- T cells regulate the production of anti-Sm and other antinuclear antibodies in autoimmune mice. In this competitive renewal, a series of recently-derived Sm-specific CD4 T cell clones will be exploited in order to understand the specificity and function of T cells in this SLE model. Cytokine production, TCR gene usage, and specificity of the clones will be determined. Using TCR data from these clones, transgenic (tg) mice will be generated in which the T cell repertoire is skewed toward Sm-recognition, and the principal investigator and his colleagues will examine the consequences of humoral anti-Sm production. The immunogenic or immunosuppressive effects of in vivo administration of immunodominant Sm peptides will be explored using Sm-reactive TCR and control MRL/lpr mice. To investigate processing of Sm by autoantigen-specific B cells and its effect on the T cell repertoire, the repertoire and function of T cells from anti-Sm immunoglobulin tg mice will be examined. In additional experiments, taking advantage of recent data concerning peptides associated with MRL/lpr class II MHC molecules, evidence for autoreactivity against the antigens from which the peptides are derived will be sought, and it will be determined whether the autoimmune mice are tolerant to these antigens. Finally, unique anti-Sm transfected CH12 B lymphoma cells will be used as model APC to ask how Sm is processed, how it is presented to Sm-antigen specific T cells, and which APC are most efficient in Sm processing.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Gretz, Elizabeth
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Kuan, Anita P; Cohen, Philip L (2005) p53 is required for spontaneous autoantibody production in B6/lpr lupus mice. Eur J Immunol 35:1653-60
Cohen, Philip L; Caricchio, Roberto (2004) Genetic models for the clearance of apoptotic cells. Rheum Dis Clin North Am 30:473-86, viii
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Caricchio, R; Cohen, P L (1999) Spontaneous and induced apoptosis in systemic lupus erythematosus: multiple assays fail to reveal consistent abnormalities. Cell Immunol 198:54-60
Fecho, K; Cohen, P L (1998) Fas ligand (gld)- and Fas (lpr)-deficient mice do not show alterations in the extravasation or apoptosis of inflammatory neutrophils. J Leukoc Biol 64:373-83
Booker, J K; Reap, E A; Cohen, P L (1998) Expression and function of Fas on cells damaged by gamma-irradiation in B6 and B6/lpr mice. J Immunol 161:4536-41

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