This proposal focuses on the development of a new therapeutic for systemic lupus erythematosus. The overall goal is to 1) modify a peptide mimetope of DNA to increase serum half life, permit oral administration, and maximize function, 2) to explore the functionality of two new compounds with similar binding properties to the peptide and 3) develop additional compounds. The mimetope binds to a subset of anti-DNA antibodies that deposit in glomeruli, cross-react with NMDA receptors and mediate excitotoxic neuron death, and, in immune complexes, activate dendritic cells. Efforts will be made to use radioisotope-tagged peptide/modified compound to ablate antigen-specific B cells. It will also be determined if peptide intercalates into DNA-containing immune complexes to diminish activation of dendritic cells. Finally, new peptide mimetopes of DNA will be sought in case more than one subset of anti-DNA antibodies or DNA-reactive B cells must be eliminated to reduce disease pathology.

Public Health Relevance

This proposal identifies a non-immunosuppressive strategy for the treatment of systemic lupus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR057084-02
Application #
8111099
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Mancini, Marie
Project Start
2010-07-15
Project End
2015-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
2
Fiscal Year
2011
Total Cost
$358,560
Indirect Cost
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Suurmond, Jolien; Calise, Justine; Malkiel, Susan et al. (2016) DNA-reactive B cells in lupus. Curr Opin Immunol 43:1-7
VanPatten, Sonya; Sun, Shan; He, Mingzhu et al. (2016) Amending HIV Drugs: A Novel Small-Molecule Approach To Target Lupus Anti-DNA Antibodies. J Med Chem 59:8859-8867
Son, Myoungsun; Porat, Amit; He, Mingzhu et al. (2016) C1q and HMGB1 reciprocally regulate human macrophage polarization. Blood 128:2218-2228
Son, Myoungsun; Kim, Sun Jung; Diamond, Betty (2016) SLE-associated risk factors affect DC function. Immunol Rev 269:100-17
Malkiel, Susan; Jeganathan, Venkatesh; Wolfson, Stacey et al. (2016) Checkpoints for Autoreactive B Cells in the Peripheral Blood of Lupus Patients Assessed by Flow Cytometry. Arthritis Rheumatol 68:2210-20
Son, Myoungsun; Diamond, Betty; Santiago-Schwarz, Frances (2015) Fundamental role of C1q in autoimmunity and inflammation. Immunol Res 63:101-6
Suurmond, Jolien; Diamond, Betty (2015) Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity. J Clin Invest 125:2194-202
Son, Myoungsun; Diamond, Betty (2014) C1q-mediated repression of human monocytes is regulated by leukocyte-associated Ig-like receptor 1 (LAIR-1). Mol Med 20:559-68
Frese, Steffen; Diamond, Betty (2011) Structural modification of DNA--a therapeutic option in SLE? Nat Rev Rheumatol 7:733-738
Diamond, B; Bloom, O; Al Abed, Y et al. (2011) Moving towards a cure: blocking pathogenic antibodies in systemic lupus erythematosus. J Intern Med 269:36-44

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