Androgens and innate immunity in rehabilitated semi-captive orangutans (Pongo pygmaeus morio) from Malaysian Borneo.

Despite the implications for the development of life-history traits, endocrine-immune trade-offs in apes are not well studied. This is due, in part, to difficulty in sampling wild primates, and lack of methods available for immune measures using samples collected noninvasively. Evidence for androgen-mediated immune trade-offs in orangutans is virtually absent, and very little is known regarding their pattern of adrenal development and production of adrenal androgens. To remedy both of these deficiencies, sera were collected from orangutans (Pongo pygmaeus morio) (N = 38) at the Sepilok Orangutan Rehabilitation Centre, Sabah, Malaysia, during routine health screenings. Testosterone, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone-sulfate (DHEA-S) were assayed, along with two measures of functional innate immunity. DHEA-S concentrations, but not DHEA, increased with age in this sample of 1-18 year old animals. DHEA concentrations were higher in animals with higher levels of serum bacteria killing ability, while DHEA-S and testosterone concentrations were higher in animals with reduced complement protein activity. Patterns of DHEA-S concentration in this sample are consistent with patterns of adrenarche observed in other apes. Results from this study suggest that in addition to testosterone, DHEA and DHEA-S may have potent effects on immunological activity in this species.

Neurosteroid-mediated regulation of brain innate immunity in HIV/AIDS: DHEA-S suppresses neurovirulence.

Neurosteroids are cholesterol-derived molecules synthesized within the brain, which exert trophic and protective actions. Infection by human and feline immunodeficiency viruses (HIV and FIV, respectively) causes neuroinflammation and neurodegeneration, leading to neurological deficits. Secretion of neuroinflammatory host and viral factors by glia and infiltrating leukocytes mediates the principal neuropathogenic mechanisms during lentivirus infections, although the effect of neurosteroids on these processes is unknown. We investigated the interactions between neurosteroid-mediated effects and lentivirus infection outcomes. Analyses of HIV-infected (HIV(+)) and uninfected human brains disclosed a reduction in neurosteroid synthesis enzyme expression. Human neurons exposed to supernatants from HIV(+) macrophages exhibited suppressed enzyme expression without reduced cellular viability. HIV(+) human macrophages treated with sulfated dehydroepiandrosterone (DHEA-S) showed suppression of inflammatory gene (IL-1ß, IL-6, TNF-α) expression. FIV-infected (FIV(+)) animals treated daily with 15 mg/kg body weight. DHEA-S treatment reduced inflammatory gene transcripts (IL-1ß, TNF-α, CD3ε, GFAP) in brain compared to vehicle-(ß-cyclodextrin)-treated FIV(+) animals similar to levels found in vehicle-treated FIV(-) animals. DHEA-S treatment also increased CD4(+) T-cell levels and prevented neurobehavioral deficits and neuronal loss among FIV(+) animals, compared to vehicle-treated FIV(+) animals. Reduced neuronal neurosteroid synthesis was evident in lentivirus infections, but treatment with DHEA-S limited neuroinflammation and prevented neurobehavioral deficits. Neurosteroid-derived therapies could be effective in the treatment of virus- or inflammation-mediated neurodegeneration.

Extrathymic CD4+CD8+ lymphocytes in Chagas disease: possible relationship with an immunoendocrine imbalance.

Double-positive (DP) CD4(+) CD8(+) T cells normally represent a thymic subpopulation that is developed in the thymus as a precursor of CD4(+) or CD8(+) single-positive T cells. Recent evidence has shown that DP cells with an activated phenotype can be tracked in secondary lymph organs. The detection of an activated DP population in the periphery, a population that expresses T cell receptors unselected during thymic negative selection in murine models of Trypanosoma cruzi infection and in humans with Chagas disease, raise new questions about the relevance of this population in the pathogenesis of this major parasitic disease and its possible link with immunoendocrine alterations.

Ajuga remota Benth.: from ethnopharmacology to phytomedical perspective in the treatment of malaria.

