Antigenic specificity of two antibodies directed against the thymic hormone serum thymic factor (FTS).
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Amino Acid Sequence↗
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Results for “Thymic Factor, Circulating”
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Two different mechanisms for the inhibition of rosette formation in mice.
The vast majority of spleen T cells (T.sRFC) which spontaneously bind to sheep red blood cells (SRBC) in an antigen-specific fashion express the Thy-1+, CD3+, CD8+ phenotype. Inhibition of rosetting by antibodies to surface molecules occurs via distinct mechanisms according to the antibody. CD8 and CD3 molecules are located in proximity to SRBC receptors and steric hindrance is the most likely explanation for the inhibition of rosetting by antibodies to these molecules. On the other hand, anti-Thy-1 antibody bound to T.sRFC induces a dynamic process involving intracellular cAMP, and which results in the inaccessibility of SRBC receptors. Thymulin could restore normal sensitivity of T.sRFC from adult thymectomized (A.Tx) mice to all inhibitory antibodies whatever the mechanism by which they hinder rosette formation. These results reinforce the idea that thymulin may act on membrane characteristics.
Animals↗
Biological response modifiers and their promise in clinical medicine.
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Animals↗
Monoclonal antibody against the serum thymic factor (FTS).
Hybrid cell lines secreting antibodies specific for synthetic serum thymic factor (FTS) were prepared by cell fusion and cloning techniques. Spleen cells from BALB/c mice immunized with BSA-coupled FTS were fused with P3-x63-Ag8.653 myeloma cells. Antibodies produced by these hybrids were screened in vitro for their ability to absorb the activity of synthetic FTS in a rosette assay and in vivo for their capacity to induce the disappearance of endogenous FTS. Subsequently, the clones selected were transferred intraperitoneally into BALB/c mice. Ascitic fluid was produced and used as a source of antibody. The monoclonal antibody was shown to bind specifically to thymic reticulo-epithelial cells, using an indirect immunofluorescence technique. Furthermore, once injected into normal mice, the antibody induced the disappearance of FTS from the serum and modified the azathioprine sensitivity of spleen rosette-forming cells for more than 3 weeks.
Animals↗
Human post-thymic precursor cells in health and disease. V. Stimulatory effect of serum thymic factor on the cell cycle of autologous-rosette forming and T gamma-cells.
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Adult↗
Identification of FTS (facteur thymique serique) on thymus ultrathin sections using monoclonal antibodies.
Using a new immunoelectromicroscopical technique, this study confirms the localization of the 'facteur thymique sérique' (FTS) in the reticulo-epithelial cells of mouse thymus. The use of anti-FTS monoclonal antibodies on ultrathin sections for electron microscopy reveals FTS in cytoplasmic vacuoles, labelling density depending on the density of the vacuolar content. The successful application of this technique opens the way to its use for double-immunolabelling.
Animals↗
Effect of a synthetic thymic factor (facteur thymique serique) on natural killer cell activity in humans.
The effect of the serum thymic factor, FTS, on human NK cells was studied. NK cell activity was measured in a 51Chromium-release assay in which effector cells were peripheral blood lymphocytes (PBL) or bone marrow (BM) lymphocytes from healthy individuals and patients, and targets were K562 cells. When added in vitro in this assay, FTS modulated NK cell activity of normal PBL. Low concentrations of FTS (10(-2) ng/ml) increased NK activity (P less than 0.001) whereas higher concentrations decreased it (P less than 0.01) for 10 and 10(2) ng/ml. FTS exhibited no effect on NK cell activity of BM lymphocytes. When administered in vivo to 4 cancer patients (10 micrograms/kg i.v. every 3 days), FTS progressively increased peripheral NK activity in two patients with low pre-treatment NK values, whereas it decreased NK activity in two patients with previously normal or high NK values. The mechanism by which FTS modulates NK cell activity is still unknown but such modulation suggests that NK cells belong in part to the T-lineage.
Bone Marrow Cells↗
The activity of synthetic analogs of serum thymic factor (FTS) to convert mouse pre-T cells into Thy-1 positive cells.
Serum thymic factor (FTS) and its 33 analogs were compared with regard to the ability to induce Thy-1 antigen on mouse pre-T cells. The pre-T cells were prepared from spleen cells of athymic nu/nu mice by passing them through a nylon wool column, and the induction of Thy-1 antigen was analysed using a fluorescence-activated cell sorter. Thy-1 negative cells were converted into Thy-1 positive cells by FTS and some of its analogs. Deletion of pGlu at the amino terminus of FTS did not alter the activity. Des ( pGlu1 , Ala2)-FTS and des ( pGlu1 , Ala2, Lys3 )-FTS were inactive and deletion of the carboxyl terminal residue, Asn, also resulted in the loss of activity. Substitution or modification of pGlu1 and Asn9 with an amino acid, an acyl group or an amine caused a marked reduction of the activity. The residue 3, Lys, could be substituted without any loss of the activity by Arg, but not by Leu. These results show that the octapeptide moiety, Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn, is the minimum essential part of the FTS molecule for the expression of activity and they suggest that the positive charge at the residue 3 is also important for its activity.
