The long-term goal of this project is to define basic mechanisms of autoimmunity in Systemic Lupus Erythematosus (SLE), by focusing on disease-relevant T helper (Th) cells that induce the production of pathogenic anti-DNA autoantibodies in SLE. The full spectrum of major peptide epitopes, including naturally processed peptide epitopes, for the pathogenic autoantibody-inducing Th cells of human lupus that recognize nucleosomes in a promiscuous manner will be defined. Shared epitopes for autoimmune B-cells of lupus will also be identified. Immunologic relevance of the epitopes in influencing autoimmune T- and B-cell functions will be studied. T-cell receptor (TCR) and MHC-contact residues in the peptide epitopes will be finely mapped for finding consensus motifs that could lead to autoantigen -specific therapy of lupus in humans using tolerogenic peptides or altered peptide ligands. Altered peptide ligands that are partial agonists or antagonists will be designed and studied for blocking pathogenic anti-DNA autoantibody production in vitro. Nucleosomal peptide-HLA-DR tetramers (or peptide-MHC-Ig chimeric dimers) will be made to track autoimmune T-cells in lupus patients and family members for diagnostic and prognostic purposes, and for studying the effects of peptide tolerogens in vitro. The second part of the project will deal with mechanisms of prolonged hyper-expression of CD40 ligand (CD40L) and resistance to anergy induction and maintenance in T-cells of human lupus. Major components of T-cell signal transduction pathways involved in T-cell activation, and anergy, particularly in the context of CD40L hyper-expression will be defined. The role of differential MAPK activity in CD40L hyper-expression and stability of CD40L mRNA in lupus T-cells will be studied. Possible anomalies in B7-CD28, and CTLA-4 expression and function in lupus T-cells that could lead to the above mentioned defects being analyzed. Identification of critical peptide epitopes for the autoimmune T helper cells of lupus and studies on regulatory defects in expression of co-stimulatory signaling molecules are leading towards an understanding of basic mechanisms of the disease and development of specific immunotherapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AR039157-20
Application #
7474708
Study Section
Special Emphasis Panel (ZRG1-IMB (02))
Program Officer
Mancini, Marie
Project Start
1993-08-01
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
20
Fiscal Year
2008
Total Cost
$275,977
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Kang, Hee-Kap; Chiang, Ming-Yi; Liu, Michael et al. (2011) The histone peptide H4 71-94 alone is more effective than a cocktail of peptide epitopes in controlling lupus: immunoregulatory mechanisms. J Clin Immunol 31:379-94
Kang, Hee-Kap; Ecklund, Diane; Liu, Michael et al. (2009) Apigenin, a non-mutagenic dietary flavonoid, suppresses lupus by inhibiting autoantigen presentation for expansion of autoreactive Th1 and Th17 cells. Arthritis Res Ther 11:R59
Datta, Syamal K (2009) Anti-CD20 antibody is an efficient therapeutic tool for the selective removal of autoreactive T cells. Nat Clin Pract Rheumatol 5:80-2
Zhang, Li; Bertucci, Anne M; Ramsey-Goldman, Rosalind et al. (2009) Regulatory T cell (Treg) subsets return in patients with refractory lupus following stem cell transplantation, and TGF-beta-producing CD8+ Treg cells are associated with immunological remission of lupus. J Immunol 183:6346-58
Xu, Luting; Zhang, Li; Bertucci, Anne M et al. (2008) Apigenin, a dietary flavonoid, sensitizes human T cells for activation-induced cell death by inhibiting PKB/Akt and NF-kappaB activation pathway. Immunol Lett 121:74-83
Zhang, Li; Bertucci, Anne M; Smith, Kimberly A et al. (2007) Hyperexpression of cyclooxygenase 2 in the lupus immune system and effect of cyclooxygenase 2 inhibitor diet therapy in a murine model of systemic lupus erythematosus. Arthritis Rheum 56:4132-41
Kang, Hee-Kap; Liu, Michael; Datta, Syamal K (2007) Low-dose peptide tolerance therapy of lupus generates plasmacytoid dendritic cells that cause expansion of autoantigen-specific regulatory T cells and contraction of inflammatory Th17 cells. J Immunol 178:7849-58
Kang, Hee-Kap; Datta, Syamal K (2006) Regulatory T cells in lupus. Int Rev Immunol 25:5-25
Kang, Hee-Kap; Michaels, Marissa A; Berner, Beate R et al. (2005) Very low-dose tolerance with nucleosomal peptides controls lupus and induces potent regulatory T cell subsets. J Immunol 174:3247-55
Datta, Syamal K; Zhang, Li; Xu, Luting (2005) T-helper cell intrinsic defects in lupus that break peripheral tolerance to nuclear autoantigens. J Mol Med 83:267-78

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