mol Cell Biol 26:3505-13
Zheng, Lixin; Lenardo, Michael (2006) T helper 2 cells' preferred way to die. Immunity 25:187-8
Deng, Guo-Min; Zheng, Lixin; Chan, Francis Ka-Ming et al. (2005) Amelioration of inflammatory arthritis by targeting the pre-ligand assembly domain of tumor necrosis factor receptors. Nat Med 11:1066-72
Lobito, Adrian A; Lopes, Marcela F; Lenardo, Michael J (2004) Ectopic T cell receptor expression causes B cell immunodeficiency in transgenic mice. Eur J Immunol 34:890-8
Miagkov, Alexei; Lobito, Adrain A; Yang, Bingzhi et al. (2003) Production and characterization of a T cell receptor transgenic mouse recognizing the immunodominant epitope of the Torpedo californica acetylcholine receptor. Ann N Y Acad Sci 998:379-83
Lobito, Adrian A; Yang, Bingzhi; Lopes, Marcela F et al. (2002) T cell receptor transgenic mice recognizing the immunodominant epitope of the Torpedo californica acetylcholine receptor. Eur J Immunol 32:2055-67
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Locksley, R M; Killeen, N; Lenardo, M J (2001) The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104:487-501
Zheng, L; Schickling, O; Peter, M E et al. (2001) The death effector domain-associated factor plays distinct regulatory roles in the nucleus and cytoplasm. J Biol Chem 276:31945-52
Siegel, R M; Lenardo, M J (2001) To B or not to B: TNF family signaling in lymphocytes. Nat Immunol 2:577-8

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