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

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

Author information

1
Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Tarry 6-718, 303 E. Chicago Ave, Chicago, IL 60611, USA.

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

PMID:
23683881
PMCID:
PMC3973032
DOI:
10.1016/j.jaut.2013.04.001
[Indexed for MEDLINE]
Free PMC Article

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