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PubMed1991

Induction of thymocyte proliferation by supernatants from a mouse thymic epithelial cell line.

The thymic stroma plays a critical role in the generation of T lymphocytes by direct cell-to-cell contacts as well as by secreting growth factors or hormones. The thymic epithelial cells, responsible for thymic hormone secretion, include morphologically and antigenically distinct subpopulations that may exert different roles in thymocyte maturation. The recent development of thymic epithelial cell lines provided an interesting model for studying thymic epithelial influences on T cell differentiation. Treating mouse thymocytes by supernatants from one of TEC line (IT-76M1), we observed an induction of thymocyte proliferation and an increase in the percentages of CD4-/CD8- thymocytes. This proliferation was largely inhibited when thymocytes were incubated with IT-76M1 supernatants together with an anti-thymulin monoclonal antibody, but could be enhanced by pretreating growing epithelial cells by triiodothyronine. We suggest that among the target cells for thymulin within the thymus, some putative precursors of early phenotype might be included.

Animals↗
PubMed1994

Prevention of diabetes by thymic hormone in alloxan-treated rats.

We investigated the effects of facteur thymique sérique (FTS), a thymic peptide hormone, on alloxan- and streptozotocin-induced diabetes in rats. Pretreatment with intravenous injection of FTS significantly suppressed both alloxan- and streptozotocin-induced hyperglycemia. The effects of FTS were time dependent. FTS suppressed hyperglycemia in a dose range of 1-6600 micrograms/kg. Alloxan-induced hyperglycemia was completely prevented when FTS was injected in doses of 40-50 micrograms/kg 1 min before injection of alloxan. Histological examination of islet areas showed that alloxan-induced destruction of beta-cells was inhibited by FTS. FTS had no significant effects on lymphocyte subsets and immunity-related cells or on plasma superoxide dismutase activity and total glutathione level. The blood half-life time of exogenously injected FTS was short (2-3 min), indicating acute internalization of FTS into pancreatic beta-cells. Our results suggested that FTS acutely and directly blocks some initial effect of alloxan, preventing the destruction of beta-cells.

Amino Acid Sequence↗
PubMed1988

Involution of thymic epithelium and low serum thymulin bioactivity in weanling mice subjected to severe food intake restriction or severe protein deficiency.

The volume of epithelium in the cortex and in the medulla of the thymus was compared in four groups of weanling male and female CBA/J mice. Well-nourished controls (C), food intake restricted (R), and animals given a low-protein diet ad libitum (LP) were fed from 23 to 37 days of age. Baseline controls (B) were studied at 23 days of age. Epithelial volume fraction was estimated for each group by point-counting morphometry on electron micrographs. Other mice were used to obtain group mean estimates of thymic index (mg/g live weight) and volume fraction of cortex and medulla (light microscope-level point-counting morphometry). Cortical and medullary epithelial volumes were calculated for each animal examined by electron microscopy by obtaining the live weight and applying, in sequence, the group mean thymic index, an assumed thymic density of 1.0 mm3/mg, the group mean cortical or medullary volume fraction, and the measured cortical or medullary volume fraction for that animal. Serum thymulin bioactivity was also measured in C, R, and LP mice. The results reveal thymic epithelial involution in the two most common rodent models of malnutrition, and suggest that this may contribute to the low serum thymulin levels found in malnourished experimental animals and humans.

Animals↗
PubMed1980

Thymic hormonal effect on human peripheral blood lymphocytes in vitro. III. Conditions for mixed lymphocyte-tumor culture assay.

Conditions for the reproducible measurement of thymic hormonal effect on the functional activity of human peripheral blood lymphocytes (PBL) were determined using a mixed lymphocyte-tumor culture assay. Three thymic hormonal preparations (thymopoietin, thymic humoral factor and TP-1) were tested by this assay and found to have a significant enhancing effect on the blastogenic response. Essential for the demonstration of the hormonal effect was the selection of suboptimal stimulation conditions, with the appropriate cell lines, including the number of stimulating cells and the time in culture. The most reproducible results were achieved when 1 x 10(5) PBL were co-cultured for 4 days with 1 x 10(4) mitomycin-C treated Raji lymphoma cells, after 1 h preincubation with one of the thymic preparations. However, strong enhancing effects of the thymic preparations could also be demonstrated with other tumor cel lines, especially IgR3 melanoma cells.

