RESUMEN
BACKGROUND: All-trans retinoic acid (ATRA) is a biologically active isomer of retinoic acid (RA). Topical ATRA (retin-a, retin-a micro, atralin, renova, and avita) is the active pharmaceutical ingredient for FDA-approved treatments for acne and skin wrinkles. Oral formulations (Vesanoid) treat acute promyelocytic leukemia, but oral dosing can induce severe side effects. Despite benefits in various rodent models of inflammatory bowel disease (IBD), toxicity and controversial clinical observations have diminished enthusiasm for ATRA IBD clinical trials. To circumvent these issues and to use ATRA's key role in maintaining gut tolerance, we developed a poly(lactic-co-glycolic acid) (PLGA) microsphere (MS) encapsulated ATRA formulation aimed at directing ATRA delivery to immune structures of the gut, limiting systemic exposure. Initially, ATRA MS was developed as a component of a combinatorial product (TreXTAM) that also contained encapsulated transforming growth factor (TGF)-ß and ATRA in a 1:2 w/w ratio. Although the combination was optimal, benefit was also observed when ATRA MS was given alone in the CD4+ CD25-T-cell adoptive transfer (ACT) colitis model. METHODS: We used the ACT and DSS-induced murine models of colitis to expand on the dose-dependent effects of oral ATRA MS when given alone. The DSS model was also used to compare the efficacy of ATRA MS and soluble ATRA, while healthy animals were used to compare the pharmacokinetics of the two drugs. RESULTS: In both the ACT and DSS-induced murine models of colitis, ATRA MS was observed to be effective in ameliorating disease. ATRA MS was also observed to be more effective than soluble ATRA in these models and displayed more favorable pharmacokinetics. CONCLUSIONS: We suggest ATRA MS, as a standalone product, may attenuate IBD and perhaps limit fibrosis, while limiting systemic side effects.
Asunto(s)
Colitis , Enfermedades Inflamatorias del Intestino , Animales , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Ratones , Roedores/metabolismo , Factor de Crecimiento Transformador beta , Tretinoina/metabolismoRESUMEN
BACKGROUND: TreXTAM® is a combination of the key regulatory cytokine transforming growth factor beta (TGFß) and all trans retinoic acid (ATRA) microencapsulated for oral delivery to immune structures of the gut. It is in development as a novel treatment for inflammatory bowel disease (IBD). AIM: To measure TGFß levels in blood and tissue after oral administration of encapsulated TGFß. METHODS: Animals were orally administered encapsulated TGFß by gavage. Levels of drug substance in blood and in gut tissues at various times after administration were measured by ELISA. RESULTS: We made the surprising discovery that oral administration of TreXTAM dramatically (approximately 50%) and significantly (P = 0.025) reduced TGFß levels in colon, but not small intestine or mesenteric lymph nodes. Similarly, levels in rat serum after 25 d of thrice weekly dosing with either TreXTAM, or microencapsulated TGFß alone (denoted as TPX6001) were significantly (P < 0.01) reduced from baseline levels. When tested in the SCID mouse CD4+CD25- adoptive cell transfer (ACT) model of IBD, oral TPX6001 alone provided only a transient benefit in terms of reduced weight loss. CONCLUSION: These observations suggest a negative feedback mechanism in the gut whereby local delivery of TGFß results in reduced local and systemic levels of the active form of TGFß. Our findings suggest potential clinical implications for use of encapsulated TGFß, perhaps in the context of IBD and/or other instances of fibrosis and/or pathological TGFß signaling.
