This application is a competitive renewal of the Autoimmunity Center of Excellence (ACE) at Duke. Its research focus will continue to be modulation of B cell responses in autoimmune disease. The ACE will be under the leadership of Dr. E. William St. Clair, Professor of Medicine and Immunology. For the past 5 years, Duke has been a productive member of the ACE network, contributing new insights into the developmental pathways of B cells and the mechanisms of B cell directed therapy. The proposed ACE builds on these discoveries and will support 2 new basic science projects, 5 ongoing and 2 new clinical trials, and an Administrative Core, and continue to emphasize a strong and fluid integration between the bench and the bedside. Tedder and colleagues have recently found that a phenotypically unqiue subset of B cells secreting IL-10 (called B10 cells) serve as critical negative regulators during adaptive CD4+ T cells responses, and dramatically suppress Th1 immune responses and autoimmune disease in mice. For Basic Research Project 1, they will examine the hypothesis that antigen-specific regulatory B10 cells modulate autoimmune responses in mice and man and that they can be manipulated for therapeutic gain. A picture is gradually emerging about the precursors of self-reactive B cells in autoimmune disease. Kelsoe and coworkers in Basic Research Project 2 will investigate developmentally regulated expression of activated cytidine deaminase (AID) in human fetal and neonatal pre-, pro, and immature/transitional B cells and its relationship to the generation of self-reactive B cells in human autoimmune disease, potentially eludidating another pathway of B cell self-reactivity outside the confines of normal tolerance mechanisms. We propose two new clinical trials to investigate lymphotoxin-beta receptor fusion protein as a treatment for primary Sjgren's syndrome, and rituximab therapy for bullous pemphigoid. A Pilot Research Project is also proposed to engineer tetramers of self-antigen enabling the identification and characterization of self-reactive B cells, which will have implications for the goals of the clinical and other basic research projects. Overall, the Duke ACE will bridge these basic and clinical studies to advance our understanding of autoimmune disease. The B cell is a type of immune cell essential to autoimmunity. The goal of the proposed Autoimmunity Center of Excellence at Duke is to improve our understanding of the roles played by B cells in human autoimmune disease. The projects are designed to be highly integrative between the bench and the bedside, with collaborations between basic and clinical scientists. These studies may lead to better treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
3U19AI056363-10S1
Application #
9474010
Study Section
Special Emphasis Panel (ZAI1-QV-I (J3))
Program Officer
Johnson, David R
Project Start
2003-09-30
Project End
2017-04-30
Budget Start
2017-04-20
Budget End
2017-04-30
Support Year
10
Fiscal Year
2017
Total Cost
$259,859
Indirect Cost
$37,068
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
St Clair, E William; Baer, Alan N; Wei, Chungwen et al. (2018) Clinical Efficacy and Safety of Baminercept, a Lymphotoxin ? Receptor Fusion Protein, in Primary Sjögren's Syndrome: Results From a Phase II Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Rheumatol 70:1470-1480
Cornec, Divi; Kabat, Brian F; Mills, John R et al. (2018) Pharmacokinetics of rituximab and clinical outcomes in patients with anti-neutrophil cytoplasmic antibody associated vasculitis. Rheumatology (Oxford) 57:639-650
Haddon, D James; Wand, Hannah E; Jarrell, Justin A et al. (2017) Proteomic Analysis of Sera from Individuals with Diffuse Cutaneous Systemic Sclerosis Reveals a Multianalyte Signature Associated with Clinical Improvement during Imatinib Mesylate Treatment. J Rheumatol 44:631-638
Ponnuswamy, Padmapriya; Joffre, Jeremie; Herbin, Olivier et al. (2017) Angiotensin II synergizes with BAFF to promote atheroprotective regulatory B cells. Sci Rep 7:4111
Su, Kuei-Ying; Watanabe, Akiko; Yeh, Chen-Hao et al. (2016) Efficient Culture of Human Naive and Memory B Cells for Use as APCs. J Immunol 197:4163-4176
Cao, Yonghao; Amezquita, Robert A; Kleinstein, Steven H et al. (2016) Autoreactive T Cells from Patients with Myasthenia Gravis Are Characterized by Elevated IL-17, IFN-?, and GM-CSF and Diminished IL-10 Production. J Immunol 196:2075-84
Cui, Ang; Di Niro, Roberto; Vander Heiden, Jason A et al. (2016) A Model of Somatic Hypermutation Targeting in Mice Based on High-Throughput Ig Sequencing Data. J Immunol 197:3566-3574
Meckel, Katherine; Li, Yan Chun; Lim, John et al. (2016) Serum 25-hydroxyvitamin D concentration is inversely associated with mucosal inflammation in patients with ulcerative colitis. Am J Clin Nutr 104:113-20
Londin, Eric; Loher, Phillipe; Telonis, Aristeidis G et al. (2015) Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs. Proc Natl Acad Sci U S A 112:E1106-15
McHugh, Michael D; Park, Jason; Uhrich, Ross et al. (2015) Paracrine co-delivery of TGF-? and IL-2 using CD4-targeted nanoparticles for induction and maintenance of regulatory T cells. Biomaterials 59:172-81

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