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PubMed1995

Zinc status of Indian children.

Zinc is a trace metal essential for human health and its deficiency is found to cause severe growth retardation in children. Information on the zinc status of Indian children is meagre perhaps due to lack of a reliable parameter. However, in view of the role of zinc in promoting growth, it has become common practice to prescribe zinc supplements to young children and newborns, particularly preterm infants. It is now clearly established that zinc confers no additional benefits to an individual with adequate zinc status while it can potentially lead to harmful effects by disturbing the milieu of other trace metals in the body. Estimation of thymulin levels in circulation is found to be a sensitive indicator of zinc status and using this parameter we found that apparently normal children have adequate zinc status. Children suffering from severe protein energy malnutrition however had very low levels of the hormone besides low leukocyte and plasma zinc levels indicating zinc deficiency. Such children showed improvement in their zinc status when zinc supplements were provided along with rehabilitation diets. Pregnant women and term newborns showed no evidence of zinc deficiency. Preterm infants had higher leukocyte zinc levels during early infancy and the breast milk of their mothers also had higher zinc content which could cater to the higher requirements of the rapidly growing preterm infant. All breast-fed infants showed decline in the zinc status gradually over the initial 4 months of life and regained adequate zinc status after appropriate weaning. These studies thus do not support the view of routine zinc supplements to pregnant women or children. However, Infants solely fed formula milk from birth had significantly impaired zinc status till the time of weaning. The functional significance of severe zinc inadequacy in such infants needs to be established.

Child, Preschool↗
PubMed1995

Role of the low zinc bioavailability on cellular immune effectiveness in cystic fibrosis.

An altered cellular immune response as a secondary phenomenon has been suggested to be probably involved in the bronchopulmonary infections by Pseudomonas aeruginosa in cystic fibrosis (CF). The difficulty to eradicate with modern anti-pseudomonal antibiotics the bronchopulmonary infections has led us to further investigate the possible existence of other cellular immune defects and their cause. Alterations in zinc turnover are present in CF. Zinc is relevant for good immune functioning. In particular, zinc is required to confer biological activity to thymulin (ZnFTS), a biochemically defined thymic hormone with a modulating action on cell-mediated immunity. The zinc-unbound form (FTS) is inactive and it can be unmasked by in vitro zinc addition to the plasma samples revealing the total amount of circulating thymulin (active + inactive). Marginal zinc deficiencies may prevent peripheral biological activation of active thymulin. Total zinc-saturable thymulin fractions in CF are similar to those observed in normal subjects, whereas the active quota is strongly reduced associated with concomitant high plasma levels of inactive thymulin compared to the values of healthy children (P < 0.01). A strict correlation exists between zinc and thymic hormone-saturable fraction (r = 0.87, P < 0.01) in CF. These findings suggest that the defect is not due to a thymic failure but to a reduced peripheral saturation of thymulin by zinc ions. This defect might depend on augmented plasma concentration of alpha 2-macroglobulin, which has a higher binding affinity for zinc than thymulin. T cell subsets are normal in CF. Reduced NK cell number and activity are present. Also, plasma IL-2 levels are reduced. The existence of positive correlations between zinc and IL-2 (r = 0.79, P < 0.01) and between zinc or active thymulin and NK activity (r = 0.70, P < 0.01 and r = 0.88, P < 0.01, respectively) suggest a close link among zinc failure, impaired IL-2 activity, low thymulin level, and reduced NK activity in CF patients with both normal and growth retardation. Although the role of NK cells is unknown in CF, a zinc supplementation, in order to induce a complete saturation of thymulin molecules, to correct some cellular immune defects and to improve the growth, may be suggested.

Adolescent↗
PubMed2006

Gene therapy for long-term restoration of circulating thymulin in thymectomized mice and rats.