RESUMEN
Type 1 diabetes (T1D) is a multifactorial autoimmune disease that develops as a consequence of macrophage- and T cell-dependent pancreatic ß-cell death. Multiple approaches for induction of anti-inflammatory/regulatory mechanisms that would attenuate T1D have been utilized, with little or no beneficial effects. To achieve prolonged stimulation of regulatory immune cells, we orally introduced microparticles (MPs) loaded with all-trans retinoic acid (ATRA) and transforming growth factor-ß (TGF-ß) to C57BL/6 mice treated with multiple low doses of streptozotocin (MLDS) for T1D induction. Disease incidence was significantly lower in ATRA/TGF-ß MPs-treated mice, as was the degree of immune cell infiltration into the pancreatic islets. In Peyer's patches (PP), ATRA/TGF-ß MPs up-regulated tolerogenic dendritic cells (tolDCs) (CD11c+CD11b-CD103+), while the proportion of mature dendritic cells was not altered. This was accompanied by reduced Th1 and Th17 proportions and up-regulation of regulatory T cells (Tregs - CD4+CD25highFoxP3+). The immune cell composition in the pancreatic lymph nodes was similar to PP. Further, the proportion of effector Tbet+CD25med cells was decreased, while the proportion of Tbet+ Treg cells that specifically inhibit Th1 response was increased. Moreover, ATRA/TGF-ß MPs treatment resulted in increased Treg proliferation and frequency of CTLA-4+PD1+ and CD39+IL-10+ Tregs, suggestive of their higher suppressive capacity. Reduced pancreatic infiltration may have been a consequence of lower cell capacity for matrix degradation. In conclusion, oral application of ATRA/TGF-ß MPs ameliorated T1D through potentiation of tolDCs and Tregs, inhibition of Th1 response and prevention of the immune cell entrance into the islets.
Asunto(s)
Diabetes Mellitus Tipo 1/tratamiento farmacológico , Portadores de Fármacos/química , Microesferas , Factor de Crecimiento Transformador beta/farmacología , Tretinoina/administración & dosificación , Tretinoina/farmacología , Administración Oral , Animales , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta/química , Factor de Crecimiento Transformador beta/uso terapéutico , Tretinoina/uso terapéuticoRESUMEN
BACKGROUND AND AIMS: We investigated oral delivery of transforming growth factor beta 1 [TGFß]- and all-trans retinoic acid [ATRA]-loaded microspheres as therapy for gut inflammation in murine models of inflammatory bowel disease [IBD]. METHODS: ATRA and TGFß were separately encapsulated in poly [lactic-co-glycolic] acid or polylactic acid microspheres [respectively]. TGFß was encapsulated using proprietary phase-inversion nanoencapsulation [PIN] technology. RESULTS: PIN particles provided sustained release of bioactive protein for at least 4 days and were stable for up to 52 weeks when stored at either 4(0)C or -20(0)C. In the SCID mouse CD4 + CD25- T cell transfer model of IBD, oral treatment starting at disease onset prevented weight loss, significantly reduced average disease score [~ 50%], serum amyloid A levels [~ 5-fold], colon weight-to-length ratio [~ 50%], and histological score [~ 5-fold]. CONCLUSIONS: Both agents given together outperformed either separately. Highest TGFß doses and most frequent dose schedule were most effective. Activity was associated with a significant increase [45%] in Foxp3 expression by colonic lamina propria CD4+ CD25+ T-cells. Activity was also demonstrated in dextran sulphate sodium-induced colitis. The data support development of the combination product as a novel, targeted immune based therapy for treatment for IBD.
