Thymulin gene therapy prevents the histomorphometric changes induced by thymulin deficiency in the thyrotrope population of mice.

There is evidence of the existence of a bidirectional relationship between the thymus gland and the thyroid axis. Since the thymic peptide thymulin possesses hypophysiotropic activity, we undertook the task of assessing the histomorphometric changes induced by thymulin deficiency on the thyrotrope population of normal mice and the action of neonatal thymulin gene therapy on the thyrotropin (TSH)-cells of nude mice. C57BL/6 mice were subjected to immunoneutralization of circulating thymulin from postnatal day 1 to the end of the study (postnatal day 32) by intraperitoneal injections of rabbit anti-factor thymulin serum (α-FTS) and normal rabbit serum in controls. Also, neonatal thymulin gene therapy was implemented in athymic nude mice using an adenoviral vector expressing a gene for thymulin (RAd-FTS). On postnatal day 1, heterozygous (nu/+) and homozygous (nu/nu) pups received a single bilateral intramuscular (i.m.) injection of either RAd-FTS or RAd-GFP (the latter being the control vector). The pituitaries were immunostained for TSH. Thymulin immunoneutralization severely reduced serum thymulin (p < 0.01). We detected a significant (p < 0.05) decrease in cell size (CS) and volume density (VD) with a nonsignificant decrease in cell density (CD) in C57BL/6 in both males and females. A single neonatal i.m. injection of RAd-FTS markedly increased the circulating levels of serum thymulin in the athymic mice and increased the CD (p < 0.05), CS (p < 0.01) and VD (p < 0.01) of the thyrotrope population in nu/nu mice. Thyroid histology was not affected. Our results suggest a possible modulating effect of thymulin on the thyrotrope population.

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.

[Thymic hormonal effects on the antigen-dependent differentiation of accessory T-lymphocytes in the humoral immune response]. / Gormonal'nye vliianiia timusa na antigenzavisimuiu differentsirovku vspomogatel'nykh T-limfotsitov gumoral'nogo immunnogo otveta.

In the conditions of experimental deficiency of serum thymic factor (FTS) theophylline (TP) recovers in the post--thymic precursors of helper T lymphocytes an ability for differentiation to the effector regulatory stage and inhibits this process in the normal conditions. In the same conditions fraction 2 of thymosin (F2T) recovers this process and in combination with TP can relieve its opposite effects. The diversity of action of F2T on the differentiation of the post--thymic precursors of helper T lymphocytes is accounted for by the possibilities of realisation of the F2T and STF hormonal signals to these cells which depend on the condition of their specific receptors controlled by intracellular cAMP levels.

Morphometric assessment of the impact of serum thymulin immunoneutralization on pituitary cell populations in peripubertal mice.

Thymulin is a thymic hormone involved in several aspects of intra- and extrathymic T-cell differentiation. Thymulin also possesses hypophysiotropic activity which suggests that this metallopeptide may play an important role in thymus-pituitary communication, particularly during early life. The aim of the present study was to evaluate the impact of serum thymulin suppression from birth to peripuberty on the morphology of different pituitary cell populations in prepubertal C57Bl/6 mice. Animals were submitted to immunoneutralization of circulating thymulin from postnatal day 1 to the end of the study (age 32 days). From their 1st day of life, the animals were submitted to a protocol of intraperitoneal injections of rabbit anti-thymulin serum (alpha-FTS) and normal rabbit serum (NRS) in the controls. On their 33rd day of life, the animals were killed and their pituitaries were immediately dissected, fixed and immunostained using the EnVision system with primary antibodies against growth hormone, thyrotropin, corticotropin, gonadotropins and prolactin. Morphometry was performed by means of an image analysis system. The following parameters were calculated: volume density = Sigma cell area/reference area (RA); cell density (CD) = number of cells/RA, and cell size (expressed in microm2). Serum thymulin was measured by a rosette bioassay while pituitary hormones were assayed by radioimmunoassay. Serum prolactin, luteinizing hormone, follicle-stimulating hormone, growth hormone and thyroid-stimulating hormone were significantly lower in the alpha-FTS animals of either sex compared with the corresponding NRS counterparts. The somatotrope, lactotrope and corticotrope populations showed a significant decrease in CD, while cell hypertrophy was observed in some of the pituitary cell populations of the alpha-FTS group compared to the NRS group. In the alpha-FTS group, there were sex differences in the morphometric changes observed. Our results suggest that serum thymulin plays a significant role during early life in the postnatal maturation of endocrine cells of the mouse anterior pituitary gland.

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.

Levels of zinc and thymulin in plasma from patients with Crohn's disease.

Levels of zinc in plasma from patients with Crohn's disease were significantly lower than those of sex and age matched controls. We also measured the level of plasmic thymulin, a hormone released by the thymus gland, which in its active form binds one zinc molecule. The zinc unbound form of thymulin is biologically inactive and its level in the blood is a very sensitive marker of even marginal zinc deficiency. Levels of active thymulin were significantly reduced in plasma from patients with Crohn's disease, whereas plasma concentrations of the inactive form was higher than in controls. The in vitro addition of zinc ions restored thymulin activity in plasma from patients with Crohn's disease, and induced the disappearance of the inactive form. These findings suggest the existence of a zinc dependent alteration regarding the biological function of thymic hormones in patients with Crohn's disease. Such a defect might explain some of the immunological abnormalities observed in these pathological conditions.

Thymic dysfunction in childhood T-acute lymphoblastic leukemia: a possible linkage with a primary thymus involvement.

Experimental models, clinical and histopathological observations suggest a thymic origin of childhood T acute lymphoblastic leukemia (T-ALL). We studied thymic epithelial function in childhood T-ALL as compared to normal controls in order to improve our understanding of the cellular immunodeficiency mechanisms operating in a thymus-linked malignant process. The levels of Facteur Thymique Sérique (FTS) were measured in 9 patients at diagnosis, according to the rosette inhibition assay of Dardenne & Bach (1975). This method is based on the capacity of human serum containing FTS activity to confer on rosette-forming cells (RFC) from adult thymectomized mice a sensitivity to azathioprine identical to that of normal mouse RFC. All patients presented low age-corrected titres of FTS. No zinc deficiency was found, suggesting that low FTS levels are not related to unexpressed FTS biological activity. Plasma from all the children studied contained factors capable of inhibiting the biological activity of FTS in vitro. However, the nature of this inhibitor has not yet been elucidated. Our study shows the presence of a thymic dysfunction in childhood T-ALL, which could partially explain the immunodeficiency described in these patients. The linkage of the leukemic process with a primitive thymic involvement is discussed.

[Multifactorial analysis of the effect of metabolic and endocrine factors on cellular immunity in patients with cancer of the uterine body]. / Mnogofaktornyi analiz vliianiia metabolicheskikh i éndokrinnykh faktorov na kletochnyi immunitet u bol'nykh rakom tela matki.

Multifactorial analysis of effects of metabolic and endocrine determinants of the host and morphology of the tumor on cellular immunity has been undertaken in 29 patients with cancer of the corpus uteri. Several regression models obtained using the Hocking-Leslie method demonstrated significant effects of age, obesity, triglyceride levels, morphologic differentiation of the tumor and magnitude of invasion on various levels of cellular immunity, presenting as an increase in T-helper and decrease in suppressor counts. The multifactorial analysis depicted additive effects of endocrine homeostatic determinants and the tumor on different aspects of cellular immunity in cancer of the corpus uteri.