IgD-Fc-Ig fusion protein, a new biological agent, inhibits T cell function in CIA rats by inhibiting IgD-IgDR-Lck-NF-κB signaling pathways

Acta Pharmacol Sin. 2020 Jun;41(6):800-812. doi: 10.1038/s41401-019-0337-2. Epub 2020 Jan 14.

Abstract

IgD-Fc-Ig fusion protein, a new biological agent, is constructed by linking a segment of human IgD-Fc with a segment of human IgG1-Fc, which specifically blocks the IgD-IgDR pathway and selectively inhibits the abnormal proliferation, activation, and differentiation of T cells. In this study we investigated whether IgD-Fc-Ig exerted therapeutic effects in collagen-induced arthritis (CIA) rats. CIA rats were treated with IgD-Fc-Ig (1, 3, and 9 mg/kg) or injected with biological agents etanercept (3 mg/kg) once every 3 days for 40 days. In the PBMCs and spleen lymphocytes of CIA rats, both T and B cells exhibited abnormal proliferation; the percentages of CD3+ total T cells, CD3+CD4+ Th cells, CD3+CD4+CD25+-activated Th cells, Th1(CD4+IFN-γ+), and Th17(CD4+IL-17+) were significantly increased, whereas the Treg (CD4+CD25+Foxp3+) cell percentage was decreased. IgD-Fc-Ig administration dose-dependently decreased the indicators of arthritis; alleviated the histopathology of spleen and joint; reduced serum inflammatory cytokines levels; decreased the percentages of CD3+ total T cells, CD3+CD4+ Th cells, CD3+CD4+CD25+-activated Th cells, Th1 (CD4+IFN-γ+), and Th17(CD4+IL-17+); increased Treg (CD4+CD25+Foxp3+) cell percentage; and down-regulated the expression of key molecules in IgD-IgDR-Lck-NF-κB signaling (p-Lck, p-ZAP70, p-P38, p-NF-κB65). Treatment of normal T cells with IgD (9 μg/mL) in vitro promoted their proliferation. Co-treatment with IgD-Fc-Ig (0.1-10 μg/mL) dose-dependently decreased IgD-stimulated T cell subsets percentages and down-regulated the IgD-IgDR-Lck-NF-κB signaling. In summary, this study demonstrates that IgD-Fc-Ig alleviates CIA and regulates the functions of T cells through inhibiting IgD-IgDR-Lck-NF-κB signaling.

Keywords: CD4+ T cell; IgD; IgD-Fc-Ig fusion protein; IgD-IgDR-Lck-NF-κB signaling; IgDR; collagen-induced-arthritis; etanercept.

MeSH terms

  • Acetic Acid
  • Animals
  • Arthritis, Experimental / chemically induced
  • Arthritis, Experimental / immunology*
  • Immunoglobulin D / chemistry
  • Immunoglobulin D / immunology*
  • Immunoglobulin Fc Fragments / chemistry
  • Immunoglobulin Fc Fragments / immunology*
  • Male
  • NF-kappa B / metabolism*
  • Rats
  • Rats, Wistar
  • Receptors, IgG / immunology*
  • Receptors, IgG / metabolism
  • Signal Transduction*
  • T-Lymphocytes / immunology*

Substances

  • Immunoglobulin D
  • Immunoglobulin Fc Fragments
  • NF-kappa B
  • Receptors, IgG
  • Acetic Acid