Healthy immune responses depend on the balanced engagement of B cells and T cells with effector functions (to protect against pathogens) and regulatory functions to avoid autoimmunity. The overarching theme of this competitive renewal of the University of Rochester Autoimmunity Center of Excellence is the investigation of how a gain-of-effector-function and/or a loss-of-regulatory-function subverts this physiological balance and results in clinical autoimmunity. This proposal builds on strong and tantalizing results obtained in the previous cycle of ACE funding to propose a coordinated approach to the study of our central tenet in a systemic autoimmune disease (SLE) and an organ-specific autoimmune disease (Type 1 Diabetes). The successful Scientific Core already established for the ACE will provide state-of-the-art single cell assays of antigen specificity and cytokine secretion as well as outstanding scientific expertise in the analysis and interpretation of cytokine secretion profiles. The current ACE retains the vast majority of previous investigators and has recruited additional outstanding investigators into the field of autoimmunity. One of the previous investigators, Dr. Anolik, who recently received her first RO1, will lead an exciting Pilot Project that builds on previous strengths and findings to investigated a related yet distinct topic (the role of bone marrow as secondary lymphoid tissue) thereby bringing another autoimmune disease (Rheumatoid Arthritis) under the umbrella of the ACE. Finally, Dr. Looney will continue his superb leadership of the ACE Clinical Component by proposing, in close interaction with the other investigators, two original, hypothesis-driven clinical and mechanistic studies in SLE and RA. These concept proposals and their mechanistic studies have great synergy with the topics and technology of the ACE the center. PROJECT 1A: Clinical Component (Looney, R) CLINICAL COMPONENT DESCRIPTION (provided by applicant): The University of Rochester ACE will be a collaborative program involving Rheumatologist, Neurologist, Endocrinologists and Basic Scientists. The diseases we will target include systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, multiple sclerosis, and type I diabetes mellitus. We have well established clinical trials programs and large patient populations for each of these diseases. The University of Rochester has an excellent infrastructure for clinical trials including the Clinical and Translational Science Institute funded by the NIH and an investigational drug service in the Department of Pharmacy. We are proposing two phase I clinical trial concepts with innovative agents that can be viewed as logical extensions of our program using rituximab to target B cells in autoimmune disease. #1 Carfilzomib for SLE: targeting the proteosome. Proteosome inhibitors can block cellular activation through their effects on NFkappaB and can induce apoptosis in susceptible cells by activating the unfolded protein response. Bortezomib, a proteosome inhibitor approved for myeloma, has been shown to be very active in a mouse model of SLE, and is able to induce apoptosis of both short- and long-lived plasma cells. In addition, we have preliminary data that bortezomib can block alpha interferon production by plasmacytoid dendritic cells. However, bortezomib can cause severe neuropathy and is therefore not appropriate non-malignant diseases. Carfilzomib, a new proteosome inhibitor, already in trails for hematologic malignancies, is not associated with neuropathy. Therefore, we propose a phase I study of Carfilzomib in patients with stable SLE. The primary mechanistic outcomes will be the effects on peripheral blood plasmablasts and plasmacytoid dendritic cells. #2 Anti-CXCL13 for Human RA: Targeting Migration into Tissue. B cell depletion using rituximab has been shown to be effective in rheumatoid arthritis and relapsing remitting multiple sclerosis. We believe that inhibition of B cell migration into target tissues is responsible for much of this benefit. Therefore, we propose inhibiting CXCL13 using a human monoclonal antibody. The primary clinical outcome will again be adverse events. The primary mechanistic outcome will be changes in peripheral blood memory B cells.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-QV-I (J3))
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Johnson, David R
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University of Rochester
Internal Medicine/Medicine
Schools of Dentistry
United States
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