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Biomedical subjects

M D Kendall

Publications and source records attributed to M D Kendall.

At least 19 recordsLinked to original sources
PubMed1998

Neuropeptides exert direct effects on rat thymic epithelial cells in culture.

To determine if major thymic neuropeptides and neurotransmitters can directly influence the functional activity of cultured rat thymic epithelium, neuropeptides and neurotransmitters were applied, and intercellular communication, proliferation, and thymulin secretion assessed. After injections of a mixture of lucifer yellow dextran (too large to pass gap junctions) and cascade blue (which does) into single cells, some neuropeptides decrease dye coupling: 0.1 mM GABA (P < 0.0001), 100 nM NPY (P < 0.0001), 100 nM VIP (P < 0.001), 100 nM CGRP (P < 0.001), 100 nM SP (P < 0.01), and 0.1 mM histamine (P < 0.01), whereas 0.1 mM 5-HT, 1 mM acetylcholine, and 1 microM isoproterenol (beta-adrenergic agonist) had no effect. Proliferation (incorporation of tritiated thymidine) was increased by CGRP (P = 0.004) and histamine (P < 0.02), but decreased by isoproterenol (P = 0.002), 5-HT (P = 0.003), and acetylcholine (P < 0.05). The percentage of multinucleate cells was decreased after isoproterenol (2.5%), and increased after 5-HT (21.3%), GABA (15%), and histamine (15.1%). Compared to controls, thymulin in the supernatant was decreased after challenge with acetylcholine (52%), isoproterenol (71%), 5-HT (73%), and histamine (84%). This study demonstrates direct effects of neuropeptides and neurotransmitters on functional aspects of cultured thymic epithelial cells.

Animals↗
PubMed1997

Thymic microenvironment at the light microscopic level.

The thymus is a primary lymphoid organ that serves the immune system by providing an optimal microenvironment for developing T cells to rearrange the genes encoding the T-cell receptor and to undergo positive and negative selection in shaping the peripheral T-cell repertoire. The microenvironment of the organ is peculiar among lymphoid organs, as the supporting stroma consists of reticular epithelial cells. Bone marrow-derived interdigitating cells and macrophages are the main accessory cell populations. The epithelium, interdigitating cells, and macrophages each contribute to the T-cell selection process. During the last decade knowledge has been gathered that these cell populations show a considerable heterogeneity, as documented for subcellular features and immunologic phenotype. This heterogeneity may reflect various stages in differentiation, but may otherwise be linked to the functional activity of the cells. The authors survey the major cell populations, i.e., epithelial cells and lymphocytes. Macrophages and interdigitating cells are briefly discussed. Emphasis is given to functional aspects of histologic/ cytologic features.

Animals↗
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↗
PubMed1997

Modulation of dye-coupling and proliferation in cultured rat thymic epithelium by factors involved in thymulin secretion.

Cultures of rat thymic epithelium were used to measure the effect of thymulin secretagogues on dye-coupling and proliferation. Dye-coupling was assessed after the injection of lucifer yellow dextran which cannot permeate the connexin pore of gap junctions and the smaller, permeant cascade blue. In addition to gap junctional communication, larger intercellular bridges were demonstrated by the transfer of lucifer yellow dextran between cells. The extent of intercellular communication was found to be influenced by both cell density and the number of passages. In control cultures, intercellular communication was reduced in cell groups of low (< 20 cells/group) or high cell densities (> 100 cells/group) compared with groups of 20-60 cells. The highest coupling indices were found in subcultures 20-30. Taking these factors into account, significant decreases in coupling index were observed after pretreatment of test cultures with factors known to influence the secretion of thymulin (5 U/ml interleukin 1 (alpha and beta), 1 microM progesterone, 1 microM oestrogen, 1 microM testosterone, 1 ng/ml adrenocorticotropic hormone, 100 nM rat growth hormone) but 7.5 ng/ml thymulin had no effect on dye-coupling. The nonspecific gap junction uncoupler, octanol, abolished dye-coupling. Cellular proliferation, as measured by the uptake of tritiated thymidine, showed that the same factors that reduced coupling also increased proliferation. None of these factors affected the number of multinucleate cells present, except interleukin-1beta which caused a significant reduction in the average number of nuclei per cell. Thus rat thymic epithelium in vitro provides a model for the study of the direct action of factors on cells of the thymic microenvironment.

1-Octanol↗
PubMed1997

Studies on rat and human thymus to demonstrate immunoreactivity of calcitonin gene-related peptide, tyrosine hydroxylase and neuropeptide Y.

The peptidergic and noradrenergic innervation of rat and human thymus was investigated by immunohistochemistry at the light and electron microscopical level (avidin-biotin-complex, sucrose-phosphate-glyoxylic-acid, and immunogold techniques). The distribution of noradrenergic neural profiles, and positive immunoreactivity for calcitonin gene-related peptide (CGRP), tyrosine hydroxylase (TH) and neuropeptide Y (NPY) is described in female rats during ageing, and in human children. In the neonatal rat thymus, the arteries and septa are well supplied by fine varicose nerves. In older animals (2 wk-1 y) the number of septa and blood vessels increase and consequently also the innervation. No nerves were found in the cortex. Apart from the innervation of the septal areas, immunoreactivity for CGRP and TH was present in thymic cells. Except for the young rats (neonatal-14 d), all rats showed CGRP positivity in subcapsular/perivascular epithelial cells (type 1 cells). All rat thymuses also contained a few TH positive cells in the medulla, which could only be confirmed as epithelial cells (type 6 cells) in children. Type 1 cells in the human thymus were not CGRP positive, but as in the rat, there were similar TH positive cells in the medulla. It was concluded that in addition to nerves containing CGRP, noradrenaline or dopamine, epithelial cells also contain these transmitters. They could therefore act on different cells (compared with neural targets) in a paracrine manner.

