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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI056390-07
Application #
7809508
Study Section
Special Emphasis Panel (ZAI1-QV-I (J3))
Program Officer
Johnson, David R
Project Start
2003-09-30
Project End
2014-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
7
Fiscal Year
2010
Total Cost
$682,356
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Asare, A; Kanaparthi, S; Lim, N et al. (2017) B Cell Receptor Genes Associated With Tolerance Identify a Cohort of Immunosuppressed Patients With Improved Renal Allograft Graft Function. Am J Transplant 17:2627-2639
Sanz, Iñaki (2017) New Perspectives in Rheumatology: May You Live in Interesting Times: Challenges and Opportunities in Lupus Research. Arthritis Rheumatol 69:1552-1559
Tanaka, Toshihiro; Zhang, Weici; Sun, Ying et al. (2017) Autoreactive monoclonal antibodies from patients with primary biliary cholangitis recognize environmental xenobiotics. Hepatology 66:885-895
Jaworski, Juan Pablo; Bryk, Peter; Brower, Zachary et al. (2017) Pre-existing neutralizing antibody mitigates B cell dysregulation and enhances the Env-specific antibody response in SHIV-infected rhesus macaques. PLoS One 12:e0172524
Sanz, Iñaki (2016) Systemic lupus erythematosus: Extent and patterns of off-label use of rituximab for SLE. Nat Rev Rheumatol 12:700-702
Chara, Luis; Sánchez-Atrio, Ana; Pérez, Ana et al. (2015) The number of circulating monocytes as biomarkers of the clinical response to methotrexate in untreated patients with rheumatoid arthritis. J Transl Med 13:2
Halliley, Jessica L; Tipton, Christopher M; Liesveld, Jane et al. (2015) Long-Lived Plasma Cells Are Contained within the CD19(-)CD38(hi)CD138(+) Subset in Human Bone Marrow. Immunity 43:132-45
Misra, Ravi; Shah, Syed; Fowell, Deborah et al. (2015) Preterm cord blood CD4? T cells exhibit increased IL-6 production in chorioamnionitis and decreased CD4? T cells in bronchopulmonary dysplasia. Hum Immunol 76:329-338
Adlowitz, Diana G; Barnard, Jennifer; Biear, Jamie N et al. (2015) Expansion of Activated Peripheral Blood Memory B Cells in Rheumatoid Arthritis, Impact of B Cell Depletion Therapy, and Biomarkers of Response. PLoS One 10:e0128269
Wei, Chungwen; Jenks, Scott; Sanz, Iñaki (2015) Polychromatic flow cytometry in evaluating rheumatic disease patients. Arthritis Res Ther 17:46

Showing the most recent 10 out of 86 publications