[Immuno-neuroendocrine interactions during growth and aging].
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Adrenocorticotropic Hormone↗
Biomedical subjects
E Mocchegiani
Publications and source records attributed to E Mocchegiani.
AIDS, zinc deficiency, and thymic hormone failure.
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AIDS-Related Complex↗
Oral zinc supplementation in Down's syndrome: restoration of thymic endocrine activity and of some immune defects.
Eighteen non-institutionalized Down's syndrome (DS) children (mean age: 7.0 +/- 10/12 years) with a history of respiratory tract, auditory and skin infections, low plasma levels of a nonapeptide thymic hormone, i.e. Serum Thymic Factor (STF), high plasma levels of inactive zinc-unbound STF molecules, and reduced absolute number of circulating T-lymphocytes, were given an oral non-pharmacological supplementation of zinc sulphate (1 mg Zn++/kg body weight/day for 2 months; two cycles, 10 months apart) and monitored immunologically before and after each cycle. A dramatic increase of plasma STF level and concomitantly an almost complete disappearance of inactive STF molecules was observed after each cycle. The absolute number of circulating T-lymphocytes was significantly increased by zinc treatment. The marginal zinc deficiency was also corrected without any appreciable influence on copper plasma levels. A reduction of recurrent infections and an improvement in school attendance after zinc supplementation were recorded. These beneficial effects of zinc supplementation were also noted in those DS children who did not show an apparent zinc deficiency, as assessed by measuring zinc plasma level. The reduced number of circulating B lymphocytes and the impaired lymphocyte responsiveness to phytohaemagglutinin and concanavalin A were not restored. On the whole, these findings suggest that there exists a defect in the bio-availability and/or in the utilization of zinc in DS. This alteration, of unknown origin, can be underestimated on the simple basis of the zinc plasma level and can be corrected with moderate nutritional zinc supplementation.
Child↗
Neuroendocrine-thymus interactions: perspectives for intervention in aging.
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Aging↗
Thymulin deficiency and low 3,5,3'-triiodothyronine syndrome in infants with low birth weight syndromes.
Experimental and clinical evidence indicates that thymic endocrine function is under neuroendocrine control. Recently, a positive correlation was found between plasma thymulin (a major endocrine product of thymus) and serum thyroid hormone concentrations. Low serum thyroid hormone concentrations are frequently found in premature newborn infants. In this study we measured plasma thymulin by bioassay and serum T3 and T4 in a series of healthy fullterm newborns and in premature infants with various disorders. The study subjects were 26 healthy fullterm infants, 23 fullterm small for gestational age infants, 30 preterm appropriate for gestational age (AGA) infants, 22 preterm small for gestational age infants and 30 infants with respiratory distress syndrome, of whom 15 were fullterm and 15 were preterm AGA. Blood samples were obtained 3, 5, 10, 20, and 40 days after delivery. In the healthy fullterm infants plasma thymulin concentrations were low during the first days of life and subsequently increased, reaching normal values for children aged 1-12 months by the 10th day after birth. Persistently low plasma thymulin and serum T3 levels were found in the majority of infants with pathological conditions; the lowest values for both hormones were found in infants with respiratory distress syndrome. A highly significant positive correlation was present in all groups between mean plasma thymulin and serum T3, but not T4. Short term T3 administration in 6 additional preterm AGA infants caused a significant increase in plasma thymulin titers compared to those in 6 untreated infants. We conclude that plasma thymulin is decreased in premature newborns with the low T3 syndrome and that this abnormality may be reversed by administration of T3. These findings indicate that thymic endocrine activity is modulated by thyroid function in early postnatal life.
Euthyroid Sick Syndromes↗
[Therapeutic prospectives in respiratory distress syndrome and their immuno-endocrinologic correlates].
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Fetal Organ Maturity↗
Recovery of age-related decline of thymic endocrine activity and PHA response by lysin-arginine combination.