Animals↗
Thymulin (FTS-Zn) induced in vitro modulation of T cell subsets markers on lymphocytes from rheumatoid arthritis and systemic lupus erythematosus patients.
Perturbations in T cells and T cell subsets of peripheral blood lymphocytes were looked for, using monoclonal antibodies, in nine patients with rheumatoid arthritis (RA) and four patients with systemic lupus erythematosus (SLE). All SLE patients were in an acute phase of their disease, but had not yet received steroids. Seven of the nine RA patients presented an active illness, recently diagnosed in five cases, and received no steroids nor D-penicillamin. T cell subsets alterations responsible for abnormal values of the OKT4 +/OKT8 + immunoregulatory ratio, were improved by in vitro incubation of the lymphocytes with synthetic thymulin in eight out of nine RA patients. No significant modification occured for SLE patients' lymphocytes. These results support the possible beneficial role of thymulin in the treatment of rheumatoid arthritis.
Adult↗
The influence of thymic humoral factor on systemic lupus erythematosus lymphocyte function.
The influence of thymic humoral factor, THF, on systemic lupus erythematosus, SLE, lymphocyte function was investigated. Increasing numbers of SLE T-cells, rosetted at 4 degrees C or 37 degrees C, were cultured with allogeneic normal B-cells and the change in IgM synthesis was assessed. Lymphocytes of some SLE patients showed improved suppression with THF when rosetted at 37 degrees C. Normal control lymphocytes did not show a net change in suppression with THF. The subgroup of SLE patients that showed improved suppression with THF in vitro might be a more appropriate group for in vivo therapeutic trials with thymic hormone, TH, than SLE patients in general.
B-Lymphocytes↗
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↗
Influences of sodium diethyldithiocarbamate, DTC (imuthiolR) on T cell defective responses of aged BALB/c mice.
The effect of chronic imuthiol treatment, 25 mg/kg weekly for 4 months initiated at the age of 12 months, on T-cell functions of aged female BALB/c mice was investigated. Imuthiol restored to normal value the impaired response to Concanavalin A (Con A) and enhanced the proliferative response to phytohemagglutinin (PHA). Impaired cytotoxic T-cell activity (CTL), was restored near to the value of young controls by imuthiol. Serum thymic factor (FTS) levels in serum of treated aged animals outpassed those of untreated young mice. Delayed-type hypersensitivity (DTH) reaction to oxazolone was increased. In contrast, the graft-vs-host (GVH) mortality induced by injecting H-2 histoincompatible cells to irradiated recipients, which GVH was impaired by aging, was not significantly modified by imuthiol. The excessive cytotoxicity for chicken red cells of macrophages (ADCC) from aged mice was reduced, as well as macrophage cytotoxicity for tumor cells. Natural killer cell activity remained unchanged. This finding confirms that imuthiol enhanced effectively T cell-dependent responses but the data on GVH reaction suggest that its effects are under a complex mode of action. Restoration of a normal production of FTS may be one mechanism by which imuthiol acts on the reinduction of the T-cell differentiating pathway in aged mice.
Aging↗
Recovery of low thymic hormone levels in cancer patients by lysine-arginine combination.
Thymic hormones are required for maturation and maintenance of the immune efficiency. It has been previously demonstrated that with advancing age there occurs a progressive reduction of the plasma level of one of the best known thymic peptides, i.e. thymulin, and that the administration of an amino acid combination (lysine-arginine, as present in the commercial preparation Lysargin, Baldacci, Italy) to elderly individuals is able to increase the synthesis and/or release of thymulin to values comparable to those recorded in young subjects. In the present paper we report evidence that cancer patients show much lower thymulin values than those recorded in healthy age-matched individuals and that the oral administration of the amino acid preparation is able to significantly increase thymulin levels even over the values of age-matched controls and to increase the number of peripheral T-cell subsets. It is suggested that such an effect is mediated through the known secretagogue activity of the amino acids on the pituitary release of growth hormone, which has a modulating effect on the thymic endocrine activity.
Adult↗
In vitro restoration by thymulin of NK activity of cells from old mice.