Treatment and control of malaria have become more difficult with the spread of drug-resistant parasites and insecticide-resistant mosquito vectors. In the search for new antimalarial drugs, ethnopharmacological sources should merit more attention. Establishing the safety of traditional herbal medicines, along with identifying their active principles, are essential steps in the production of a properly standardized and accessible herbal medicine. Phytochemical characterization could also serve as a base for the development of new chemical compounds. The genus of Ajuga belongs to the family Lamiaceae and contains at least 301 species. Many of these plants have been used in traditional medicine. Ajuga remota in particular is traditionally used as a herbal remedy for fever and infections, and is prescribed for malaria by 66% of the Kenyan herbalists. A large number of compounds have already been isolated from A. remota, including ergosterol-5,8-endoperoxide (6), ajugarin-I (1), 8-O-acetylharpagide (5) and several phytoecdysteroids. In vitro pharmacological studies have been conducted on constituents of A. remota of which some of them displayed a concentration-dependent inhibition of chloroquine-sensitive and -resistant Plasmodium falciparum and Mycobacterium tuberculosis. Inhibition of parasitaemia was demonstrated in mouse models with P. berghei, supporting the traditional use of the plant against malaria. In this state-of-the-art review, A. remota as a possible therapeutic tool for malaria is discussed.

Does dehydroepiandrosterone influence the expression of urticaria?-a mini review.

Chronic urticaria is a challenging problem since the exact cause and mechanism involved in the disease development have still remained unknown. This disease is associated with mast cells activation and immunoinflammatory processes. Interestingly, dysfunctions of the neuroendocrine-immune system due to stress and other factors seem to appear as a very interesting theory for urticaria pathogenesis. Dehydroepiandrosterone and its sulfate derivative (DHEA-S) appear to have regulatory effects in immune homeostasis and are regulated by the nervous system, and it is suggested that they may be an integral element of neuroimmunomodulation. Our studies showed substantially decreased serum concentration of DHEA-S in patients with chronic urticaria. However, current knowledge prevents answering whether lower circulating DHEA-S concentration is a primary phenomenon or just an accompanying one which appears as a response of different systems to the course of the illness and may not be of any importance for the pathogenesis of urticaria whatsoever. This review is a summary of clinical research on the role of DHEA in chronic urticaria.

Impact of DHEA(S) and cortisol on immune function in aging: a brief review.

A decline in the human immune system that occurs with aging is known as immunosenescence. Several factors are involved in the process, including reduced neutrophil function and cytotoxic capacity of natural killer (NK) cells, thymus atrophy and reduced naïve T cell number, and lowered B cell antibody production in response to antigen. The endocrine system, specifically the hypothalamus-pituitary-adrenal axis, plays an important role in modulating immune function. With aging an imbalance occurs between two adrenal hormones, cortisol and DHEA, that have opposing actions on immune function. This brief review explores the interactions between cortisol and DHEA and their effects on immune function in aging, as well as potential methods to combat the endocrine-related contribution to immunosenescence, including DHEA supplementation and exercise.

Dehydroepiandrosterone sulphate enhances IgG and Interferon-gamma production during immunization to tuberculosis in young but not aged mice.

Ageing of the endocrine system (endocrinosenescence) has been closely related to immunosenescence. Dehydroepiandrosterone sulphate (DHEAS), a steroid hormone produced by the adrenals with reported enhancing immunomodulatory properties, consistently decline during ageing in parallel to detrimental increase in peripheral glucocorticoids. We investigated here the adjuvant effects of DHEAS during intraperitoneal immunization to Mycobacterium tuberculosis heat shock protein 70 (mycHSP70) in old (24 months) as well as young (3 months) BALB/c mice. Both young and old mice had significantly higher Immunoglobulin G (IgG) levels following immunization. Young mice co-immunized with mycHSP70-DHEAS presented an early increase in specific IgG levels and showed increased Interferon-gamma production compared to old mice. Also, T cells of immunized young animals were consistently more resistant to the immunosuppressive effects of glucocorticoids and to DHEAS. DHEAS was not effective in modulating antigen-specific T-cell proliferation, Interleukin-2 production or percentage of recent activated T-cell subsets (CD4 + CD69 + and CD8 + CD69 +). Our data further indicate mycHSP70 as a putative good antigen in vaccine to tuberculosis. Our data also suggest that DHEAS produced adjuvant effects upon humoral and some cellular immune responses of young, but not old mice and indicate that immunization with DHEAS is capable of changing T-cell responses to steroids.