The frequent association of malnutrition, infectious diseases and aging has stressed the role played by some nutrients on the immune efficiency and by nutrient supplementation on the age-dependent immunological decline. In the present paper there are reported evidences that oral administration of two amino acids--lysine and arginine--recovers, in old Balb/c mice, the mitogen responsiveness, the expression of T-cell markers and the production of thymic serum factor (thymuline). The effect of the amino acids or of their combination, as present in a commercially available form (Neoiodarsolo), seems to consist mainly of the reactivation of the endocrine activity of the thymus. Similar reactivation is achieved also in old humans. These data suggest that the age-dependent decline of thymic hormonal activity is not an intrinsic and irreversible event and that some nutritional intervention, such as amino acid treatment, likely through the stimulation of neuroendocrine network, may reactivate the endogenous production of thymic hormones.
Aging↗
Thyroid function modulates thymic endocrine activity.
The thymus produces humoral factors that induce proliferation and differentiation of T-cells, which are responsible for cell-mediated immunity. Recent data in animals suggest that such thymic hormone activity is modulated by the neuroendocrine network and, in particular, by thyroid hormones, but no information is presently available in humans. To study this question, we measured the circulating thymic factor called thymulin (Zn-FTS) in hyperthyroid and hypothyroid patients. Thymulin levels were higher in hyperthyroid patients than in normal subjects, whereas hypothyroid patients had lower thymulin levels than normal subjects. A significant correlation was found between circulating thymulin and serum T4 and T3 levels. Thymulin changes could be reversed by appropriate treatment in both groups of patients. Recent data indicate that zinc is required to confer biological activity on thymic hormone molecules. This raised the question of whether the influence of thyroid status on thymulin activity could be mediated by changes in serum zinc concentrations. No support for such an explanation was obtained by thymulin measurements by a modified bioassay using an optimal zinc concentration in the assay system. In conclusion, thyroid status modulates thymic endocrine function in humans. Whether and to what extent such modulation is relevant to the function of the immune system remain to be established.
Adolescent↗
Endocrine control of thymic serum factor production in young-adult and old mice.
The influence of different endocrinological manipulations on the blood concentration of serum thymic factor (FTS) was studied in young-adult and old mice. Among the experimentally induced endocrinopathies in youth, hypothyroidism and diabetes caused strong reductions of FTS levels, which were restored to normal by the appropriate hormonal substitutive therapy. Removal of adrenals or gonads has no significant effect on FTS level. Old mice, which show undetectable levels of FTS and low levels of thyroxine, can regain the capacity to produce FTS, provided they are treated with thyroxine. The variations of FTS blood levels in the course of endocrinological manipulations were due to a direct or indirect effect exerted on the recipient thymus. Hormonal treatment of thymectomized mice did not induce any FTS-like activity in their sera, nor did hormones interfere in vitro with the bioassay used to test for FTS. These data suggest that the neuroendocrine balance modulates the synthesis and/or the release of FTS from the thymus during the whole life of the organism and that the decline of FTS production with advancing age is largely dependent on age-associated endocrinological imbalances.
Adrenal Glands↗
The pharmacodynamics of thymomodulin in elderly humans.
It has been shown that, after oral administration of thymomodulin (Leucotrofina, Ellem Industria Farmaceutica SpA, Milan, Italy) nude mice show in their sera inductive activity on null cells, as measured by the Thy 1.2 antigen bioassay. The appearance of thymic hormone-like activity, as measured by the rosette inhibition assay, was investigated after oral administration of thymomodulin in elderly humans, who show no detectable levels of FTS ("facteur thymique sérique") in their serum. In human subjects over 70 years old, thymomodulin administration induced the appearance of FTS-like activity which reached maximum level at 2-6 h, was maintained for up to 12 h and disappeared by the 48th hour. By using different thymomodulin doses (80, 160, 320, 640, 800 mg) in a single administration, a dose-dependent effect appeared to exist: the higher the dose, the longer the maintenance of FTS levels. These data suggest that oral administration of thymomodulin induces, in humans, the appearance in the serum of substances with a modulating effect on the maturation of T-cells, and that the intestinal absorption of thymomodulin is efficient also in advanced age.
Administration, Oral↗
Thymic hormone deficiency in normal ageing and Down's syndrome: is there a primary failure of the thymus?
