Journal
JOURNAL OF AUTOIMMUNITY
Volume 44, Issue -, Pages 71-81Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jaut.2013.04.001
Keywords
Autoimmunity; B7-H4; CD4(+) T-cell; Costimulatory/co-inhibitory molecule; EAE; Regulatory T-cells
Categories
Funding
- National Multiple Sclerosis Society Fast Forward Program
- Amplimmune, Inc.
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS026543] Funding Source: NIH RePORTER
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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 naive 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. (C) 2013 Elsevier Ltd. All rights reserved.
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