Down-regulation of stromal cell-derived factor-1alpha-induced T cell chemotaxis by a peptide based on the complementarity-determining region 1 of an anti-DNA autoantibody via up-regulation of TGF-beta secretion

J Immunol. 2005 Jan 1;174(1):302-9. doi: 10.4049/jimmunol.174.1.302.

Abstract

Systemic lupus erythematosus (SLE) can be induced in mice by immunizing them with a monoclonal human anti-DNA Ab that expresses a major Id, designated 16/6Id. In addition, a peptide based on the sequence of the CDR 1 (hCDR1) of the 16/6Id ameliorated the clinical manifestations of SLE in experimental models. In this study we examined the effects of treating mice with human complementary-determining region 1 (hCDR1) on the subsequent chemotaxis of T cells derived from 16/6Id-primed mice. First we demonstrated elevated levels of stromal cell-derived factor-1alpha (SDF-1alpha) in the sera of SLE-afflicted mice and in the sera and lymphoid tissues of 16/6Id-immunized BALB/c mice shortly after the immunization. We then found that administration of hCDR1 to 16/6Id-immunized mice specifically down-regulated SDF1alpha-induced T cell chemotaxis through fibronectin and collagen type I. This was accompanied by diminished SDF1-alpha-induced T cell adhesion and ERK phosphorylation. Treatment with hCDR1 up-regulated TGF-beta secretion, which, in turn, inhibited the murine T cell adhesion to and chemotaxis through fibronectin as well as their ERK phosphorylation. Thus, the secretion of TGF-beta after treatment of 16/6Id-immunized mice with hCDR1 plays an important role in the down-regulation of SDF-1alpha-mediated T cell activation and the interactions with extracellular matrix moieties observed in the present study.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Antinuclear / immunology*
  • Blotting, Western
  • Cell Adhesion / immunology
  • Chemokine CXCL12
  • Chemokines, CXC / immunology*
  • Chemokines, CXC / pharmacology
  • Chemotaxis, Leukocyte / drug effects
  • Chemotaxis, Leukocyte / immunology*
  • Complementarity Determining Regions / immunology*
  • Disease Models, Animal
  • Down-Regulation
  • Fibronectins / metabolism
  • Humans
  • Lupus Erythematosus, Systemic / immunology
  • Lymphocyte Activation / immunology
  • Mice
  • Peptides / immunology
  • T-Lymphocytes / immunology*
  • Transforming Growth Factor beta / metabolism*
  • Up-Regulation

Substances

  • Antibodies, Antinuclear
  • CXCL12 protein, human
  • Chemokine CXCL12
  • Chemokines, CXC
  • Complementarity Determining Regions
  • Cxcl12 protein, mouse
  • Fibronectins
  • Peptides
  • Transforming Growth Factor beta