Adenocarcinoma↗
PubMed1987

An enzyme immunoassay for synthetic thymulin.

Thymulin, a metallononapeptide with the following aminoacid sequence: pyroGlu-Ala-Lys-Ser-Gln-Gly-Gly-Ser-AsnOH is a thymic hormone involved in T cell differentiation requiring zinc to express biological activity as measured by the rosette assay. We established an enzyme immunoassay (EIA) for synthetic zinc-free thymulin with a thymulin-acetylcholinesterase conjugate as tracer and specific polyclonal rabbit antithymulin antibodies. The assay is performed as a classical competition assay in microtiter plates previously coated with mouse monoclonal IgG to rabbit IgG. A quantitative thymulin assay more sensitive than radioimmunoassays (RIAs) previously described was obtained with a sensitivity (IC50) of 32.5 +/- 5 pg/ml and a detection limit of 5 pg/ml. Analysis in the EIA of synthetic thymulin analogs showed that the minimal peptidic structure necessary for enzymatic tracer competition is the C-terminal part Lys3 to Asn9. It was also shown that the biologically active form of thymulin (zinc-bound) has the same immunoreactivity as zinc-free thymulin and that other thymic hormones, thymosin alpha 1 and thymopoietin II (or TP5) and unrelated short peptides do not cross-react with thymulin. These data demonstrate the specificity of this EIA for thymulin and show its suitability for application in biological fluids.

Antibody Specificity↗
PubMed1990

A new radioimmunoassay for the thymic peptide thymulin, and its application for measuring thymulin in blood samples.

A new, specific and sensitive radioimmunoassay, using a polyclonal antiserum raised in rabbits, is described for quantitating plasma thymulin. As little as 300 fg thymulin can be measured in one assay tube. The method has been used to measure thymulin in human blood (umbilical vessel blood, 2191 +/- 123 fg/ml; children and adults up to the age of 20 years, 1499 +/- 119 fg/ml; and adults between 21-65 years, 371 +/- 18 fg/ml). There is a highly significant decrease within these three groups (P less than 0.001 by one way analysis of variance). Also plasma thymulin levels were determined in rats (601 +/- 127 fg/ml) and in pooled plasma samples from mice (638 +/- 56 fg/ml). No thymulin was detected in plasma obtained from nude rats, nude mice and thymectomised mice. These results show that the radioimmunoassay described here is a useful quantitative tool for measuring plasma thymulin that will have applications in basic, applied and clinical research.

Animals↗
PubMed1983

Dihydrotestosterone regulation of thymocyte function in the rat mediation by serum factors.

We have previously reported that reticuloepithelial cells of rat thymic tissue contain specific, high-affinity estrogen (E) and dihydrotestosterone (DHT) receptors which are not present in thymocytes, and that stimulation of the concanavalin A (Con A) sensitive thymocyte population is by means of a thymic serum substance depressed by estradiol. To ascertain if a serum substance modulated by DHT could also effect a thymocyte population, we incubated thymocytes in vitro for 3 days in the presence of the mitogens Con A or phytohaemagglutinin (PHA) + tissue culture media + 20% specific rat serum preparations and pulse labelled with tritiated thymidine. Rat serum samples were prepared from control, castrate, thymectomized (Tx) and castrate-Tx animals as well as from similar groups of animals treated in vitro for 3 days with physiological doses of DHT. It was found that there was a significant enhancement of thymocyte blastogenesis in cultures incubated with castrate rat serum + Con A or PHA vs control serum cultures (P less than 0.001). Direct replacement of DHT either to normal or castrate sera in vitro at physiological concentrations did not alter the level of thymocyte blastogenesis from normal or castrate controls. Sera prepared from castrate animals treated with DHT at physiological concentrations did not depress the blastogenic response, but sera from animals treated with testosterone were successful in depressing the blastogenic response to noncastrate levels. Sera prepared from Tx animals were stimulatory on thymocyte blastogenesis when PHA were utilized (P less than 0.02) and this stimulation was depressed in sera from animals treated in vivo with DHT. Sera prepared from Tx or castrate-Tx animals were not able to stimulate thymocyte blastogenesis when Con A was utilized but were stimulatory when prepared from castrate-Tx animals pretreated in vivo with DHT. It is hypothesized that Con A sensitive thymocytes are depressed by a thymic serum factor under the control of E and that both Con A and PHA sensitive thymocytes are depressed by a serum factor possibly of extrathymic origin that is under the control of DHT. A tentative hypothesis for the regulation of thymocytes by gonadal steroid hormones is presented.