Papel da atividade física regular realizada durante vários anos na função imune do idoso / Role of regular practice of physical activity over several plus om immune function in the elderly

Para avaliar o efeito da atividade física regular na imunosenescência, comparou-se parâmetros imunológicos de 20 idosos corredores aos de 20 idosos sedentários e 10 jovens sedentários. Os idosos corredores apresentaram resposta proliferativa de linfócitos T a OKT-3 e produção de interleucina-2 maiores do que os idosos sedentários, porém similares aos jovens. Eles apresentaram produção de interleucina-3 menor, mas também semelhante aos jovens. A interleucina-6 sérica deles foi menor do que a dos idosos sedentários. Conclui-se que a prática regular de atividade física por longos anos tem o potencial de desacelerar a imunosenescência / To access the effect of regular physical activity on immunosenescence, the immunological parameters of 20 elderly runners were compared to those of 20 elderly sedentary persons and 10 sedentary young persons. The running elderly subjects presented a higher T lymphocyte proliferative response to OKT-3 and a higher interleukin-2 production than elderly sedentary subjects, but similar to that of young subjects, plus a lower production of interleukin-3, but also similar to that of young subjects. Their serum interleukin-6 was lower than that of sedentary elderly subjects. We conclude that practicing regular physical activity for many years has the potential to decelerate immunosenescence...

The effects of androstenediol and dehydroepiandrosterone on the immune response to BCG at puberty.

In order to assess the effects of age-related changes of serum dehydroepiandrosterone sulphate (DHEAS) and androstenediol (AED) concentrations on BCG vaccination throughout the puberty period, we matched 41 prepubertal (mean age 8.63 +/- 1.36 years, range 8-14 years) and 43 pubertal (mean age 13.8 +/- 1.31 years, range 10-16 years) schoolchildren who were PPD negative and free of disease or medication known to affect immune function. The tuberculin test was performed 8 weeks after vaccination and tuberculin response and hormone levels were compared between prepubertal and pubertal subjects. We found a higher tuberculin response in the pubertal group when compared with the prepubertal ones. The pubertal children had 79.1 per cent tuberculin positivity compared with 46.4 per cent of prepubertal children (p < 0.05). Diameters of induration of the tuberculin test among prepubertal students vs. pubertal students were 9.5 +/- 3.8 mm and 11.9 +/- 3.7 mm, respectively (p < 0.005). Pubertal stage, testis volume, and pubic stage were also found to have significant effects on tuberculin test results. No difference was observed between both sexes with regard to responses of the tuberculin test in either the prepubertal or the pubertal group (p > 0.05). DHEAS and AED levels in the tuberculin-positive subjects were found to be significantly higher than tuberculin-negative ones (p = 0.040 and p = 0.046, respectively). Among both these hormones, only AED levels were correlated with tuberculin test responses. These results suggest that AED may play a role in the immunity to BCG vaccination and further immunological investigations are warranted to provide support for this idea.

Adrenocortical hormones in survivors and nonsurvivors of severe sepsis: diverse time course of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and cortisol.

