Patients with autoimmune diseases are categorized by clinical manifestations and simple laboratory values. However recent mechanistic investigations, and experience with directed biological therapies, have demonstrated that these autoimmune disease categories are very heterogeneous. Despite this apparent heterogeneity most, if not all, autoimmune diseases share a common theme. They arise from failures in self tolerance. Therefore, we propose to establish the University of Chicago Autoimmunity Center of Excellence (UCACE) with the purpose of studying and manipulating lymphocyte tolerance in patients with diverse autoimmune diseases including systemic lupus erythematosus (SLE), myasthenia gravis (MG) and inflammatory bowel disease (IBD). Central to this effort will be the establishment of a core facility, the Autoimmune Lymphocyte Repertoire Core (ALRC) that will enable investigators from multiple disciplines to assess the evolution of humoral autoimmunity in rare human lymphocyte subpopulations. The singular research focus of the UCACE will be complemented by an innovative clinical trials program, and administrative structure, that will facilitate mechanistic studies in patients receiving novel lymphocyte-directed therapies. Understanding how lymphocyte tolerance is breached in different autoimmune diseases will reveal commonalities and differences that will enable the development of new biomarkers and novel therapeutics.

Public Health Relevance

Autoimmunity is manifest in a myriad of diseases that preferentially afflict younger patients who are often pursing careers and raising families. The total burden of autoimmune diseases on society is substantial. The focus of the current application is the pathogenesis of human autoimmunity. It is anticipated that these studies will contribute to the development of new therapies to treat those afflicted with autoimmune diseases. Clinical Component: Clinical Component of University of Chicago Autoimmunity Center of Excellence (Hanauer, S) CLINICAL COMPONENT DESCRIPTION (Provided by applicant): The University of Chicago clinical, translational and basic science programs form an interactive network of research and clinical resources focused on understanding and treating human disease. Integration of clinical and basic science missions is ensured by a common administrative structure in which both the University of Chicago Medical Center and Biological Sciences Division (BSD) are under a single Dean/CEO Office that oversees and defines the priorities of both enterprises. Integration is then reinforced by a system of common core facilities, multidisciplinary research institutes, centers and programs and, ultimately, by faculty who broadly collaborate in both the research and clinical activities of the University. The University of Chicago Autoimmunity Center of Excellence proposes to establish a Clinical Trials Program (UCACE-CTP) that will capitalize on this established clinical-academic structure to create and conduct clinical trials in autoimmunity that are tightly coupled to mechanistic studies. Successful models for accomplishment of this aim are already well established within the participating clinical sections and departments of the UCACE. Therefore, the primary goal of the UCACE-CTP will be to standardize procedures for clinical trials management across clinical center participants and to provide a common platform integrating efforts within the UCACE and ACE networks. Finally, the UCACE-CTP will develop a system of mentorship and peer review that will encourage clinical and translational investigators to develop novel therapeutic and mechanistic studies on patients with autoimmune disease.

Public Health Relevance

The purpose of the University of Chicago Autoimmunity Center of Excellence (UCACE) Clinical Trials Program is to promote clinical trials in autoimmunity that are tightly coupled to insightful mechanistic studies. This goal is highly relevant to developing new therapies for patients with autoimmunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082724-04
Application #
8301739
Study Section
Special Emphasis Panel (ZAI1-QV-I (J3))
Program Officer
Johnson, David R
Project Start
2009-06-10
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$656,684
Indirect Cost
$235,733
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Liarski, Vladimir M; Kaverina, Natalya; Chang, Anthony et al. (2014) Cell distance mapping identifies functional T follicular helper cells in inflamed human renal tissue. Sci Transl Med 6:230ra46
Steinsbø, Øyvind; Henry Dunand, Carole J; Huang, Min et al. (2014) Restricted VH/VL usage and limited mutations in gluten-specific IgA of coeliac disease lesion plasma cells. Nat Commun 5:4041
Chang, Anthony; Ko, Kichul; Clark, Marcus R (2014) The emerging role of the inflammasome in kidney diseases. Curr Opin Nephrol Hypertens 23:204-10
Kinloch, Andrew J; Chang, Anthony; Ko, Kichul et al. (2014) Vimentin is a dominant target of in situ humoral immunity in human lupus tubulointerstitial nephritis. Arthritis Rheumatol 66:3359-70
Iversen, Rasmus; Di Niro, Roberto; Stamnaes, Jorunn et al. (2013) Transglutaminase 2-specific autoantibodies in celiac disease target clustered, N-terminal epitopes not displayed on the surface of cells. J Immunol 190:5981-91
Andrews, Sarah F; Zhang, Qingzhao; Lim, Samuel et al. (2013) Global analysis of B cell selection using an immunoglobulin light chain-mediated model of autoreactivity. J Exp Med 210:125-42
Di Niro, Roberto; Mesin, Luka; Zheng, Nai-Ying et al. (2012) High abundance of plasma cells secreting transglutaminase 2-specific IgA autoantibodies with limited somatic hypermutation in celiac disease intestinal lesions. Nat Med 18:441-5
Hsieh, Christine; Chang, Anthony; Brandt, Daniel et al. (2011) Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring. Arthritis Care Res (Hoboken) 63:865-74
Chang, Anthony; Henderson, Scott G; Brandt, Daniel et al. (2011) In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis. J Immunol 186:1849-60
Kaur, Kaval; Sullivan, Meghan; Wilson, Patrick C (2011) Targeting B cell responses in universal influenza vaccine design. Trends Immunol 32:524-31

Showing the most recent 10 out of 11 publications