application) Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that frequently involves the kidney causing approximately 1% of all cases of adult, and 5% of pediatric, end- stage renal failure in the USA every year. The MRL mouse strain, when combined with either a defect in Fas (MRL-1pr/1pr) or in Fas ligand (MRL- gld/gld), develops a disease resembling human SLE and also, in a broader sense, serves as a model of autoimmunity due to failure of peripheral tolerance. The long-term goal of this application is to understand the function and regulation of pathogenic antigen-specific autoreative CD4+ T lymphocytes (ART) in this model by: 1) isolating ART clones, ideally specific for nucleosomal determinants, and providing their pathogenicity in adoptive transfer experiments; these ARTs will be used as a source of the T cell receptor DNA from which a T cell receptor transgenic mouse will be constructed. The ART will be derived from double mutant 1pr/gld MRL mice (with combined defects of Fas and Fas ligand) in order to facilitate these adoptive transfer experiments; in additional to conventional antigen presenting cells (APC), rheumatoid factor expressing transgenic B cells pulsed with immune complexes will be used as a source of APC; 2) developing a mouse transgenic for the alpha and beta chains of the T cell receptor of the selected pathogenic ART clone using appropriate molecular techniques to obtain rearranged V-alphaJ-alpha and VDJ-beta sequences, inserting these into appropriate vectors and establishing founders by blastocyst injection of the constructs; 3) characterizing T cell education, function and recirculation in the TCR transgenic mouse developed; this will be done by analyzing thymic selection, TCR-transgene expression, in vitro reactivity, in vivo disease-inducing properties of the transgenic T cell and in vivo sites of interaction of the transgenic T cell with autoantibody-producing B cells. This project should provide insights into basic mechanisms of autoimmunity relevant not only to SLE but also to other immunologically mediated renal disease in which autoreactive T cells play a pathogenic role. It will also serve as a valuable training vehicle whereby the applicant will extend his expertise in cellular immunology and acquire new understanding and skills in state of the art molecular biology, transgenic technology and immunohistochemistry.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (SRC)
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Bishop, Terry Rogers
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Boston Medical Center
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