Thymulin is a thymic peptide possessing hypophysiotropic activity and antiinflammatory effects in the brain. We constructed a synthetic DNA sequence encoding met-FTS, a biologically active analog of thymulin, and subsequently cloned it into different expression vectors. A sequence optimized for expression of met-FTS in rodents, 5'-ATGCAGGCCAAGTCGCAGGGGGGGTCGAACTAGTAG-3', was cloned in the mammalian expression vectors pCDNA3.1(+) and phMGFP (which expresses the Monster Green Fluorescent Protein), thus obtaining pcDNA3.1-metFTS and p-metFTS-hMGFP, which express met-FTS and the fluorescent fusion protein metFTS-hMGFP, respectively. The synthetic sequence was also used to construct the adenoviral vector RAd-metFTS, which expresses met-FTS. Transfection of HEK293 and BHK cells with pcDNA3.1-metFTS (experimental groups) or pcDNA3.1 (control), led to high levels of thymulin bioactivity (>600 versus <0.1 pg/ml in experimental and control supernatants, respectively). Transfection of HEK293 and BHK cells with pmetFTS-hMGFP revealed a cytoplasmic and nuclear distribution of the fluorescent fusion protein. A single intramuscular (i.m.) injection (10(7) plaque forming units (PFU)/mouse or 10(8) PFU/rat) of RAd-metFTS in thymectomized animals (nondetectable serum thymulin) restored serum thymulin levels for at least 110 and 130 days post-injection in mice and rats, respectively. We conclude that RAd-metFTS constitutes a suitable biotechnological tool for the implementation of thymulin gene therapy in animal models of chronic brain inflammation.

Adenoviridae↗
PubMed1990

Evidence that appearance of thymulin in plasma follows lymphoid chimerism and precedes development of immunity in patients with lethal combined immunodeficiency transplanted with T cell-depleted haploidentical marrow.

Thymulin, a peptide secreted by human thymic epithelial cells, circulates in peripheral blood. Levels of plasma thymulin (FTS-Zn) activity were analyzed in 21 patients with lethal combined immunodeficiency disorders who were treated with transplantation of HLA-haplotype-mismatched parental bone marrow depleted of T cells by differential agglutination with soybean agglutinin and E-rosetting (SBA-E-BMT). Among these 21 infants, 15 were patients with severe combined immunodeficiency (SCID) and 6 had combined immunodeficiency (CID) with Omenn's syndrome or CID with T cell predominance (CIDTP). In contrast to normal infants who possess high levels of plasma thymulin activity, 20 of the 21 patients demonstrated undetectable or low plasma thymulin levels for their age at admission prior to transplantation. Following SBA-E-BMT, however, thymulin became detectable in the plasma of 17 of 18 evaluable patients and reached normal or near-normal levels between 21 and 125 days posttransplant. In patients in whom the timing of engraftment could be established by emergence of donor lymphocytes, thymulin appeared in the plasma at approximately the same time as lymphoid chimerism was detected, and in all patients who were engrafted and immunologically reconstituted, the increment in thymulin levels preceded development of immune functions. These studies support the concept that normal marrow-derived cells in the graft can provide a stimulus necessary for induction of thymic epithelial secretory function in patients with thymic dysplasia. Further, immunologic reconstitution in these patients was not seen following SBA-E-BMT unless and until recovery of thymus function had been observed.

Bone Marrow Transplantation↗
PubMed1989

Effect of oral zinc administration on prolactin and thymulin circulating levels in patients with chronic renal failure.

High serum PRL and low zinc (Zn) levels are common findings in patients with chronic renal failure (CRF); in such patients serum Zn concentrations have been reported to be inversely correlated to serum PRL levels. Moreover, Zn regulates both thymus growth and the biological activity of the thymic hormone thymulin, and PRL-thymic interrelationships have been described. To determine whether hypozincemia alters serum PRL and plasma thymulin concentrations in CRF, 9 men with CRF treated by chronic hemodialysis were given 400 mg/day Zn sulfate, orally (4.96 meq/day Zn), for 6 months. Before treatment, serum PRL levels were significantly higher (P less than 0.001) in these patients than in normal men [mean, 28.7 +/- 20.7 (+/-SD) vs. 7.5 +/- 3.7 micrograms/L], and their serum PRL response to TRH (200 micrograms, iv) was impaired (mean maximal percent increase, 38.2 +/- 10.9 vs. 641 +/- 335; P less than 0.001). The plasma Zn-bound bioactive thymulin titer (1.3 +/- 0.7 1/log2), total thymulin titer (Zn-bound plus Zn-unbound forms, 2.1 +/- 0.8 1/log2), and serum Zn (13.1 +/- 2.4 mumol/L) were lower (P less than 0.001) in men with CRF than in normal men. Zn therapy did not induce any significant change in basal and TRH-stimulated serum PRL levels, while serum Zn levels significantly increased, reaching the normal range after the first week of treatment (17.8 +/- 6.3 mumol/L). Plasma total thymulin increased rapidly, reaching normal levels after 1 week, but Zn-bound thymulin increased modestly during the first month of treatment and more after 3 and 6 months of treatment. There was no age-related difference in plasma thymulin levels during therapy. We conclude that oral Zn administration in patients with CRF significantly increases both total and Zn-bound thymulin, but does not modify basal and TRH-stimulated serum PRL levels. The observation that Zn supplementation markedly increased plasma thymulin levels in uremic patients suggests that Zn is a potent stimulus for thymic hormone synthesis, and it can reverse the age-related diminution of thymic activity in CRF patients.