Old mice show a reduced natural killer (NK) cell activity. Among the causes proposed to explain this defect, both intrinsic failure of NK cells or age-related alteration of microenvironmental factors relevant for NK function, have been taken into consideration. The findings reported in the present paper, demonstrate that thymic peptides, and in particular the facteur timique serique (FTS), more recently called thymulin (ZnFTS) in its zinc-bound form, whose production and activity is generally reduced in old age, is able, when administered in vitro, to restore the crippled NK cytotoxicity of spleen cells from old mice. Neither the zinc-unbound form of the hormone (FTS) nor zinc ions alone are effective. The action is exerted on the basal NK activity and not on IFN-boosted NK cytotoxicity, at variance with the restoration obtained in similar experimental conditions with thyroid hormones, thus suggesting that different mechanisms or maturative steps of NK cells are involved.
Aging↗
Thymic serum activity inhibitors study.
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Adolescent↗
Restorative effect of short term administration of thymulin on thymus-dependent antibody production in restraint-stressed mice.
Thymulin is a well defined nonapeptide produced by thymic epithelial cells, and plays an important role in thymocyte differentiation. We investigated the restorative effect of thymulin on the stress-induced reduction in the production of antibodies against SRBC in mice. Antibody production in stressed mice was reduced to about 50% of that in normal mice. A 3-day period of administration of thymulin (1 ng/kg) restored antibody production to close to the normal level, whereas thymulin (1 ng-1 microgram/kg) did not affect antibody production in normal mice. These results indicated that thymulin normalizes the altered thymus-dependent immune responses.
Animals↗
Reversibility of the thymic involution and of age-related peripheral immune dysfunctions by zinc supplementation in old mice.
With advanced ageing the zinc pool undergoes progressive reduction as shown by the low zinc plasma levels and the negative crude zinc balance, both in humans and in rodents. It has been suggested that such zinc deficiency might be involved in many age-related immunological dysfunctions, including thymic failure. The relevance of zinc for good functioning of the entire immune system is, at present, well documented. In particular, zinc is required to confer biological activity to one of the best-known thymic peptides, thymulin, which is responsible for cell-mediated immunity. In deep zinc deficiencies, in humans and other animals, the low thymulin levels are due not to a primary failure of the thymus, but to a reduced peripheral saturation of thymic hormones by zinc ions. In aged mice both a reduced peripheral saturation of the hormone and a decreased production by the thymus were present. Oral zinc supplementation in old mice (22 months old) for 1 month induced a complete recovery of crude zinc balance from negative (-1.82) to positive values (+1.47), similar to those of young animals (+1.67). A full recovery of thymic functions with a regrowth of the organ and a partial restoration of the peripheral immune efficiency, as measured by mitogen responsiveness (PHA and ConA) and natural killer cell (NK) activity, were observed after zinc supplementation. These findings clearly pin-point for relevance of zinc for immune efficiency and suggest that the age-related thymic involution and peripheral immunological dysfunctions are not intrinsic and irreversible events but are largely dependent on the altered zinc pool.
Administration, Oral↗
Benefit of oral zinc supplementation as an adjunct to zidovudine (AZT) therapy against opportunistic infections in AIDS.
Zinc is perhaps the most important trace element for immune function. Congenital or acquired zinc deficiencies are associated with immune abnormalities and increased susceptibility to infectious diseases. AIDS subjects suffer from reduced zinc bioavailability, more severe in stage IV than in stage III. Such zinc deficiency causes, among other effects, a profound reduction in the biological activity of one of the thymic hormones, thymulin (zinc-facteur-timique-serique, ZnFTS). With these premises, zinc sulphate was administered orally at a daily dose of 200 mg for 30 days to AZT-treated stage III subjects with generalized lymphadenopathy (17 subjects) and stage IV subgroup C1 (12 subjects) AIDS patients. 18 stage III subjects with generalized lymphoadenopathy and 10 stage IV subgroup C1 subjects treated only with AZT served as controls. Zinc sulphate supplementation of stage III and in stage IV C1 patients was followed by an increase or a stabilization in the body weight and an increase of the number of CD4+ cells and the plasma level of active zinc-bound thymulin. The frequency of opportunistic infectious episodes in the 24 months following entry into the study was reduced after zinc supplementation in stage IV C1 subjects (11 infections vs 25 in controls) and delayed in stage III zinc-treated subjects (1 infection/24 months vs 13 infections/24 months in controls). The effect of zinc on opportunistic infections is restricted to infections due to Pneumocystis carinii and Candida, whereas no variations have been observed in the frequencies of cytomegalovirus and toxoplasma infections. These data may support the benefit of zinc as an adjunct to AZT therapy in AIDS pathology.
AIDS-Related Opportunistic Infections↗