Asunto(s)
Antiinflamatorios/administración & dosificación , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Factor de Crecimiento Transformador beta/administración & dosificación , Tretinoina/administración & dosificación , Administración Oral , Animales , Antiinflamatorios/uso terapéutico , Biomarcadores/metabolismo , Esquema de Medicación , Quimioterapia Combinada , Femenino , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Microesferas , Factor de Crecimiento Transformador beta/uso terapéutico , Resultado del Tratamiento , Tretinoina/uso terapéuticoRESUMEN
17α-Ethynyl-androst-5-ene-3ß,7ß,17ß-triol (HE3286) is a synthetic androstenetriol in Phase II clinical development for the treatment of inflammatory diseases. HE3286 was evaluated for blood-brain barrier (BBB) permeability in mice, and efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinson's disease (PD). We found that HE3286 freely penetrated the BBB. HE3286 treatment significantly improved motor function compared to vehicle in the rotarod test (mean 58.2 sec versus 90.9 sec, P < 0.0001), and reduced inflammatory mediator gene expression in the brain (inducible nitric oxide synthase, 20%, P = 0.002; tumor necrosis factor α, 40%, P = 0.038, and interleukin-1ß, 33%, P = 0.02) measured by reverse-transcriptase polymerase chain reaction. Brain tissue histopathology and immunohistochemistry showed that HE3286 treatment increased the numbers of tyrosine hydroxylase-positive cells by 17% compared to vehicle (P = 0.003), and decreased the numbers of damaged neurons by 38% relative to vehicle (P = 0.029). L-3,4-dihydroxyphenylalanine (L-DOPA) efficacy was not enhanced by concurrent administration of HE3286. HE3286 administration prior to MPTP did not enhance efficacy. Our data suggest a potential role for HE3286 in PD treatment, and provides incentive for further investigation.
RESUMEN
Androst-5-ene-3ß,7ß,17ß-triol (ßAET) is an anti-inflammatory metabolite of DHEA that is found naturally in humans, but in rodents only after exogenous DHEA administration. Unlike DHEA, C-7-oxidized DHEA metabolites cannot be metabolized into potent androgens or estrogens, and are not peroxisome proliferators in rodents. The objective of our current studies was to characterize the pharmacology of ßAET to enable clinical trials in humans. The pharmacology of ßAET was characterized by pharmacokinetics, drug metabolism, nuclear hormone receptor interactions, androgenicity, estrogenicity, and systemic toxicity studies. ßAET's acute anti-inflammatory activity and immune modulating characteristics were measured in vitro in RAW264.7 cells and in vivo in murine models with parenteral administration. ßAET was rapidly metabolized and cleared from circulation in mice and monkeys. ßAET was weakly androgenic and estrogenic in immature rodents, but not bound by androgen, estrogen, progesterone, or glucocorticoid nuclear hormone receptors. ßAET did not induce peroxisome proliferation, nor was it systemically toxic or trophic for sex hormone responsive tissues in mature rats and monkeys. ßAET significantly attenuated acute inflammation both in vitro and in vivo, augmented immune responses in adult mice, and reversed immune senescence in aged mice. ßAET may contribute to the anti-inflammatory activity in rodents attributed to DHEA. Unlike DHEA, ßAET's anti-inflammatory activity cannot be ascribed to activation of PPARs, androgen, or estrogen nuclear hormone receptors. Exogenous ßAET is unlikely to produce untoward toxicity or hormonal perturbations in humans.
Asunto(s)
Androstenoles/farmacología , Deshidroepiandrosterona/metabolismo , Sistema Inmunológico/efectos de los fármacos , Androstenos/metabolismo , Androstenoles/metabolismo , Animales , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Factores Inmunológicos/metabolismo , Factores Inmunológicos/farmacología , Macaca fascicularis , Masculino , Metaboloma/fisiología , Ratones , Ratones Endogámicos BALB C , Ratas , Ratas WistarRESUMEN
5-Androstene-3ß,7ß,17ß-triol (AET) is a naturally occurring anti-inflammatory adrenal steroid that limits acute and chronic inflammation. HE3286 (17α-ethynyl-5-androstene-3ß,7ß,17ß-triol) is a synthetic derivative of AET with improved pharmaceutical properties and efficacy in some animal models of autoimmunity. Here, daily oral doses of HE3286 led to a suppression of spontaneous autoimmune diabetes in the non-obese diabetic mouse model of type 1 diabetes mellitus when administered either shortly before or after the first incidence of disease onset. Efficacy was associated with reduced insulitis and a suppression of the pathogenic T helper cell type 1 and type 17 phenotypes in peripheral lymphoid organs. These results demonstrate that daily oral treatment with HE3286 administrated relatively late in the destructive autoimmune process led to a suppression of type 1 diabetes mellitus onset and of the pathological inflammatory status, supporting its clinical evaluation in type 1 diabetes mellitus subjects.
