As described in this Program Project Grant application, these projects seek to develop innovative therapies for the treatment of animal models of autoimmune diseases and study the mechanisms of effect. The therapies are derived from work carried out in the initial funding period of thePO1. Dr. Lawrence Steinman, in collaboration with Dr. C. Garrison Fathman, developed a model of DNA vaccination that will be used in the studies proposed in Project 3 concerning therapy of EAE. Dr. Fathman, in collaboration with Dr Nolan, developed the model of adoptive cellular gene therapy described in Project 1. The model of CIA will be used instead of EAE in Project 1 for ease of tissue analysis for the microarray studies proposed. Dr. Garry Nolan (Project 2) has developed novel techniques to assess intracellular kinases and will adapt this technology to studying mechanisms of therapy of these animal models of autoimmune disease. In collaboration with Drs. Fathman and Steinman, the intracellular kinase assays will be used in concert with the microarray studies to begin to look at mechanisms of therapy of autoimmune diseases. Allthree projects rely upon the utilization of experimental animal models to test the hypotheses put forward in these separate but interrelated projects. The strains of mice to be used include conventional mice, PL/J, SJL/J, and B 10.P1/j for EAE (Project 3), as well as DBA/1 and B10.P1 mice for CIA (Project 1), and DBA/1 for studies in Project 2. Conventional mice have been bred in our animal colony at Stanford University in the Department of Comparative Medicine (DCM) for the past ten years. All of the mice are kept in specific pathogen free animal rooms and tended by animal caretakers under the guidance of Ms. Cariel Taylor, the LSRA III in charge of the Animal Core. The animal model of EAE requires daily individual animal observation and, according to the guidelines of the DCM, individual mice must be monitored and records kept daily in ink in a lab notebook. CIA mice must also be scored daily. For this reason, we have developed the concept of an animal core overseen by one of our most competent LSRA III individuals so that the micecan be monitored and scored in a uniform manner for the interrelated projects in this PPG.These animals will be purchased from Jackson Labs and maintained in DCM under guidelinesapproved by the NIH for animal maintenance and breeding. Ms. Cariel Taylor, the LSRA III in charge of the Animal Core technical aspects, has spent the last fifteen years working with Dr. Fathman, in part, maintaining his animal colonies which include convention mice as well as many transgenic and immunodeficient mice. Mice or mouse lymphocytes will be utilized in all three projects and the representative number being used for each project in each year is indicated in the appropriate project. The Department of Comparative Medicine is a fully accredited facility and the animals will be housed according to strict and approved veterinarian guidelines.
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