The broad aim of this application is to translate advances in immunology and molecular biology into practical, safe, and effective therapies for people with autoimmune diseases. Toward this end, we will participate in collaborative clinical trials of novel immunotherapies, and we will conduct basic research into the mechanisms that lead to autoimmunity as well as the mechanisms that can be harnessed to prevent autoimmunity. This proposal to become an Autoimmunity Center of Excellence consists of a Clinical Center, two basic research projects, and an Immune Function Monitoring Core as described below: Clinical Center (David Wofsy, PI). Investigators involved in this application have extensive experience in the conduct of clinical trials in diverse autoimmune diseases. This application focuses primarily on systemic lupus erythematosus (SLE), multiple sclerosis (MS), and type I diabetes mellitus (IDDM). Two clinical protocols are proposed, both based on basic research conducted at UCSF by participants in this proposal. Protocol 1 is based on the observation that blockade of T cell co-stimulation by CTLA4Ig, in combination with conventional therapy with cyclophosphamide, produces long-lasting benefit in murine lupus. It tests the hypothesis that this approach to therapy will be effective in people with lupus nephritis. Protocol 2 is based on the observation that HMG-CoA inhibitors ('statins') retard murine models for MS. It tests the hypothesis that atorvastatin will prevent progression to MS in patients at high risk. Project 1 - Activation and functions of regulatory T lymphocytes (Abul Abbas and Jeffrey Bluestone, co-PIs): The principal goals of this project are: (1) to clarify the signals involved in the induction and maintenance of regulatory T cells (Treg); and (2) to understand the mechanisms by which Treg control potentially pathogenic effector cells. Project 2 - Targeting antigen-specific T cells in SLE (David Daikh, PI): The principal goals of this project are: (1) to use murine models for SLE to clarify the mechanisms of disease, and to understand the basis for the efficacy of specific therapeutic interventions; and (2} to develop novel antigen-specific approaches to the treatment of autoimmune disease in murine models as a prelude to clinical trials in humans. Immune Function Monitoring Core (Lawrence Fong, PI): This core facility will provide the capability for developing and performing cellular and antibody-based immune assays on samples (e.g., blood, lymph node, etc.) derived from patients participating in ACE trials. Assays that will be available include: flow cytometry; MHC/peptide tetramer production and staining; cytokine analysis by ELISA, ELISPOT, and flow; T cell proliferation; and cytotoxicity assays. This core will support the Clinical Center and Project 2. Together, the Clinical Center, individual projects, and Immune Monitoring Core comprise a tightly linked program to bring novel therapies from bench to bedside and to investigate the mechanisms by which these therapies retard autoimmune disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI056388-04
Application #
7039235
Study Section
Special Emphasis Panel (ZAI1-CL-I (M2))
Program Officer
Johnson, David R
Project Start
2003-09-30
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2006
Total Cost
$843,828
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Dall'Era, Maria; Pauli, Mariela L; Remedios, Kelly et al. (2018) Adoptive Regulatory T Cell Therapy in a Patient with Systemic Lupus Erythematosus. Arthritis Rheumatol :
Wofsy, David; Diamond, Betty; Houssiau, Frédéric A (2015) Crossing the Atlantic: the Euro-Lupus Nephritis regimen in North America. Arthritis Rheumatol 67:1144-6
DuPage, Michel; Chopra, Gaurav; Quiros, Jason et al. (2015) The chromatin-modifying enzyme Ezh2 is critical for the maintenance of regulatory T cell identity after activation. Immunity 42:227-238
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Jeker, Lukas T; Zhou, Xuyu; Blelloch, Robert et al. (2013) DGCR8-mediated production of canonical microRNAs is critical for regulatory T cell function and stability. PLoS One 8:e66282
Jeker, Lukas T; Bluestone, Jeffrey A (2013) MicroRNA regulation of T-cell differentiation and function. Immunol Rev 253:65-81
de Kouchkovsky, Dimitri; Esensten, Jonathan H; Rosenthal, Wendy L et al. (2013) microRNA-17-92 regulates IL-10 production by regulatory T cells and control of experimental autoimmune encephalomyelitis. J Immunol 191:1594-605
Gratz, Iris K; Truong, Hong-An; Yang, Sara Hsin-Yi et al. (2013) Cutting Edge: memory regulatory t cells require IL-7 and not IL-2 for their maintenance in peripheral tissues. J Immunol 190:4483-7

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