This Clinical ACE application is driven by the hypothesis that organ-targeted autoimmune diseases are mediated by unique pathogenic interactions between cells of the immune system and parenchymal cells of the target organ, which play both afferent and efferent roles in disease initiation and target organ destruction. By understanding these disease-specific processes, new avenues to disease-specific treatment should come into view, along with novel biomarkers that reflect disease-specific interactions between lymphocytes and cells of the target organ. This hypothesis underlies the three proposed projects of this Clinical ACE. The Primary Clinical Project: """"""""Mechanistic studies of Phase III trial with BAF312 in Secondary Progressive Multiple Sclerosis"""""""", led by Yang Mao-Draayer, PhD, MD and Benjamin M. Segal, MD, will study the mechanisms of clinical benefit of a novel sphingosine-1-phosphate receptor modulator, focusing both on pathogenic T cell autoreactivity characteristic of MS, and on the ability of the damaged central nervous system to initiate repair and recovery from immune attack. The Alternate Clinical Project: """"""""Mechanistic studies of treatment of systemic sclerosis with Abatacept"""""""", led by Dinesh Khanna, MD, MS, with co-investigator David A Fox, MD, Robert Lafyatis, MD (Boston U), and Michael Whitfield, PhD (Dartmouth), will assess the effects of T cell co-stimulation blockade in scleroderema on both immune cell activation, and biomarkers of tissue damage and fibrosis in the skin. The Collaborative Project: """"""""Role of organ-specific parenchymal cells in human organ-targeted autoimmune diseases"""""""", led by Massimo Pietropaolo, MD, with co-investigators David A. Fox, MD, Roberto Gianani, MD, and Terry J. Smith, MD, will study target organ phenomena potentially involved in the initiation of autoimmune diabetes, rheumatoid arthritis and autoimmune thyroid disease, three conditions that cluster epidemiologically. The Administrative Core and overall project will be led by David A. Fox, MD, who has two decades of experience in directing multidisciplinary NIH-funded center grant awards.

Public Health Relevance

The University of Michigan Clinical ACE, by linking experienced investigators in multiple sclerosis, scleroderma, diabetes, rheumatoid arthritis and autoimmune thyroid disease in the exploration of related yet distinct mechanisms of target organ damage in these conditions, will develop new approaches to understanding and treating human autoimmunity.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project with Complex Structure Cooperative Agreement (UM1)
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Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Johnson, David R
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Smith, Terry J; Kahaly, George J; Ezra, Daniel G et al. (2017) Teprotumumab for Thyroid-Associated Ophthalmopathy. N Engl J Med 376:1748-1761
Smith, Terry (2017) TSHR as a therapeutic target in Graves' disease. Expert Opin Ther Targets 21:427-432
Soltys, John; Wang, Qin; Mao-Draayer, Yang (2017) Optical coherence tomography and T cell gene expression analysis in patients with benign multiple sclerosis. Neural Regen Res 12:1352-1356
Mao-Draayer, Yang; Sarazin, Jeffrey; Fox, David et al. (2017) The sphingosine-1-phosphate receptor: A novel therapeutic target for multiple sclerosis and other autoimmune diseases. Clin Immunol 175:10-15
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Wu, Qi; Wang, Qin; Mao, Guangmei et al. (2017) Dimethyl Fumarate Selectively Reduces Memory T Cells and Shifts the Balance between Th1/Th17 and Th2 in Multiple Sclerosis Patients. J Immunol 198:3069-3080
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Li, Yan; Singer, Nora G; Whitbred, Joy et al. (2017) CD6 as a potential target for treating multiple sclerosis. Proc Natl Acad Sci U S A 114:2687-2692
Fernando, Roshini; Atkins, Stephen J; Smith, Terry J (2016) Intersection of Chemokine and TSH Receptor Pathways in Human Fibrocytes: Emergence of CXCL-12/CXCR4 Cross Talk Potentially Relevant to Thyroid-Associated Ophthalmopathy. Endocrinology 157:3779-3787

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