This proposal aims to define mechanisms of T cell tolerance induced in vivo in NZB/NZW F1 lupus-like mice lupus by administration of a novel, artificial peptide (consensus peptide, pCONS). Tolerance results in dramatic delay in appearance of high titer IgG anti-dsDNA and nephritis, and prolongs life 7 months or more. PCONS is constructed from an algorithm based on spontaneous proliferation of BWF1 T cells to wild peptides from the VH regions of BWF1 monoclonal antibodies to DNA. The algorithm predicts amino acid sequences likely to stimulate BWF1 T cells. A wild peptide (p33B) sharing 10 of 15 amino acids with pCONS, representing a sequence in the VH region (CDR1/FR2) of a mAb BWF1 IgG2a anti-dsDNA, has similar effects. Treatment with an artificial peptide that violates the algorithm, pNEG, produces no clinical benefits. Mice treated with pCONS or p33B, but not saline or pNEG, have reduced proliferation of T cells to immunization with the tolerizing peptide, and reduced T cell help for production of IgG anti-dsDNA in vitro. They also fail to develop the high plasma levels of IFN (and IL-4 that characterize saline-treated BWF1 females. We hypothesize that the large effects of these tolerogens result from induction of apotosis, cytokine deviation, or both in a large population of helper T cells - possibly a population that recognizes different peptides from multiple autoantigens, either early in life or later, after determinant spreading. These effects may correlate with affinity and stability of peptide/MHC Class II binding. The hypothesis will be tested by determining peptide/Class II binding affinities and stability (including peptide variants), developing surrogate rapid measures of effects on BWF1 T cells that predict clinical efficacy of peptides with different MHC binding characteristics, determining the effect of peptide/MHC engagement of TCR on T cell survival and cytokines, and testing peptide variants in vivo for clinical effects. Differences between the T cell responses to peptide/MHC complexes in BWF1 and normal mice expressing the MHC Class II molecules restricting these peptides, will identify novel characteristics of Th activation that characterize the autoimmune mice. Since patients with SLE have T cells that recognize Ig-derived peptides from human monoclonal antibodies to DNA, the information from these experiments may suggest a novel therapeutic approach to this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI046776-02
Application #
6349930
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Johnson, David R
Project Start
2000-02-15
Project End
2004-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
2
Fiscal Year
2001
Total Cost
$338,941
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Wong, Maida; La Cava, Antonio; Hahn, Bevra H (2013) Blockade of programmed death-1 in young (New Zealand Black x New Zealand White)F1 mice promotes the suppressive capacity of CD4+ regulatory T cells protecting from lupus-like disease. J Immunol 190:5402-10
Sawla, Priya; Hossain, Awlad; Hahn, Bevra H et al. (2012) Regulatory T cells in systemic lupus erythematosus (SLE); role of peptide tolerance. Autoimmun Rev 11:611-4
Dinesh, R; Hahn, B H; La Cava, A et al. (2011) Interferon-inducible gene 202b controls CD8(+) T cell-mediated suppression in anti-DNA Ig peptide-treated (NZB × NZW) F1 lupus mice. Genes Immun 12:360-9
Liu, S D; Lee, S; La Cava, A et al. (2011) Galectin-1-induced down-regulation of T lymphocyte activation protects (NZB x NZW) F1 mice from lupus-like disease. Lupus 20:473-84
Skaggs, B J; Lourenco, E V; Hahn, B H (2011) Oral administration of different forms of a tolerogenic peptide to define the preparations and doses that delay anti-DNA antibody production and nephritis and prolong survival in SLE-prone mice. Lupus 20:912-20
Dinesh, Ravi K; Hahn, Bevra H; Singh, Ram Pyare (2010) PD-1, gender, and autoimmunity. Autoimmun Rev 9:583-7
Dinesh, Ravi K; Skaggs, Brian J; La Cava, Antonio et al. (2010) CD8+ Tregs in lupus, autoimmunity, and beyond. Autoimmun Rev 9:560-8
Singh, R P; Dinesh, R; Elashoff, D et al. (2010) Distinct gene signature revealed in white blood cells, CD4(+) and CD8(+) T cells in (NZBx NZW) F1 lupus mice after tolerization with anti-DNA Ig peptide. Genes Immun 11:294-309
Hahn, B H; Lourencço, E V; McMahon, M et al. (2010) Pro-inflammatory high-density lipoproteins and atherosclerosis are induced in lupus-prone mice by a high-fat diet and leptin. Lupus 19:913-7
Wong, Maida; La Cava, Antonio; Singh, Ram P et al. (2010) Blockade of programmed death-1 in young (New Zealand black x New Zealand white)F1 mice promotes the activity of suppressive CD8+ T cells that protect from lupus-like disease. J Immunol 185:6563-71

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