Adult↗
PubMed1997

Immuno-electron microscopy of the thymic epithelial microenvironment.

Normal T cell development depends upon interactions between progenitor cells and the thymic microenvironment. Monoclonal antibodies (Mabs) have been used to define subtypes of thymic epithelium by light microscopy (clusters of thymic epithelial staining [CTES]). We have now used a range of these Mabs together with gold-coupled reagents in immuno-electron microscopy to study the fine cellular distribution of the molecules to which the antibodies bind. Anti-cytokeratin antibodies were used to identify all thymic epithelial cells, while the distribution of MHC class II molecules was revealed with Mabs to shared nonpolymorphic determinants. MR6, a CTES III Mab, shows strong surface labelling of cortical epithelial cells and thymic nurse cells and very weak surface staining of thymocytes, medullary macrophages, and interdigitating cells. Mab 8.18 (CTES V) also labels a cell surface molecule; this is present on Hassall's corpuscles and associated medullary epithelial cells. The molecules detected by Mabs MR6 and 8.18 are therefore located in a position where they are available to interact with external cellular and soluble signals within the thymus. In contrast, Mabs MR10 and MR19 (CTES II) recognise intracellular molecules within subcapsular, perivascular, and medullary epithelium. A similar distribution was seen with Mab 4beta, directed against the thymic hormone thymulin, although, in addition to the expected intracellular epithelial staining, large lymphoblasts in the subcapsular zone showed surface positivity, indicating the presence of thymulin bound to surface receptors on these early lymphoid cells. As expected, MHC class II molecules were expressed on some medullary and essentially all cortical epithelial cells. However, although most subcapsular epithelium was class II-negative, some cells did express these MHC molecules on their apical surface and on the surface of their cytoplasmic extensions into the cortex. Interestingly, some cortical epithelial cells surrounding capillaries were positive for both MR6 (CTES III) and for MR10, MR19, and 4beta (CTES II). Double-labelling experiments, using MR6 and MR19 simultaneously, revealed a double-positive perivascular epithelial cell population in the thymic cortex. The possibility that these cells represent a thymic epithelial progenitor population is discussed.

Animals↗
PubMed1980

Cell-mediated immunity in patients with mycosis fungoides in clinical remission: effect of thymic humoral factor on the immunocompetence of the lymphocytes.

In 10 patients with mycosis fungoides (MF) who were in clinical remission following local treatment with nitrogen mustard, cell-mediated immunity was investigated by means of tests for lymphocytes, forming rosettes in the peripheral blood, and the graft-vs-host reaction as well as intradermal skin tests. The effect of thymic humoral factor (THF) on T lymphocytes with impaired immunecompetence was also investigated. The results provided evidence of various kinds of damage to the immunologic system in most of the patients. Of the 10 patients, 4 had low percentages of T cells. Eight of the 10 had a graft-vs.-host reaction which was weak or negative, and in 4 of these, the administration of THF to the lymphocytes induced an improvement in immunoreactivity. These results together with other recently reported data indicate that the determination of cell-mediated immunity in patients with MF may be of prognostic importance. Those patients whose T lymphocytes respond to treatment with THF are probably the best candidates for immunotherapy.

Adult↗
PubMed1984

Immune modulation of a T-suppressor cell lymphoma by thymic humoral factor, a thymic hormone.

Lymphoid cells obtained from a mediastinal mass and bone marrow as well as peripheral blood of a patient with poorly differentiated diffuse malignant lymphoma were found to have both E and complement receptors. Addition of the bone marrow lymphoblasts to normal human T-lymphocytes induced a suppression of normal T functional activity as measured by a local xenogeneic graft versus host reaction. Incubation of the same cells with thymic humoral factor (THF), a thymic hormone, reversed their functional activity from suppression to help. Control studies with normal T-suppressor lymphocytes also showed a reversal of function to helper activity upon incubation with THF. In studies of normal T-lymphocytes with monoclonal antibodies, incubation with THF induced no change in phenotype in either theophylline-sensitive (suppressor) cells or theophylline-resistant (helper) cells. The ability of THF to modulate helper and suppressor activities suggests that this or similar agents may provide a useful means of therapy for disorders of immunoregulation.

