Neuroendocrine-thymus interactions: perspectives for intervention in aging.
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Aging↗
Biomedical subjects
N Fabris
Publications and source records attributed to N Fabris.
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↗
Thyroxine-dependent modulation of natural killer activity.
The influence of "in vitro" treatment with thyroia hormones on basal or lymphokine-induced NK cytotoxicity was analyzed in Balb/c mice using YAC-1 as target cells in a 51 Cr release assay. "In vitro" treatment with IFN or IL-2 causes a considerable increase of the natural cytotoxic activity of spleen cells from young-middle aged mice. An additive effect is observed when the two lymphokines are administered simultaneously. "In vitro" spleen cells preincubation with thyroxine increases NK citotoxic activity induced by IFN but it does not modify the basal activity or that induced by IL-2. Furthermore, thyroxine was able to significantly amplify even the maximal boosting effect induced by the simultaneous addition of both IFN and IL-2. These findings suggest a role for thyroid hormones in the modulation of natural cell-mediated citotoxicity and particularly in the espression of NK cell sensitivity to IFN.
Animals↗
Immunotherapy of bladder cancer with intralesional injection with BCG.
Immunotherapy of bladder cancer with non specific immunostimulants, such as bacillus Calmette Guerin (BCG), has been shown to significantly reduce tumor recurrences, and, when applied through intravesical BCG instillation to induce the regression of some established tumors, including carcinomas "in situ" and even some invasive tumors. Since in other tumors, namely melanomas, BCG has been proved to be most successful when infected directly into the tumor, intralesional therapy with BCG (1.5 x 10 BCG weekly for four weeks) has been applied in 20 patients affected by bladder cancer (T1 - T2). The local reaction has induced substantial reduction of the tumor mass and, in some cases, (four) total disappearance of the tumor. On the sixteen patients without total disappearance of the tumor, TUR was applied. The successive follow-up of these patients offer at present the following figures: 3 out of the four patients with remission after BCG alone are disease-free after 26-30 months, whereas one has developed after 18 months a papilloma surgically removed; 15 out of the sixteen patients treated with BCG followed by TUR are disease-free after 26-30 months. These data, compared with literature findings, support the idea that intratumoral BCG instillation of bladder cancer permits a longer disease-free period than other therapeutical approaches.
Adult↗
[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 role of neuroendocrine-immunological interrelations in the development of tumors].
There is at present an experimental evidence of neuroendocrine-immunological interactions in tumor development both in experimental models and man. In fact, different hormone receptors have been found in both experimental and spontaneous tumors in animals and man. Such tumors are therefore under the influence of the neuroendocrine system. In addition, some hormone-metabolic alterations such as those observed in advancing age are often associated with a high incidence of the neoplastic growth. Interestingly, tumor incidence increases with advancing age in both man and animals and experimental tumors are more easily transplanted in old mice than in young adult mice. On the ground of these observations it can be suggested that tumor growth results from the interactive action of both the immunological and neuroendocrine systems.
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↗
Decline of thymus-cell potential in diabetic and aged men.
Human peripheral blood thymus lymphocytes are capable of forming, when stimulated by phytohemagglutinin, single-cell-derived colonies in an in vitro soft-agar system. Blood samples were obtained from 33 healthy men ranging in age from 20 to 96 years of age and from 11 diabetic men ranging in age from 42 to 60 years and 11 age-matched controls. With increasing age a reduction in the number of single-cell-derived colonies and a decrease in their residual in vitro proliferation potential was observed. Such a defect appeared at an earlier age in diabetic men. The defect in proliferative potential of cells of either old or diabetic men did not depend on factors present in their blood plasma.
Adult↗
Age related patterns of immunoglobulin serum levels in the Quechua Indians of Andean Mountains.
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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↗
Electron-microscopic morphometric analysis of mouse liver. I. Experimental studies on the morphogenetic significance of the thymus in nude and normal mice.
Haired, nude, thymus-grafted nude and haired thymectomized Balb/c-nu mice 2 months of age were studied by electron-microscopic stereology. Each group consisted of 5 animals and a complete morphometric analysis was carried out on their livers. In the absence of the thymus there is a slowing down of the development of the whole organism. Among the liver parameters especially the nuclear ones displayed alterations. Namely, the volume of hepatocyte nuclei increased above the normal level and this phenomenon was reversed by thymus graft into the nude mice. The hepatocyte volume also increased significantly in the surgically thymectomized group, influencing all the morphometric parameters regarding mitochondria and endoplasmic reticulum, when measured per hepatocyte. On the basis of the results obtained, one can conclude that the thymus has a regulatory role in the development of hepatocyte morphology. The findings agree with the biochemical observations demonstrating non-immunological effects of the thymus on cellular development.
Animals↗