B7-H4Ig inhibits mouse and human T-cell function and treats EAE via IL-10/Treg-dependent mechanisms

J Autoimmun. 2013 Aug;44:71-81. doi: 10.1016/j.jaut.2013.04.001. Epub 2013 May 14.

Abstract

We evaluated the therapeutic efficacy and mechanisms of action of both mouse and human B7-H4 Immunoglobulin fusion proteins (mB7-H4Ig; hB7-H4Ig) in treating EAE. The present data show that mB7-H4Ig both directly and indirectly (via increasing Treg function) inhibited CD4⁺ T-cell proliferation and differentiation in both Th1- and Th17-cell promoting conditions while inducing production of IL-10. B7-H4Ig treatment effectively ameliorated progression of both relapsing (R-EAE) and chronic EAE correlating with decreased numbers of activated CD4⁺ T-cells within the CNS and spleen, and a concurrent increase in number and function of Tregs. The functional requirement for Treg activation in treating EAE was demonstrated by a loss of therapeutic efficacy of hB7-H4Ig in R-EAE following inactivation of Treg function either by anti-CD25 treatment or blockade of IL-10. Significant to the eventual translation of this treatment into clinical practice, hB7-H4Ig similarly inhibited the in vitro differentiation of naïve human CD4⁺ T-cells in both Th1- and Th17-promoting conditions, while promoting the production of IL-10. B7-H4Ig thus regulates pro-inflammatory T-cell responses by a unique dual mechanism of action and demonstrates significant promise as a therapeutic for autoimmune diseases, including MS.

Keywords: Autoimmunity; B7-H4; B7-H4-Immumoglobulin fusion protein; B7-H4Ig; C-EAE; CD4(+) T-cell; CFA; CNS; CTLA-4; Costimulatory/co-inhibitory molecule; EAE; MBP; MS; OVA; PLP; R-EAE; Regulatory T-cells; T cell receptor; T1D; TCR; Type I diabetes; central nervous system; chronic experimental autoimmune encephalomyelitis; complete Freund's adjuvant; cytotoxic T lymphocyte associated antigen-4; hB7-H4Ig; human B7-H4Ig; mB7-H4Ig; mouse B7-H4Ig; multiple sclerosis; myelin basic protein; myelin proteolipid protein; ovalbumin; relapsing experimental autoimmune encephalomyelitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmune Diseases / drug therapy
  • Autoimmune Diseases / immunology
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Female
  • Humans
  • Immunoglobulins / immunology
  • Immunoglobulins / pharmacology*
  • Interleukin-10 / immunology*
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Mice
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1 / immunology
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1 / pharmacology*

Substances

  • Immunoglobulins
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1
  • VTCN1 protein, human
  • Vtcn1 protein, mouse
  • Interleukin-10