- 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR033887-15
Application #
6171473
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Gretz, Elizabeth
Project Start
1984-12-01
Project End
2003-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
15
Fiscal Year
2000
Total Cost
$283,395
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
Suh, Chang-Hee; Freed, John H; Cohen, Philip L (2003) T cell reactivity to MHC class II-bound self peptides in systemic lupus erythematosus-prone MRL/lpr mice. J Immunol 170:2229-35
Caricchio, Roberto; McPhie, Lenese; Cohen, Philip L (2003) Ultraviolet B radiation-induced cell death: critical role of ultraviolet dose in inflammation and lupus autoantigen redistribution. J Immunol 171:5778-86
Freed, J H; Marrs, A; VanderWall, J et al. (2000) MHC class II-bound self peptides from autoimmune MRL/lpr mice reveal potential T cell epitopes for autoantibody production in murine systemic lupus erythematosus. J Immunol 164:4697-705
Weintraub, J P; Cohen, P L (1999) Ectopic expression of B7-1 (CD80) on T lymphocytes in autoimmune lpr and gld mice. Clin Immunol 91:302-9
Caricchio, R; Kovalenko, D; Kaufmann, W K et al. (1999) Apoptosis provoked by the oxidative stress inducer menadione (Vitamin K(3)) is mediated by the Fas/Fas ligand system. Clin Immunol 93:65-74
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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