Animals↗
PubMed1988

Thymic hormone containing cells--IX. Steroids in vitro modulate thymulin secretion by human and murine thymic epithelial cells.

We investigated the in vitro effects (kinetics and dose-response) of adrenal and sexual steroid hormones on the secretion of thymulin, a thymic hormone, by human thymic epithelial cells in primary cultures as well as in a rat epithelial cell line. We demonstrated that all steroids tested, in a range of physiological doses, stimulated thymulin production to various extents. Progesterone and estradiol, however, were revealed to be the most efficient. Specific steroid antagonists abrogated the steroid-induced stimulation of thymulin production. These findings confirm our previous in vivo results and demonstrate that steroid hormones can act directly on thymic epithelial cells to modulate their endocrine production.

Animals↗
PubMed1990

Neuroendocrine control of thymic hormonal production. II. Stimulatory effects of endogenous opioids on thymulin production by cultured human and murine thymic epithelial cells.

Data have now accumulated to strongly demonstrate that several neuropeptides, including endogenous opioids, can have immunomodulatory functions. Most of the studies have so far focused on the direct action of these substances on lymphocytes. We decided to investigate whether thymic epithelial cells (TEC) - the major component of the thymic microenvironment - could also be modulated by endogenous opioids. Primary cultures of human and murine TEC were subjected to several opioids (alpha-beta- or gamma-endorphins, as well as met- or leuenkephalins) applied in concentrations ranging from 10(-6) to 10(-9) M. On the following days we measured the levels of thymulin (a chemically-defined thymic hormone known to stimulate some steps of T-cell differentiation) in the culture supernatants, as well as the numbers of thymulin containing cells, evaluated by immunofluorescence with an anti-thymulin monoclonal antibody. After treatment of TEC cultures with beta-endorphin or leu-enkephalin a significant increase in the levels of thymulin in the culture media was observed, paralleled by a rise in the percentage of thymulin containing cells. In addition, this stimulatory effect was dose-dependent. Preincubation of the opioids with the specific antibodies abrogated the opioid-induced stimulatory effect on TEC. Moreover, naloxone, an opioid receptor antagonist, blocked the effect of beta-endorphin on thymulin production, suggesting that the effect of this neuropeptide on epithelial cells was mediated by an opioid receptor. Importantly, no effect on thymulin production was observed with the other opioids used, whatever the dose. These results suggest that, at least in vitro, beta-endorphin and leu-enkephalin stimulate the hormonal function of the thymic epithelium. These findings lead to the general concept that the modulatory role of endogenous opioids on the immune system is not restricted to lymphocytes but can also take place at the level of cells belonging to T-cell differentiating microenvironments.

Animals↗
PubMed1982

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↗
PubMed1982

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↗
PubMedDate not supplied

Alloreactivity. I. Effects of age and thymic hormone treatment on cell-mediated immunity in C57B1/6NNia mice.

