A new orally bioavailable synthetic androstene inhibits collagen-induced arthritis in the mouse: Androstene hormones as regulators of regulatory T cells

Dominick L. Auci, L. Kaler, Sandhya Subramanian, Yugin Huang, J. Frincke, C. Reading, H. Offner

Research output: Chapter in Book/Report/Conference proceedingConference contribution

30 Scopus citations

Abstract

Dehydroepiandrosterone (DHEA) has attracted much interest because of its many antiaging, metabolic and immune-modulating effects in rodents. Synthetic derivatives, such as 5-androstene-16α-fluoro-17-one (HE2500) and certain natural metabolites also provide benefit in various animal models of autoimmune and metabolic diseases. But, like DHEA, low potency and low oral bioavailability suggested limited usefulness of these compounds in humans. We hypothesized that HE3286, a novel 17-ethynyl derivative would be orally bioavailable, more potent, and chemically more useful in man than its parent compound. We found that on a dose/mass basis, HE3286 demonstrated up to 25% oral bioavailability in mice. In the DBA mouse model of collagen-induced arthritis (CIA), animals receiving oral treatment with HE3286 (50 mg/kg), beginning at onset of disease, significantly decreased CIA peak scores and daily severity of arthritis scores. Benefit was associated with decreases in: (1) production of TNF-α, IL-6, and IL-17; and (2) decreases in joint inflammation, erosion, and synovial proliferation as judged by histological analysis. HE3286 was not found to be immune suppressive in any of the classical models tested, including mitogen-induced proliferation, delayed-type hypersensitivity, or mixed lymphocyte reaction. Instead, benefit was associated with increases in numbers and function of CD4+CD25+FOXp3+CD127- regulatory T cells (Treg). To our knowledge, this is probably the first study to report that an orally bioavailable synthetic analogue of DHEA can ameliorate ongoing disease in a CIA mouse model with relevance to rheumatoid arthritis (RA) and to correlate that finding with decreases in proinflammatory cytokines and increases in T reg cells. Hormones targeting Treg cells hold the intriguing potential to treat autoimmune, infectious, and neoplastic diseases.

Original languageEnglish (US)
Title of host publicationAutoimmunity, Part B Novel Applications of Basic Research
PublisherBlackwell Publishing Inc.
Pages630-640
Number of pages11
ISBN (Print)1573317098, 9781573317092
DOIs
StatePublished - Sep 2007

Publication series

NameAnnals of the New York Academy of Sciences
Volume1110
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

Keywords

  • Androstene
  • Arthritis
  • Cytokines
  • DHEA metabolites
  • Regulatory T cells

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Fingerprint Dive into the research topics of 'A new orally bioavailable synthetic androstene inhibits collagen-induced arthritis in the mouse: Androstene hormones as regulators of regulatory T cells'. Together they form a unique fingerprint.

  • Cite this

    Auci, D. L., Kaler, L., Subramanian, S., Huang, Y., Frincke, J., Reading, C., & Offner, H. (2007). A new orally bioavailable synthetic androstene inhibits collagen-induced arthritis in the mouse: Androstene hormones as regulators of regulatory T cells. In Autoimmunity, Part B Novel Applications of Basic Research (pp. 630-640). (Annals of the New York Academy of Sciences; Vol. 1110). Blackwell Publishing Inc.. https://doi.org/10.1196/annals.1423.066