Asunto(s)
Deshidroepiandrosterona/análogos & derivados , Deshidroepiandrosterona/metabolismo , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Administración Oral , Animales , Disponibilidad Biológica , Antígenos CD4/metabolismo , Deshidroepiandrosterona/administración & dosificación , Deshidroepiandrosterona/farmacocinética , Deshidroepiandrosterona/farmacología , Deshidroepiandrosterona/uso terapéutico , Diabetes Mellitus Tipo 1/inmunología , Femenino , Inflamación/tratamiento farmacológico , Islotes Pancreáticos/efectos de los fármacos , Ratones , Ratones Endogámicos NOD , Bazo/efectos de los fármacos , Bazo/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
Metabolic syndrome is marked by perturbed glucocorticoid (GC) signaling, systemic inflammation, and altered immune status. Dehydroepiandrosterone (DHEA), a major circulating adrenal steroid and dietary supplement, demonstrates antiobesity, anti-inflammatory, GC-opposing and immune-modulating activity when administered to rodents. However, plasma DHEA levels failed to correlate with metabolic syndrome and oral replacement therapy provided only mild benefits to patients. Androstene-3ß,7ß,17ß-triol (ß-AET) an anti-inflammatory metabolite of DHEA, also exhibits GC-opposing and immune-modulating activity when administered to rodents. We hypothesized a role for ß-AET in obesity. We now report that plasma levels of ß-AET positively correlate with BMI in healthy men and women. Together with previous studies, the observations reported here may suggest a compensatory role for ß-AET in preventing the development of metabolic syndrome. The ß-AET structural core may provide the basis for novel pharmaceuticals to treat this disease.
Asunto(s)
Androstenoles/sangre , Antiinflamatorios/sangre , Fármacos Antiobesidad/sangre , Síndrome Metabólico/metabolismo , Obesidad/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Deshidroepiandrosterona/sangre , Deshidroepiandrosterona/uso terapéutico , Femenino , Glucocorticoides/antagonistas & inhibidores , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Esteroides/farmacología , Adulto JovenRESUMEN
Two natural 5-androstene steroid tetrols, androst-5-ene-3ß,7ß,16α,17ß-tetrol (HE3177) and androst-5-ene-3α,7ß,16α,17ß-tetrol (HE3413), were discovered in human plasma and urine. These compounds had significant aqueous solubility, did not bind or transactivate steroid-binding nuclear hormone receptors, and were not immunosuppressive in murine mixed-lymphocyte studies. Both compounds appear to be metabolic end products, as they were resistant to primary and secondary metabolism. Both were orally bioavailable, and were very well tolerated in a two-week dose-intensive toxicity study in mice. Anti-inflammatory properties were found with exogenous administration of these compounds in rodent disease models of multiple sclerosis, lung injury, chronic prostatitis, and colitis.
Asunto(s)
Androstenoles/farmacología , Antiinflamatorios/farmacología , Colitis/tratamiento farmacológico , Esclerosis Múltiple/tratamiento farmacológico , Prostatitis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Androstenoles/química , Androstenoles/metabolismo , Animales , Antiinflamatorios/química , Antiinflamatorios/metabolismo , Colitis/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos , Persona de Mediana Edad , Conformación Molecular , Esclerosis Múltiple/metabolismo , Prostatitis/metabolismo , Ratas , Solubilidad , Estereoisomerismo , Adulto JovenRESUMEN
Androstenediol (androst-5-ene-3ß,17ß-diol; 5-AED), a natural adrenal steroid, has been shown to suppress experimental autoimmune encephalomyelitis (EAE) in female SJL/J mice. We here report that 5-AED limits inflammation and proinflammatory cytokines including TNFα in murine models of carrageenan-induced pleurisy and lippopolysaccaride- (LPS) induced septic shock. 5-AED binds to and transactivates sex steroid receptors with the same general rank order of potency (ERß > ERα â« AR). 5-AED provides benefit in EAE in a dose-dependent fashion, even when treatment is delayed until onset of disease. The minimally effective dose may be as low as 4 mg/kg in mice. However, benefit was not observed when 5-AED was given in soluble formulation, leading to a short half-life and rapid clearance. These observations suggest that treatment with 5-AED limits the production of pro-inflammatory cytokines in these animal models and, ultimately, when formulated and administered properly, may be beneficial for patients with multiple sclerosis and other Th1-driven autoimmune diseases.