OBJECTIVE: Activation and suppression of immune responses are crucial events during sepsis. Based on substantial new data, a complex picture of differential immune-enhancing and immunosuppressive actions of adrenocortical steroids is emerging. The adrenal androgen dehydroepiandrosterone and its precursor, dehydroepiandrosterone-sulfate, show a considerable decrease with increasing age and serve as functional antagonists to endogenous glucocorticoids. Therefore, we examined time-dependent changes in dehydroepiandrosterone, dehydroepiandrosterone-sulfate, cortisol, adrenocorticotropin, and inflammatory variables in surviving and nonsurviving patients with severe sepsis. DESIGN: Prospective observational study in consecutive patients. SETTING: Medical and interdisciplinary intensive care units in two university hospitals and one city hospital. PATIENTS: Thirty nonsurgical patients (25 men and 5 women) with severe sepsis (American College of Chest Physicians/Society of Critical Care Medicine criteria); 15 survivors (mean age, 54 +/- 14 yrs; Acute Physiology and Chronic Health Evaluation III score, 59 +/- 35) and 15 nonsurvivors (mean age, 63 +/- 15 yrs; Acute Physiology and Chronic Health Evaluation III score, 67 +/- 24) were included. Hormones were compared individually and between survivors/nonsurvivors by sequential blood drawings from early sepsis till time of recovery/death. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During early sepsis, cortisol (nmol/L) was not significantly higher in survivors than nonsurvivors (750 +/- 121 vs. 454 +/- 92, p <.08) and decreased in survivors (p <.01) during late sepsis. During early sepsis, dehydroepiandrosterone-sulfate (percentage of age-matched normal levels) was higher in survivors than nonsurvivors (85 +/- 19 vs. 22 +/- 7, p <.01). Dehydroepiandrosterone-sulfate decreased in survivors (p =.0001) but remained low in nonsurvivors during late sepsis. Dehydroepiandrosterone (percentage of age-matched normal levels) was not significantly elevated in survivors compared to nonsurvivors during early sepsis (282 +/- 42 vs. 214 +/- 63, p <.08). Dehydroepiandrosterone decreased in survivors (p <.01) but not in nonsurvivors during late sepsis. Linear regression for dehydroepiandrosterone levels showed a reconstitution of age dependence only in survivors during recovery. Adrenocorticotropin levels did not change. The dehydroepiandrosterone-sulfate/cortisol ratio decreased significantly in both survivors and nonsurvivors, whereas dehydroepiandrosterone/cortisol ratio only decreased in survivors during course of sepsis. CONCLUSIONS: During sepsis, adrenal androgens and glucocorticoids show a diverse time-dependent course in survivors and nonsurvivors.

Analysis of the binding energies of testosterone, 5alpha-dihydrotestosterone, androstenedione and dehydroepiandrosterone sulfate with an antitestosterone antibody.

Molecular dynamics simulations and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) free energy calculations were used to study the binding of testosterone (TES), 5alpha-dihydrotestosterone (5ADHT), androstenedione (AND), and dehydroepiandrosterone sulfate (DHEAS) to the monoclonal antitestosterone antibody 3-C(4)F(5). The relative binding free energy of TES and AND was also calculated with free energy perturbation (FEP) simulations. The antibody 3-C(4)F(5) has a relatively high affinity (3 x 10(8) M(-1)) and on overall good binding profile for testosterone but its cross-reactivity with DHEAS has been the main reason for the failure to use this antibody in clinical immunoassays. The relative binding free energies obtained with the MM-PBSA method were 1.5 kcal/mol for 5ADHT, 3.8 kcal/mol for AND, and 4.3 kcal/mol for DHEAS, as compared to TES. When a water molecule of the ligand binding site, observed in the antibody-TES crystal structure, was explicitly included in MM-PBSA calculations, the relative binding energies were 3.4, 4.9, and 5.4 kcal/mol for 5ADHT, AND, and DHEAS, respectively. The calculated numbers are in correct order but larger than the corresponding experimental energies of 1.3, 1.5, and 2.6 kcal/mol, respectively. The fact that the MM-PBSA method reproduced the relative binding free energies of DHEAS, a steroid having a negatively charged sulfate group, and the neutrally charged TES, 5ADHT, and AND in satisfactory agreement with experiment shows the robustness of the method in predicting relative binding affinities. The 800-ps FEP simulations predicted that the antibody 3-C(4)F(5) binds TES 1.3 kcal/mol tighter than AND. Computational mutagenesis of selected amino acid residues of the ligand binding site revealed that the lower affinities of AND and DHEAS as compared to TES are due to a combined effect of several residues, each contributing a small fraction to the tighter binding of TES. An exception to this is Tyr99H, whose mutation to Ala lowered the binding of DHEAS 0.7 kcal/mol more than the binding of TES. This is probably due to the hydrogen bonding interaction formed between the OH group of Tyr99H and the sulfate group of DHEAS. Computational mutagensis data also showed that the affinity of the steroids to the antitestosterone antibody 3-C(4)F(5) would be enhanced if Trp47H were repositioned so that it would make more extensive contacts with the bound ligands. In addition, the binding of steroids to antitestosterone, antiprogesterone, and antiestradiol antibodies is discussed.