Adult↗
PubMed2003

Developmental immunotoxicity of lead: impact on thymic function.

BACKGROUND: Since the potential effects of early exposure to lead on thymic functions have not been fully characterized, in this study we evaluated the capacity of lead to alter thymic function in juvenile chickens following embryonic exposure. METHODS: Cornell K strain White Leghorn chicken eggs were administered lead acetate (400 microg/egg) or sodium acetate (control) on embryonic development (E12) with and without thymulin supplementation. Ex vivo production of interferon-gamma (IFN-gamma)-like cytokine by thymocytes and a delayed-type hypersensitivity (DTH) reaction were measured in the juvenile. Additionally, the effects of in vitro exposure to lead on both thymocytes and thymic stromal cells (TSCs) were evaluated. RESULTS: Following E12 exposure to lead, ex vivo production of IFN-gamma-like cytokine by juvenile-derived thymocytes decreased significantly compared to the control. The same effect was observed when thymocytes were directly exposed to lead in vitro and stimulated with thymic stromal supernatant. In contrast, when TSCs were exposed to lead in vitro, no change was seen in their functional capacity for promoting cytokine production. In ovo supplementation with thymulin partially reversed lead-induced DTH depression without any change in IFN-gamma-like cytokine production. Embryonic exposure to thymulin alone partially depressed the DTH response. CONCLUSIONS: These results suggest that lead can directly influence thymocyte function in the absence of the thymic microenvironment. Since thymulin levels may influence lead-induced immunotoxicity, embryonic endocrine status may be an important consideration. Lead exposure appears to alter thymic functions directly; however, indirect effects via endocrine factors are not precluded.

Animals↗
PubMed1992

Mechanoluminescence: an assay for lymphocyte analysis in neoplasia.

We have studied the mechano-electrochemical activation of optical emission (mechanoluminescence, ML) from the surface of lymphocytes. In C57BL/6 mice with B16 melanoma at the terminal stage of tumour growth and after immunotherapy with thymic agents, there is a correlation between light emission and the value of lymphocyte surface charge and titres of thymic serum factor (FTS).

Adult↗
PubMed1983

Peptide studies using a fast atom bombardment high field mass spectrometer and data system. 1--Sample introduction, data acquisition and mass calibration.

Conditions were established for analyzing as little as 5 pmol of an underivatized peptide delivered in a glycerol sample matrix as a thin film onto a gold-plated copper sample stage and then bombarded with xenon fast atoms. Calibration of the fast atom bombardment high field mass spectrometer and data system was achieved using cesium iodide/glycerol as a reference. Calibration at several accelerating potentials permitted a mass range from 393 to 5941 u. Several factors were examined that contribute to the quality of the mass spectrum: components within the glycerol such as other peptides, alkali salts, acid and reducing agents; the nature of the fast atom gas; concentration of the peptide delivered to the sample stage; and the effect of the sample stage and sample matrix on sensitivity.

Angiotensin I↗
PubMed1983

Peptide studies using a fast atom bombardment high field mass spectrometer and data system. 3--Negative ionization: mass calibration, data acquisition and structural characterization.

Under negative ionization conditions, nominal mass calibration of the fast bombardment high field mass spectrometer and data system was accomplished using cesium iodide/glycerol as a reference. Mass calibration at --8 kV accelerating potential extends from m/z 387 to m/z 2170 using xenon fast atoms. Negative xenon FAB mass spectra for human angiotensin I and human gastrin I complement their positive fast atom bombardment spectra. Negative xenon fast atom bombardment spectra of underivatized peptides exhibit molecular proton-abstracted ion envelopes and structurally significant fragment ions. Peptide mixture analysis under negative xenon fast atom bombardment reveals peptide molecular ion envelopes of higher relative intensities than under positive xenon fast atom bombardment.

Angiotensin I↗
PubMed1979

Restoration by serum thymic factor of colony-forming unit (CFU-S) entry into DNA synthesis in thymectomized mice after T-dependent antigen treatment.

Adult thymectomy prevents stimulation of hematopoietic stem cells as measured by colony-forming units (CFU-S) if T-dependent antigens are injected, but not when T-independent antigens are used. This can be observed as soon as 10 to 15 days after thymectomy. The serum thymic factor can restore CFU-S response to T-dependent antigens in thymectomized mice.

Animals↗
PubMed1980

Evidence of the presence in normal serum of a carrier of the serum thymic factor (FTS).