RESUMEN
5-Androstene-3ß,7ß,17ß-triol (ß-AET), an active metabolite of dehydroepiandrosterone (DHEA), reversed glucocorticoid (GC)-induced suppression of IL-6, IL-8 and osteoprotegerin production by human osteoblast-like MG-63 cells and promoted osteoblast differentiation of human mesenchymal stem cells (MSCs). In a murine thermal injury model that includes glucocorticoid-induced osteopenia, ß-AET significantly (p<0.05) preserved bone mineral content, restored whole body bone mineral content and endochondral growth, suggesting reversal of GC-mediated decreases in chondrocyte proliferation, maturation and osteogenesis in the growth plate. In men and women, levels of ß-AET decline with age, consistent with a role for ß-AET relevant to diseases associated with aging. ß-AET, related compounds or synthetic derivatives may be part of effective therapeutic strategies to accelerate tissue regeneration and prevent or treat diseases associated with aging such as osteoporosis.
Asunto(s)
Envejecimiento , Androstenoles/farmacología , Enfermedades Óseas Metabólicas/fisiopatología , Quemaduras/fisiopatología , Osteoporosis/fisiopatología , Absorciometría de Fotón , Adulto , Anciano , Anciano de 80 o más Años , Animales , Enfermedades Óseas Metabólicas/etiología , Quemaduras/complicaciones , Diferenciación Celular , Línea Celular Tumoral , Femenino , Citometría de Flujo , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana EdadRESUMEN
BACKGROUND: 17α-Ethynyl-5-androsten-3ß, 7ß, 17ß-triol (HE3286) is a synthetic derivative of an endogenous steroid androstenetriol (ß-AET), a metabolite of the abundant adrenal steroid deyhdroepiandrosterone (DHEA), with broad anti-inflammatory activities. We tested the ability of this novel synthetic steroid with improved pharmacological properties to limit non-productive lung inflammation in rodents and attempted to gauge its immunological impact. METHODS AND RESULTS: In mice, oral treatment with HE3286 (40 mg/kg) significantly (p < 0.05) decreased neutrophil counts and exudate volumes (~50%) in carrageenan-induced pleurisy, and myeloperoxidase in lipopolysaccharide-induced lung injury. HE3286 (40 mg/kg) was not found to be profoundly immune suppressive in any of the classical animal models of immune function, including those used to evaluate antigen specific immune responses in vivo (ovalbumin immunization). When mice treated for two weeks with HE3286 were challenged with K. pneumoniae, nearly identical survival kinetics were observed in vehicle-treated, HE3286-treated and untreated groups. CONCLUSIONS: HE3286 represents a novel, first-in-class anti-inflammatory agent that may translate certain benefits of ß-AET observed in rodents into treatments for chronic inflammatory pulmonary disease.
