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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
5UM1AI110557-03
Application #
9036325
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Johnson, David R
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Mills, Elizabeth A; Mao-Draayer, Yang (2018) Aging and lymphocyte changes by immunomodulatory therapies impact PML risk in multiple sclerosis patients. Mult Scler 24:1014-1022
O'Brien, Martin J; Shu, Qiang; Stinson, W Alexander et al. (2018) A unique role for galectin-9 in angiogenesis and inflammatory arthritis. Arthritis Res Ther 20:31
Lu, Yan; Atkins, Stephen J; Fernando, Roshini et al. (2018) CD34- Orbital Fibroblasts From Patients With Thyroid-Associated Ophthalmopathy Modulate TNF-? Expression in CD34+ Fibroblasts and Fibrocytes. Invest Ophthalmol Vis Sci 59:2615-2622
Mills, Elizabeth A; Mao-Draayer, Yang (2018) Understanding Progressive Multifocal Leukoencephalopathy Risk in Multiple Sclerosis Patients Treated with Immunomodulatory Therapies: A Bird's Eye View. Front Immunol 9:138
Elshabrawy, Hatem A; Volin, Michael V; Essani, Abdul B et al. (2018) IL-11 facilitates a novel connection between RA joint fibroblasts and endothelial cells. Angiogenesis 21:215-228
Mills, Elizabeth A; Begay, Joel A; Fisher, Caitlyn et al. (2018) Impact of trial design and patient heterogeneity on the identification of clinically effective therapies for progressive MS. Mult Scler :1352458518800800
Mills, Elizabeth A; Mirza, Ali; Mao-Draayer, Yang (2017) Emerging Approaches for Validating and Managing Multiple Sclerosis Relapse. Front Neurol 8:116
Carmona-Rivera, Carmelo; Carlucci, Philip M; Moore, Erica et al. (2017) Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. Sci Immunol 2:
Smith, Terry J; Kahaly, George J; Ezra, Daniel G et al. (2017) Teprotumumab for Thyroid-Associated Ophthalmopathy. N Engl J Med 376:1748-1761
Enyindah-Asonye, Gospel; Li, Yan; Ruth, Jeffrey H et al. (2017) CD318 is a ligand for CD6. Proc Natl Acad Sci U S A 114:E6912-E6921

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