The overall goals of this ACE renewal application will be to further develop our interdisciplinary basic and clinical research program at Columbia primarily focused on the evaluation of novel therapeutic approaches to human autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid and psoriatic arthritis (RA), multiple sclerosis (MS), type I diabetes mellitus (TIDM), biliary cirrhosis and scleroderma. In each of these diseases, there are ongoing basic and clinical research programs involving pathophysiologic and/or clinical immunotherapeutic studies. We hypothesize that there are four principal events involved in the immunopathogenesis of these diseases: (1) predisposing genes establish a T-cell repertoire capable of recognizing self peptides intrinsic to the autoimmune process; (2) previously tolerant autoreactive T-cell clones are activated, expand to change the T cell repertoire to reflect autoreactive effector T cells and migrate to sites of inflammation; (3) regulatory mechanisms, including cytokines and CD4+ and CD8+ regulatory T cells fail and (4) pathogenic autoantibodies and T cells effect tissue injury. We predict that reducing the clonal expansion and migration of relevant autoreactive T cells by blockade of TCR signaling with agents like anti-CD3 or interruption of the signaling and migration of autoreactive memory T cells with agents like anti-VLA-1 could down-modulate disease activity. We propose to test these hypotheses during the natural history of disease and during specific immune intervention. In this ACE renewal, we plan to continue ongoing studies of anti-CD3 therapy of TIDM, initiate trials of biliary cirrhosis employing Mycophenolate Mofetil and continue pre-clinical assessment of the VLA-1 pathway as a prelude to clinical trials with anti-VLA-1 moAbs anticipated to begin in 2004. During these studies, we will: (1) identify by PCR based CDR3 length techniques and TCR sequencing, autoantigen-driven expansions in the CD4 and CD8 cz_ TCR repertoire; (2) Identify changes in the T cell functional response to autoantigens and (3) directly study the regulatory interactions of TH1, TH2 as well as CD4+ and CD8+ T cells in controlling the TCR repertoire. In select patients, we will directly study cells at the site of inflammation (CNS, skin, kidney, joints) using HVS immortalization techniques as well as by laser capture technology for repertoire and microarray analysis of activated genes. In addition, we plan new basic studies of the control of the autoreactive T cell repertoire in autoimmune disease by analysis of EAE in the mouse and studies of human regulatory cells in TIDM.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Johnson, David R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
United States
Zip Code
Winchester, Robert; Wiesendanger, Margrit; Zhang, Hui-Zhu et al. (2012) Immunologic characteristics of intrarenal T cells: trafficking of expanded CD8+ T cell ?-chain clonotypes in progressive lupus nephritis. Arthritis Rheum 64:1589-600
Ablamunits, Vitaly; Henegariu, Octavian; Preston-Hurlburt, Paula et al. (2011) NKG2A is a marker for acquisition of regulatory function by human CD8+ T cells activated with anti-CD3 antibody. Eur J Immunol 41:1832-42
Jiang, Hong; Canfield, Steve M; Gallagher, Mary P et al. (2010) HLA-E-restricted regulatory CD8(+) T cells are involved in development and control of human autoimmune type 1 diabetes. J Clin Invest 120:3641-50
Wu, Yilun; Zheng, Zongyu; Jiang, Yihua et al. (2009) The specificity of T cell regulation that enables self-nonself discrimination in the periphery. Proc Natl Acad Sci U S A 106:534-9
Jiang, Hong; Chess, Leonard (2009) How the immune system achieves self-nonself discrimination during adaptive immunity. Adv Immunol 102:95-133
Jiang, Hong; Chess, Leonard (2008) Qa-1/HLA-E-restricted regulatory CD8+ T cells and self-nonself discrimination: an essay on peripheral T-cell regulation. Hum Immunol 69:721-7
Chen, Weiling; Zhang, Linging; Liang, Bitao et al. (2007) Perceiving the avidity of T cell activation can be translated into peripheral T cell regulation. Proc Natl Acad Sci U S A 104:20472-7
Wu, Henry D; Maurer, Mathew S; Friedman, Richard A et al. (2007) The lymphocytic infiltration in calcific aortic stenosis predominantly consists of clonally expanded T cells. J Immunol 178:5329-39
Harris, Paul E; Malanga, Donatella; Liu, Zhuoro et al. (2006) Effect of interferon alpha on MHC class II gene expression in ex vivo human islet tissue. Biochim Biophys Acta 1762:627-35
Ben-Horin, Shomron; Green, Peter H R; Bank, Ilan et al. (2006) Characterizing the circulating, gliadin-specific CD4+ memory T cells in patients with celiac disease: linkage between memory function, gut homing and Th1 polarization. J Leukoc Biol 79:676-85

Showing the most recent 10 out of 32 publications