RESUMEN
HE3286 (17alpha-ethynyl-5-androstene-3beta, 7beta, 17beta-triol) is an orally bio-available synthetic derivative of naturally occurring androstene-3beta, 7beta, 17beta-triol. Our present data show that oral treatment with HE3286, favourably influenced the course of arthritis in the rat model of adjuvant-induced arthritis (reduced cumulative disease scores and paw edema), and in the mouse model of collagen antibody-induced arthritis (reduced clinical paw scores). Importantly, HE3286 was not immune suppressive in human mixed lymphocyte reaction or in animals challenged with Coxsackie B3 virus. HE3286 is currently in phase I/II clinical trials in rheumatoid arthritis and ulcerative colitis and these findings further strengthen the possibility that HE3286 may represent an effective anti-inflammatory agent useful for treating chronic inflammation with a more attractive safety profile than glucocorticoids or cyclooxygenase inhibitors.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Deshidroepiandrosterona/análogos & derivados , Administración Oral , Animales , Artritis Experimental/sangre , Artritis Experimental/enzimología , Artritis Experimental/patología , Artritis Reumatoide/sangre , Artritis Reumatoide/enzimología , Artritis Reumatoide/patología , Peso Corporal , Deshidroepiandrosterona/administración & dosificación , Deshidroepiandrosterona/farmacología , Deshidroepiandrosterona/uso terapéutico , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Enterovirus Humano B/fisiología , Humanos , Inmunización , Interleucina-6/sangre , Prueba de Cultivo Mixto de Linfocitos , Masculino , Ratones , Miocarditis/tratamiento farmacológico , Miocarditis/virología , Tamaño de los Órganos , Peroxidasa/metabolismo , Ratas , Factores de Tiempo , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Dehydroepiandrosterone (DHEA) treatment provides diverse anti-inflammatory benefits in rodent models of diseases, including rheumatoid arthritis (RA), but only limited benefits to patients. In rodents, DHEA is metabolized to (among others) androstene-3beta,7beta,17beta-triol (AET), which retains potent anti-inflammatory activity. 17Alpha-ethynyl-5-androstene-3beta,7beta,17beta-triol (HE3286) is a novel, metabolically stabilized, orally bioavailable derivative of AET. In the DBA mouse model of collagen-induced arthritis (CIA), once-daily oral treatments (gavage) with HE3286 (40 mg/kg), beginning at onset of disease, significantly decreased disease. Benefit was associated with reduction in joint inflammation, erosion, and synovial proliferation as measured by histological analysis and mRNA of proinflammatory cytokines, including tumor necrosis factor-alpha, interleukin (IL)-6, IL-1beta, and IL-23. Significant benefit was also observed in the CIA model even when treatments were delayed until 7 days after the onset of arthritis. Furthermore, dose-dependent benefit was observed in the DBA mouse model of collagen antibody-induced arthritis, as well as reductions in IL-6 and matrix metalloproteinase-3 mRNA levels in joints at the peak of disease and at the end of the study. HE3286, in contrast to dexamethasone, was not immune-suppressive in several classic animal models of immune function. Instead, HE3286 treatment was associated with reduced nuclear factor-kappaB activation and in our previous studies, with increased regulatory T cells. We hypothesize that HE3286 may represent a novel, perhaps first-in-class, anti-inflammatory agent and may more fully translate the benefits of DHEA, heretofore largely limited to rodents, into treatments for human diseases, including autoimmune disorders such as RA.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Deshidroepiandrosterona/análogos & derivados , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Anticuerpos/inmunología , Formación de Anticuerpos/efectos de los fármacos , Formación de Anticuerpos/inmunología , Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/patología , Colágeno/inmunología , Citocinas/genética , Citocinas/metabolismo , Deshidroepiandrosterona/administración & dosificación , Deshidroepiandrosterona/farmacología , Deshidroepiandrosterona/uso terapéutico , Modelos Animales de Enfermedad , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Hipersensibilidad Tardía/inmunología , Sistema Inmunológico/efectos de los fármacos , Sistema Inmunológico/inmunología , Interleucina-6/genética , Articulaciones/efectos de los fármacos , Articulaciones/metabolismo , Articulaciones/patología , Lipopolisacáridos/farmacología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Masculino , Metaloproteinasa 3 de la Matriz/genética , Ratones , Ratones Endogámicos DBA , Ratones Endogámicos ICR , FN-kappa B/metabolismo , Bazo/efectos de los fármacos , Bazo/metabolismoRESUMEN
The metabolome of dehydroepiandrosterone (DHEA), the most abundant adrenal steroid in the human body, includes androgens, estrogens and a series of immune regulating hormones that lack androgenic or estrogenic activity. Of these, 7-hydroxy derivatives, once considered physiologically inactive end products of metabolism, possess a combination of potent anti-inflammatory and immune modulating activity without androgenic or estrogenic capacity. Oxygenated metabolites derived from androstenediol (AED), the predominant precursor in rodents, may be responsible for many activities initially attributed to exogenous DHEA administered to rodents. We here review the discovery of these compounds in models of inflammation and autoimmune diseases, discuss the potential mode of action and trace the development of a specific synthetic derivative, which is less labile to metabolism and which may at last deliver to humans the benefits of DHEA observed in rodents.