Chromatography of normal human or mouse serum on Sephadex G-150 revealed the presence of two peaks of activity in the rosette assay used for the characterization of the serum thymic factor (FTS). One peak corresponded to the elution volume of FTS (mol. wt. 867), the other to molecules with mol. wts. of 40 000-60 000. Both peaks were absent in serum of thymectomized (Tx) mice but could be induced in such Tx mice by injection of synthetic FTS. Study of the biological half-life of both peaks (assessed by the rosette assay) and demonstration of their specific retention on anti-FTS immunosorbent indicate, altogether with direct binding experiments, that FTS is transported in serum by a molecule with a mol. wt. of the order of that of albumin or prealbumin. It is apparent that FTS bound to this molecule is responsible for the biological FTS-like activity associated with large mol. wt. fractions of normal serum.

Adult↗
PubMed1982

Development and continuous growth in culture of interleukin 2-producer lymphocytes from athymic nu/nu mice.

Splenocytes of nu/nu mice treated with serum thymic factor (FTS) for 3 or more days followed by stimulation with either phorbol myristate acetate (PMA) or concanavalin A (Con A) produced interleukin 2 (IL 2) as determined in two indicator systems, namely, support of growth of IL 2-dependent T cells and promotion of Con A-initiated mitogenesis of thymocytes. However, neither mitogens nor FTS alone could induce nude mice cells to product IL 2. Supernatants derived from the tumor cell line WEHI-3 (WEHI-3 conditioned media) induced and supported continuous growth in culture of Thy-1.2+, Lyt-1+2- lymphocytes from athymic nude mice capable of producing IL 2 after their stimulation by either PMA or Con A. The growth of these IL 2-producer cell lines strickly depends on the presence of WEHI-3 conditioned media, as in the absence of it they die 24-48 h later. In addition, WEHI-3 conditioned media have been supporting the growth of IL 2-producer cell lines derived from nude mice for 3 1/2 months. The helper factor contained in WEHI-3 conditioned media responsible for the above biological activity has an apparent mol. wt. of approximately 40 000 as determined by Sephadex G-100 chromatography and lacks IL 1 and IL 2 activities, but efficiently supports the growth of IL 2-producer cells derived from nude mice and the peripheral blood of normal human volunteers. These results indicate that the helper factor in WEHI-3 conditioned media which enables the generation and continuous proliferation in culture of IL 2-producer cells in nude mice is distinct from interleukin 1, IL 2 and FTS (mol. wt. 864). Finally, the possibly functional relationship of FTS and the helper factor produced by WEHI-3 cells is discussed.

Animals↗
PubMed1984

In vivo and in vitro studies of thymulin in marginally zinc-deficient mice.

Thymulin (or serum thymic factor, FTS-Zn), a well-defined thymic hormone previously shown to be a nonapeptide binding the metal zinc, was studied in mice subjected to a long-term marginally Zn-deficient diet. In spite of the absence of thymic atrophy, we observed a significant decrease in the serum levels of thymulin as early as two months after the onset of treatment. However, these levels could be consistently restored after in vitro addition of ZnCl2. The analysis of thymuses from Zn-deficient mice showed that, despite the apparently normal network of epithelial cells, there was a progressive increase in the number of thymulin -containing cells (assessed by immunofluorescence with anti- thymulin monoclonal antibodies) that was already significant after two months of treatment. These results are in keeping with those of previous investigators, showing a specific, altered, thymic endocrine function following Zn deprivation. Nonetheless, our results strongly suggest that the nonactive Zn-deprived peptide is secreted under these experimental conditions. Furthermore, the fact that the augmented numbers of thymulin -containing cells were observed in the thymuses following a decrease in the peripheral thymulin (biologically active) brings further evidence for the existence of a feedback mechanism for the secretion of this hormone.

Animals↗
PubMed1984

Thymic hormone-containing cells VI. Immunohistologic evidence for the simultaneous presence of thymulin, thymopoietin and thymosin alpha 1 in normal and pathological human thymuses.

The localization of the three best-defined thymic hormones, namely, thymulin, thymopoietin and thymosin alpha 1 was studied by immunofluorescence using antibodies directed against these three molecules. With both human thymus frozen sections and cultured cells, thymic hormones were found exclusively in the epithelial component (recognized by its keratin content), in normal as well as pathological thymuses. The double-labeling experiments using the different anti-thymic hormone antibodies showed that the same epithelial cells contained the three hormones. These results suggest that the production of different hormones in the thymus is accomplished by the same epithelial cells.

Cells, Cultured↗