title: B7-H4Ig inhibits mouse and human T-cell function and treats EAE via IL-10/Treg-dependent mechanisms.
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.
authors.affiliation: 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.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Podojil
authors.forename: Linda N
authors.initials: LN
authors.lastname: Liu
authors.forename: Shannon A
authors.initials: SA
authors.lastname: Marshall
authors.forename: Ming-Yi
authors.initials: MY
authors.lastname: Chiang
authors.forename: Gwen E
authors.initials: GE
authors.lastname: Goings
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Solomon
authors.initials: S
authors.lastname: Langermann
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology / Q000494:pharmacology*; D016753:Interleukin-10 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000276:immunology / Q000494:pharmacology*
chemical_list: D007136:Immunoglobulins; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human; C475824:Vtcn1 protein, mouse; D016753:Interleukin-10
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