Asunto(s)
Antiinflamatorios/inmunología , Artritis Experimental/tratamiento farmacológico , Colitis/tratamiento farmacológico , Deshidroepiandrosterona/análogos & derivados , Neumonía/tratamiento farmacológico , Choque Séptico/tratamiento farmacológico , Animales , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Artritis Experimental/inmunología , Ensayos Clínicos como Asunto , Colitis/inmunología , Deshidroepiandrosterona/química , Deshidroepiandrosterona/inmunología , Deshidroepiandrosterona/uso terapéutico , Modelos Animales de Enfermedad , Humanos , Ratones , Neumonía/inmunología , Ratas , Choque Séptico/inmunologíaRESUMEN
Dehydroepiandrosterone (DHEA), a precursor of immune-regulating hormones (IRH) including the androstenes, has attracted much interest over the last several decades because of its many antiaging, metabolic, and immune modulating effects. 5-Androstene-16alpha fluoro-17-one (fluasterone, also known as HE2500) is a synthetic androstene analogue that retains anti-inflammatory, antiproliferative, and immune-regulating activities of the parent molecule, but is nontoxic and practically devoid of androgenic or estrogenic side effects. In the present studies, we tested the ability of fluasterone to limit disease in the DBA mouse model of collagen-induced arthritis (CIA). We found that mice receiving injections of fluasterone displayed significant delay in onset, decrease in CIA peak score, and significant decrease of the daily mean clinical score. Benefit was associated with significant decreases in (1). bovine type II collagen (bCII)-specific IgG(1) and IgG(2a) antibody levels in serum; (2). production of TNF-alpha, IL-6, IFN-gamma, but not IL-10; (3). lymphocyte proliferative response to bCII protein; and (4). joint inflammation, erosion, and synovial proliferation as judged by histological analysis. This is the first study to report that an IRH can ameliorate ongoing disease in a CIA mouse model with relevance to RA and to correlate that finding with decreases in pro-inflammatory cytokines.
Asunto(s)
Antiinflamatorios/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/inmunología , Deshidroepiandrosterona/análogos & derivados , Deshidroepiandrosterona/farmacología , Animales , Artritis Experimental/patología , División Celular/efectos de los fármacos , División Celular/inmunología , Citocinas/sangre , Ensayo de Inmunoadsorción Enzimática , Histocitoquímica , Inmunoglobulina G/sangre , Ganglios Linfáticos/citología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Masculino , Ratones , Ratones Endogámicos DBA , Bazo/citología , Bazo/efectos de los fármacos , Bazo/inmunologíaRESUMEN
Experimental allergic encephalomyelitis (EAE), a Th1 polarized demyelinating disease of the central nervous system (CNS), shares many pathological and clinical similarities with multiple sclerosis (MS), and thus represents an attractive animal model for this disease. The goal of this study was to evaluate the suppressive effects of fluasterone (HE2500), a synthetic androstene derivative, and androstenetriol (HE2200), a natural androstene hormone on EAE. SJL mice were immunized with proteolipid protein (PLP) 139-151 peptide/CFA to induce EAE. Starting on day -7, animals were given daily injections (s.c.) of derivatives (3.0 mg) in vehicle, or vehicle alone for 33 days. Both HE2500 and HE2200 significantly delayed the onset, reduced the peak clinical score and cumulative disease index of EAE, and prevented or significantly attenuated relapses. Lower doses or other routes of administration were less effective. Moreover, T cells from treated mice had significantly reduced PLP 139-151-specific T cell proliferation responses and reduced numbers of TNF-alpha- and IFN-gamma-producing cells in the CNS. Daily treatment of B10.PL mice with HE2500, starting on day 0, completely prevented the development of disease in these animals. Finally, SJL mice treated with HE2500 at EAE onset showed significantly reduced mean clinical scores. Thus, these compounds, which have been reported to have a few androgenic or estrogenic side effects, appear to have a potent inhibitory activity in EAE. These observations suggest that HE2500 and/or HE2200 limit the production of autoimmune Th1 associated cytokines, and ultimately may be beneficial for patients with MS or other autoimmune diseases.