Estudio mediante Radioinmunoanálisis (RIA) y análisis inmunorradiométrico (IRMA) del equilibrio de la reacción antígeno-anticuerpo de algunas sustancias / Studing of binding antigen-antibody of some substances by means of radioinmunoanalysis (RIA) and inmunoradiometric analysis (IRMA)

Se ha estudiado el equilibrio de la unión, a sus anticuerpos específicos, de las siguientes sustancias: Insulina y dehidroepiandrosterona sulfato (DHEAs), mediante RIA en fase sólida, osteocalcina y fracción c-terminal de la parathormona (PTHc), mediante RIA en disolución y enolasa específica neuronal (NSE), tiroglobulina (Tg) y el marcador tumoral CA549, mediante IRMA. Se pretende determinar un modelo que explique, de manera general, dichas reacciones antígeno-anticuerpo, así como establecer la influencia de algunos factores: temperatura, clase de anticuerpo, reacción en fase sólida o en disolución, características del antígeno, etc., sobre esta unión.Los resultados obtenidos en el estudio del equilibrio no se ajustan al modelo de sitios idénticos e independientes, sin embargo proporcionan un excelente ajuste a la ecuación de Hill.Las reacciones estudiadas presentan un valor bajo de la entalpía de reacción concordante con la naturaleza de la unión antígeno-anticuerpo (AU)

Immune enhancing effects of dehydroepiandrosterone and dehydroepiandrosterone sulphate and the role of steroid sulphatase.

Steroid hormones, such as glucocorticoids (GC), influence immune and inflammatory responses through their suppressive actions. Recent evidence suggests that another steroid hormone, dehydroepiandrosterone (DHEA), provides an immunostimulatory influence opposing the effect of GC. DHEA circulates in its inactive sulphated form, DHEAS, requiring conversion to DHEA by a steroid sulphatase (SS) enzyme for biological activity. Therefore, inhibition of SS activity may affect immune responses, allowing endogenous GC effects to predominate. We have shown that administration of DHEA and DHEAS in contact sensitization (CS) augments ear swelling by 39 and 46% respectively (P < 0.001). DHEAS at doses of 0.5, 5 and 50 mg/kg reverses the inhibitory effect of corticosterone (5 mg/kg) (P < 0.01). In CS, CT2251 (SS inhibitor) at 10 and 0.1 mg/kg inhibited ear swelling by 61 and 38% (P < 0.05) respectively. In addition, it inhibited DHEAS-augmented responses by 49 and 35% respectively (P < 0.05), with no effect on DHEA-augmented responses. DHEAS reversed CT2251 inhibition of the CS response with complete reversal at 50 mg/kg (P < 0.05). DHEAS and CT2251 appear to affect cellular infiltration into the ear, since DHEAS increased the number of lymphocytes by 63.8% and macrophages by 107% (P < 0.001), whereas CT2251 at 0.1 mg/kg decreased the number of lymphocytes by 65% (P < 0.001) and macrophages by 80% (P < 0.001). DHEAS, CT2251 and dexamethasone had no effect on oedema in the ear. From our data we have shown that steroid hormones, such as DHEA, have the potential to act as immunostimulatory factors in vivo. Inhibiting the conversion of DHEAS to DHEA by SS enzyme leads to an anti-inflammatory effect.

The effect of DHEAS on influenza vaccination in aging adults.