C57B1/6NNia mice 1, 12, and 24 months old showed loss of cellular-mediated cytotoxicity with aging. Treatment of the three age groups with different thymic hormone preparations effected their cellular mediated cytotoxicity differently. When cytotoxicity of the thymic hormone treated groups was compared to that of the physiological saline treated group, 1-month-old mice treated with serum thymic factor (FTS) at 1 microgram/mouse and 10 ng/mouse had significantly higher activity, and lower to similar activities at 12 and 24 months; TP5 (active fragment of thymopoietin) at 1 microgram and 10 ng caused significantly higher activity in 1-month-old mice, and lower to higher and significantly lower to similar activity at 12 and 24 months, respectively; TM4 (an analogue of TP5) at 1 ng showed significantly depressed activity in 1-month-old mice, and significantly enhanced activity in 12- and 24-month-old mice; thymosin at 10 micrograms and 1 microgram had slightly lower, but not significant, depression at 1 month, similar activities at 12 months and significantly depressed to higher activity at 24 months. Unimmunized control mice showed significant protection in the 12-month-old mice in comparison to 1- and 24-month-old mice. Different hormone preparations showed age- and dose-dependent effects on the ability of spleen cells to kill P815 mastocytoma. Partial restoration of cytotoxicity was observed in 24-month-old mice treated with FTS, TP5 and thymosin fraction V.

Aging↗
PubMed1995

Reduced ability of hypothalamic and pituitary extracts from old mice to stimulate thymulin secretion in vitro.

There is substantial evidence that growth hormone (GH) is particularly important in the control of the age-related decline of thymus function. It was therefore of interest: (a) to assess the overall capacity of tissue extracts from mediobasal hypothalamus (MBH), anterior pituitary (AP) and testis, obtained from young (3 months, Yc), middle-aged (13 months, MAc) and old (18 months, Oc) intact C57BL/6 mice to stimulate in vitro the release of thymulin, a Zn-bound immunoregulatory thymic peptide, from pure cultures of mouse thymic epithelial cells (TEC); (b) to perform the same evaluation utilizing MBH, AP and testicular extracts from mice of the same age-range but treated for 45 days with a sc dose of ovine GH (2 micrograms/g body wt) known to stimulate thymulin secretion in vivo. Pituitary hormones were measured by heterologous rat RIAs, whereas thymulin release was estimated by a rosette assay. Untreated animals showed a significant age-dependent increase in the AP content of follicle stimulating hormone but not in other AP hormones. In both control and treated animals, pituitary GH content decreased significantly with age. MBH extracts from C57BL/6 males evidenced thymulin-releasing activity on mouse TEC lines. This activity was maximal in the MBH from young animals and declined with the age of the MBH donors. The thymulin-releasing activity of MBHs from GH-treated mice was higher than that of the control animals and showed a less pronounced decline with age. AP extracts from the same animals showed a higher thymulin-releasing activity than did MBH preparations. This activity showed a progressive age-associated reduction in the APs from untreated mice, whereas in the GH-treated group, an age-related decline was only seen in the old donors. Control testicular extracts had little effect on thymulin release whereas GH treatment induced a definite thymulin-release inhibiting activity in the testicular homogenates of our animals which increased progressively with the age of the testis donors. We conclude that the MBH, AP and testis of the young mouse contain factors able to affect directly the endocrine activity of the thymic epithelium. The amount of these substances declines with age and seems to be modulated by GH.

Aging↗
PubMed1992

Plasma thymulin concentrations, the thymus and organochlorine contaminant levels in seals infected with phocine distemper virus.

Blood samples collected from live common seals (Phoca vitulina) and grey seals (Halichoerus grypus) around the coast of Scotland and Northern Ireland during, and immediately after, an epizootic caused by phocid distemper virus (PDV) were analysed for thymulin content. Thymulin levels were compared with neutralization titres and concentrations of organochlorine contaminants (DDT and its metabolites, seven chlorinated biphenyl congeners) derived from blood and blubber samples collected from the same animals and analysed independently. Thymulin levels in grey seals (mean 2827 +/- 1355 fg/ml) were negatively correlated with the logarithm of virus neutralization titre. In common seals they varied significantly between age classes. There was no direct relationship between thymulin levels and contaminant levels in either species. However, when an estimate of time since exposure was included in the regression analysis for common seals, there was a highly significant relationship between thymulin and the two chlorinated biphenyl congeners with the highest concentrations in blubber.

Adipose Tissue↗