Asunto(s)
Androstenos/farmacología , Androstenoles/farmacología , Deshidroepiandrosterona/análogos & derivados , Deshidroepiandrosterona/farmacología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Inmunosupresores/farmacología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Androstenos/metabolismo , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , División Celular/efectos de los fármacos , División Celular/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/fisiopatología , Femenino , Inmunoglobulina G/sangre , Inmunoglobulina G/efectos de los fármacos , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Proteína Proteolipídica de la Mielina/inmunología , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Factores Sexuales , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
We previously identified a group of long-term pediatric survivors who had acquired HIV-1 through maternal transmission; had not received antiretroviral therapy; are now >8 years old, in good health, and with no opportunistic infections; and have not failed to thrive, although they have greatly decreased numbers of blood CD4+ T cells (<500/mm(3)). All the children have elevated total serum IgE levels (210-2475 IU/ml) and make anti-HIV-1 IgE or IgE directed against non-HIV-1 specificities (radioimmunoassay, Western blot assay); they have no detectable antigenemia. We have now studied the ability of anti-HIV-1 IgE in serum obtained from these children to regulate (1) production of HIV-1 by interleukin 2/phytohemagglutinin (IL-2/PHA)-stimulated peripheral blood mononuclear cells (PBMCs) taken from HIV-1-seronegative donors and infected with a T cell-tropic clone of HIV-1, and (2) transmission of a primary HIV-1 strain from adult AIDS patients to uninfected IL-2/PHA-stimulated PBMCs (p24 core antigen production). High levels of HIV-1 production were observed when PBMCs were cultured for 5 days in the presence of HIV-1-seronegative donor serum that was either IgE positive or IgE negative (IgE, >100 or <100 IU/ml, respectively). HIV-1 production also was observed when PBMCs were cultured with HIV-1-infected donor serum that either contained IgE directed against non-HIV-1 specificities or was IgE negative; these levels were 40% less than those seen with sera from the HIV-1-seronegative donors. Far greater inhibition of virus production was observed if the serum in culture contained anti-HIV-1 IgE (>95%). Virus neutralization did not appear to account for the inhibition obtained with anti-HIV-1 IgE-containing serum because virus production was not suppressed in cultures to which serum was added immediately preinfection (<10%), but was strongly suppressed when serum was added 1.5 hr postinfection (>95%). The inhibition of virus production obtained with serum containing anti-HIV-1 IgE was reversed when (1) serum was depleted of IgE (immunoaffinity), but not when it was depleted of IgG (protein G-Sepharose) before inclusion in culture postinfection, (2) anti-IgE, but not anti-IgG, was included in culture, or (3) serum was heat treated before culture. The results indicate that serum from certain HIV-1-infected pediatric long-term survivors contains agents that inhibit HIV-1 production in vitro, and that these agents include anti-HIV-1 IgE. They suggest that a cytotoxic event, rather than virus neutralization, plays an important role in anti-HIV-1 IgE-mediated inhibition of virus production.