Normal individuals aged over 50 and most young Down's syndrome (DS) subjects had markedly reduced concentrations of circulating thymic hormone (facteur thymique sérique, FTS). Plasma from these two groups contained factors capable of inhibiting biological activity of FTS in vitro. Addition of zinc sulphate to plasma samples from DS subjects or the older individuals induced concentrations of FTS comparable to those observed in young healthy people and completely prevented FTS-inhibitory activity. These findings suggest that biologically active circulating thymic hormone is bound to zinc. The decline in thymic hormone activity in older individuals and DS subjects may be the result of changes in the mechanism of zinc-dependent activation of FTS molecules, which are probably associated with marginal zinc deficiency rather than with a primary failure of the thymus. Addition of zinc salt to plasma samples unmasks the presence of inactive FTS molecules.
Adolescent↗
Age-dependent decline of T-cell cloning potential in mice.
Mice spleen cells capable of forming, under stimulation by phytohemagglutinin (PHA), single-cell derived colonies in an in vitro soft-agar system, show with advancing age a progressive reduction of their number, which occurs earlier than the decline of PHA response in fluid phase. In addition to their reduced number, old colony-forming T-cells show the same phenomena recorded in fibroblasts; for example, a decrease of their residual in vitro proliferation potential, as measured by the size of the colonies, reached during the culture period. The reduced number of responding units and the decreased colony size seem to be distinct phenomena, since in the immunodeficiency state of hypopituitary dwarf mice only the first defect is observable, whereas the size distribution is normal. Both the reduced number of T-cell colonies and their decreased proliferative potential in vitro observed in old age, can be restored by transplanting a neonatal FTS ("facteur thymique serique")-producing thymus, but not by injecting isolated thymocytes into old mice. A correlation seems to exist between the decline of T-cell colony potential with advancing age and the progressive deterioration of thymic endocrine activity.
Aging↗
Recovery of age-dependent immunological deterioration in Balb/c mice by short-term treatment with L-thyroxine.
The progressive decline of immune efficiency with advancing age has been investigated in Balb/c mice by measuring the spleen-cell responsiveness to both T- and B-mitogens and the capacity to form plaques after immunization with sheep erythrocytes. While the responsiveness to concanavalin A and lipopolysaccharide is not significantly decreased in old mice, the responsiveness to phytohaemagglutinin and the plaque-forming-cell capacity progressively diminish with advancing age. Such a functional decline has been correlated with the age-associated deterioration of the neurohormonal balance and particularly with the reduction of thyroxine blood levels. Reconstitution experiments carried out by treating animals of increasing ages with 15 daily injections of L-thyroxine have demonstrated that such a treatment is able to restore the age-related decline of immune efficiency, and that this recovery is associated with the reactivation of the thymic endocrine activity. These data are consistent with the idea that the neurohormonal balance may influence the immune efficiency and that its derangement with advancing age may represent one of the factors responsible for the aging of the immune system.
Animals↗
Deficiency of autologous mixed lymphocyte reactions and serum thymic factor level in Down's syndrome.
The immune competence of the T lymphocyte system was studied in 28 noninstitutionalized subjects with Down's syndrome (DS) and were compared with sex- and age-matched healthy controls. The ability of enriched T lymphocytes to respond to 3 different T cell stimulants revealed a selective impairment of T lymphocyte subset(s). Subjects with DS showed normal responsiveness in allogeneic mixed lymphocyte reactions, but their response to phytohemagglutinin and in autologous mixed lymphocyte reactions was severely impaired. Non-T cells from DS subjects stimulated equally well both normal and DS allogeneic T lymphocytes. The blood concentration of serum thymic factor in the majority of DS subjects was much lower than that found in age-matched healthy controls. These data support the hypothesis that a deficiency of the T-dependent regulatory system is an intrinsic feature of DS and confirm the precocious aging of the immune system in these subjects.
Adolescent↗
Increased immunological efficiency in young mice by short-term treatment with L-thyroxine.