OBJECTIVE: To determine whether simultaneous administration of dehydroepiandrosterone sulfate (DHEAS) exhibits adjuvant activity in the immune response of aging humans by supplementing influenza vaccination with the maximum single dose of DHEAS that could be practically injected subcutaneously (approximately 7.5 mg). DESIGN: A randomized, double-blind, placebo-controlled trial of DHEAS injection with 1993-94 and 1994-95 influenza vaccine in older subjects. In addition, initial safety, tolerability, and control testing with 1993-94 influenza vaccine was conducted in young subjects. SETTING: An urban primary care geriatrics clinic. PARTICIPANTS: Seventy-eight older adult volunteers (mean age 78.61 +/- 3.43 years, range 73-90 years) and 20 younger controls (< 40 years, means age 32.76 +/- 5.39 years) were recruited from clinic and community advertising. Subjects were free of disease or medication known to affect immune function. MEASUREMENTS: Immune responses to vaccine at 0, 2, and 4 weeks were measured by vaccine antigen-induced lymphoproliferation in peripheral blood mononuclear cells (PBMC) and serum antibody response by hemagglutination inhibition (HI). RESULTS: The maximum DHEAS dose that could be practically administered subcutaneously was 7.5 mg. Baseline DHEAS levels were significantly lower in older adults (52.1 vs 236.4 micrograms/dL, P < .001). The 1993 old adult DHEAS group HI response tended to be higher for the H3N2 Beijing antigen but not for the H1N1 or B antigen. In subjects with HI titers less then 1:40 for the H3N2 Beijing antigen (n = 29), the post-vaccination titer response tended to be higher among the 16 subjects who received DHEAS (P = .06). The peak response for the H3N2 antigen was associated with the initial DHEAS serum concentration in the DHEAS and placebo groups (R2 = .22, P = .04 and R2 = .21, P = .06, respectively). No significant differences were found for antibody responses to the H1N1 and B antigens or vaccine-antigen induced lymphoproliferation. CONCLUSION: A one-time supplemental dose of DHEAS with influenza vaccination appeared to enhance the specific HI antibody response to the 1993-94 H3N2 antigen in a small group of older adults. These findings were limited to those with lower prevaccination titers and lower DHEAS concentrations. Although clinical implications of these findings for influenza vaccine are uncertain, these results suggest additional detailed immunologic investigations on the role of DHEAS in the aging human immune response are warranted.

Production and characterization of monoclonal antibodies to dehydroepiandrosterone sulfate: application to direct enzyme-linked immunosorbent assays of dehydroepiandrosterone sulfate and androsterone/epiandrosterone sulfates in plasma.

Mice were immunized with 5-androstene-3 beta-ol-7,17-dione-7-CMO:bovine serum albumin (DHEA-7-O-CMO-BSA) or 5-androstene-3 beta-ol-17-one hemisuccinate-bovine serum albumin (DHEA-3HS-BSA) conjugates and monoclonal antibodies were produced, characterized, and selected for maximum DHEAS binding. Of these hybridomas, four clones from DHEA-3HS-BSA-immunized mice had acceptable criteria for the development of a competitive enzyme-linked immunosorbent assay (ELISA) for DHEAS in plasma. One hybridoma supernatant from DHEA-7-O-CMO-BSA-immunized mice showed 360% cross-reactivity to both androsterone sulfate and epiandrosterone sulfate. This allows the possibility of the direct determination of androsterone sulfate and epiandrosterone sulfate in plasma after correction for the DHEAS contribution. Both ELISAs employ a DHEA-3HS-thyroglobulin conjugate adsorbed to the wells of a standard 96-well microtiter plate. DHEAS in the standards or diluted plasma sample competes with immobilized DHEA-3HS-thyroglobulin for antibody-binding sites. Antibody is detected with anti-mouse-lg peroxidase by further washing, adding o-phenylenediamine substrate, and reading the absorbance at 492 nm. The ELISAs are simple, reproducible, and reliable and, to our knowledge, they are the first tests employing monoclonal antibodies to DHEAS.

The use of oral dehydroepiandrosterone sulfate as an adjuvant in tetanus and influenza vaccination of the elderly.

Elderly individuals often exhibit a poorer immune response and shorter duration of immunity to vaccines than younger persons. Improvement in vaccine response has been demonstrated when administering the hormone dehydroepiandrosterone sulfate (DHEAS) as an adjuvant in animal trials. Two separate, randomized double-blinded vaccine trials were therefore conducted using DHEAS as an oral adjuvant in individuals age 65 or older. Sixty-six individuals were randomized to DHEAS, 50 mg po bid for 4 days, or a placebo capsule. Tetanus vaccination was given immediately before the fifth dose. At entry the level of protective antibody was age-dependent (P = 0.009), and by 28 days post-vaccination most individuals had protective levels of antibody, with no difference noted between treatment groups. In the second study, 67 individuals received placebo capsules or DHEAS immediately before and 24 h after influenza vaccination. The number of individuals who developed protective titers (> or = 1:40) was not different in the two groups. The mean log increase in HAI response was greater in the DHEAS group to all three vaccine components, although this did not achieve significance. Minimal side-effects of DHEAS administration were noted. Given the trend toward improved response in the elderly to influenza, larger trials using DHEA as an adjuvant in vaccines that are neoantigens may be indicated.