TY - GEN
T1 - A new orally bioavailable synthetic androstene inhibits collagen-induced arthritis in the mouse
T2 - Androstene hormones as regulators of regulatory T cells
AU - Auci, Dominick L.
AU - Kaler, L.
AU - Subramanian, Sandhya
AU - Huang, Yugin
AU - Frincke, J.
AU - Reading, C.
AU - Offner, H.
PY - 2007/9
Y1 - 2007/9
N2 - 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.
AB - 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.
KW - Androstene
KW - Arthritis
KW - Cytokines
KW - DHEA metabolites
KW - Regulatory T cells
UR - http://www.scopus.com/inward/record.url?scp=35748933207&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=35748933207&partnerID=8YFLogxK
U2 - 10.1196/annals.1423.066
DO - 10.1196/annals.1423.066
M3 - Conference contribution
C2 - 17911478
AN - SCOPUS:35748933207
SN - 1573317098
SN - 9781573317092
T3 - Annals of the New York Academy of Sciences
SP - 630
EP - 640
BT - Autoimmunity, Part B Novel Applications of Basic Research
PB - Blackwell Publishing Inc.
ER -