Treatment of young mice with L-thyroxine increases their capacity to form hemolytic plaques after sheep erythrocyte immunization. Such an increment is independent from the quantity of antigenic challenge, from sex and strains variations and from the temporal relationship between timing of hormonal treatment and antigenic challenge. The increment seems to depend on an increased number of both T and B reactive cells, rather than on an augmented proliferation rate of antigen triggered cells. The thyroxine induced increase of T reactive cells requires the presence of a functional thymus. These data suggest that the maximal immune response obtained under physiological conditions does not correspond to the maximal potentiality which can be expressed through appropriate manipulation of the internal microenvironment and further confirm the relevance that thyroxine may have as an immunostimulant agent.
Adjuvants, Immunologic↗
Oxidative stress and brain aging: is zinc the link?
Zn(2+) dyshomeostasis has been strongly linked to neuronal injury in many neurological conditions. Toxic accumulation of intracellular free Zn(2+) ([Zn(2+)](i)) may result from either flux of the cation through glutamate receptor-associated channels, voltage-sensitive calcium channels, or Zn(2+)-sensitive membrane transporters. Injurious [Zn(2+)](i) rises can also result from release of the cation from intracellular sites such as metallothioneins (MTs) and mitochondria. Chronic inflammation and oxidative stress are hallmarks of aging. Zn(2+) homeostasis is affected by oxidative stress, which is a potent trigger for detrimental Zn(2+) release from MTs. Interestingly, Zn(2+) itself is a strong inducer of oxidative stress by promoting mitochondrial and extra-mitochondrial production of reactive oxygen species. In this review, we examine how Zn(2+) dyshomeostasis and oxidative stress might act synergistically to promote aging-related neurodegeneration.
Aging↗
Antioxidant enzyme activities in healthy old subjects: influence of age, gender and zinc status: results from the Zincage Project.
Enzymatic activities of plasma superoxide dismutase (pSOD), catalase (CAT) and glutathione peroxidase (GPx) and erythrocyte superoxide dismutase (eSOD) were assayed in 981 healthy community dwelling old subjects participating in the Zincage Project. The relationship between antioxidant enzyme activities and, respectively, gender, age and zinc status were assessed. eSOD activity was higher in nonagenarians than in 80 year old subjects. Plasma Zn was lower in nonagenarians compared with younger subjects. The prevalence of Zn deficiency increased with age, with normal Zn levels observed in about 80% of adult subjects and only in 37% of the nonagenarians. Women showed higher eSOD and CAT activities compared to men, whereas plasma Zn was higher in men than in women. There was a positive correlation between eSOD activity and age and a negative correlation between eSOD activity and plasma Zn concentrations. An inverse correlation was also found between plasma Zn concentration and age. Further studies on different aspects of Zn metabolism--intake, plasma concentration, peripheral cell concentration, activity and amount of Zn-dependent enzymes--are warranted.
Age Distribution↗
Plasticity of neuroendocrine-thymus interactions during aging.
Thymic regrowth and reactivation of thymic endocrine activity may be achieved even in old animals by different endocrinological or nutritional manipulations such as, (a) intrathymic transplantation of pineal gland or treatment with melatonin, (b) implantation of a growth hormone (GH) secreting tumor cell line or treatment with exogenous GH, (c) castration or treatment with exogenous luteinizing hormone-releasing hormone (LH-RH), (d) treatment with exogenous thyroxine or triiodothyronine, and (e) nutritional interventions such as arginine or zinc supplementation. These data strongly suggest that thymic, involution is a phenomenon secondary to age-related alterations in neuroendocrine-thymus interactions and that it is the disruption of such interactions in old age that is responsible for age-associated dysfunction. With regard to the mechanisms involved in hormone-induced thymic reconstitution, it is at present, difficult to draw any definitive conclusions. The effect of GH, thyroid hormones, and LH-RH may be due to the presence on thymic epithelial cells supposed to produce thymic peptides, of the specific hormone receptors. Melatonin or other pineal factors may also act through specific receptors, but experimental evidence is still lacking. The role of zinc, whose turnover is usually reduced in old age, is diverse. The effects range from the reactivation of zinc-dependent enzymes, required for both cell proliferation and apoptosis, to the reactivation of thymulin, a zinc-dependent thymic hormone. The role of zinc may even be more crucial. According to recent preliminary data obtained both in animal and human studies, it appears that the above reported endocrinological manipulations capable of restoring thymic activity in old age, may act also by normalizing the altered zinc pool.
Aging↗