Aging↗
PubMed1996

Characterisation of inorganic microparticles in pigment cells of human gut associated lymphoid tissue.

Macrophages at the base of human gut associated lymphoid tissue (GALT), become loaded early in life with dark granular pigment that is rich in aluminium, silicon, and titanium. The molecular characteristics, intracellular distribution, and source of this pigment is described. Laser scanning and electron microscopy showed that pigmented macrophages were often closely related to collagen fibres and plasma cells in GALT of both small and large intestine and contained numerous phagolysosomes, previously described as granules, that are rich in electron dense submicron sized particles. Morphological assessment, x ray microanalysis, and image electron energy loss spectroscopy showed three distinct types of microparticle: type I - spheres of titanium dioxide, 100-200 nm diameter, characterised as the synthetic food-additive polymorph anatase; type II - aluminosilicates, < 100-400 nm in length, generally of flaky appearance, often with adsorbed surface iron, and mostly characteristic of the natural clay mineral kaolinite; and type III - mixed environmental silicates without aluminium, 100-700 nm in length and of variable morphology. Thus, this cellular pigment that is partly derived from food additives and partly from the environment is composed of inert inorganic microparticles and loaded into phagolysosomes of macrophages within the GALT of all human subjects. These observations suggest that the pathogenicity of this pigment should be further investigated since, in susceptible individuals, the same intracellular distribution of these three types of submicron particle causes chronic latent granulomatous inflammation.

Aluminum Silicates↗
PubMed1995

Assessment of toxic metal exposure following the Camelford water pollution incident: evidence of acute mobilization of lead into drinking water.

Following the incident of acidic pollution of water by aluminium sulfate centred around Camelford in July 1988, we have carried out a retrospective analysis of the mobilization of toxic metals to residents of the area. An advanced nuclear technique was used to measure trace levels of elements within hair, thus, avoiding surface contamination. In contrast to controls, lead, but no other toxic metals, was consistently found within sections of hair that dated to mid-1988 from four residents; they must, therefore, have consumed this metal around the time of the incident. The source of this lead was probably local water pipe residue, and this was found on analysis to have a matrix specific to such soft-water areas that, prior to the incident, had slowly accumulated certain toxic metals such as cadmium and uranium and particularly lead. Lead is mobilized from such residues by acidic water and could, therefore, have heavily contaminated mains water after the incident. However, analyses of residents' plasma and whole blood, and of urine following a lead-chelation test, showed no evidence of either long-term increased body burdens of toxic metals or depletion of essential elements. In addition, we found no evidence of continued poor water quality in the area. In conclusion, during a short period following the pollution, some residents who consumed mains water would have been acutely exposed to lead and other toxic metals. Prediction of the scale of metal exposure to individuals was not possible owing to heterogeneity of the water distribution network, but long-term effects to residents from lead are not anticipated.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1995

Hemopoiesis in the thymus.

The presence in the thymus of hemopoietic cells other than thymocytes has been known for many years, but the extent of the hemopoietic activity of the thymus and the possible functional implications have only recently begun to receive much attention. This review summarizes the literature in this field, especially in the light of current cytokine and thymic-factor knowledge, and includes clinical relevance where possible.

Animals↗
PubMed1994

Involution of the rat thymus in experimentally induced hypothyroidism.

The thymus, as part of the immune-neuroendocrine axis, is greatly influenced by factors from most endocrine glands, especially the thyroid. Antithyroid drugs (carbimazole and methimazole) were used to induce hypothyroidism in rats. Histological and ultrastructural examination of the thymus showed progressive thymic involution after 4 weeks of drug treatment to the end of observations (7 weeks). The involution was characterised by increased thymocyte apoptosis and thymocyte phagocytosis by macrophages. This resulted in thymocyte depopulation, increases in numbers of interdigitating cells, alterations to mainly subcapsular and medullary epithelial cells, an apparent increase of mast cells and collagen in the capsule and septa, and increased numbers of B cells and plasma cells. Lymphoid cells immuno-reactive with MRC OX12 (which detects B cells) were observed within blood vessel walls, suggesting that they may have been moving in and out of the thymus. The administration of drugs causing hypothyroidism, therefore, also caused marked involution of the thymus.

Animals↗
PubMed1994

The effects of pregnancy on the mouse thymic epithelium.

Changes in the murine thymus during pregnancy were studied using immunocytochemistry with monoclonal antibodies against thymic epithelial, neuroendocrine, and thymulin-producing cells, fibroblasts, blood vessels and connective tissue components. Extensive alterations occur in mid-pregnancy. The medulla was greatly enlarged in the involuted thymus, and there were greater numbers of epithelial cells. These epithelial cells had an altered distribution forming large structures surrounding spherical masses of mononuclear cells, lacked epithelial cells and often contained a central blood vessel with fibroblasts and connective tissue. We have called these structures 'medullary epithelial rings' (MERs). To our knowledge these structures have not been described before. Late in pregnancy the loss of the central mononuclear cells leaves collapsed structures in a smaller medulla that nevertheless retains many epithelial cells. In virgins and early-pregnancy, there are cortical channels free of epithelial cells that are very infrequent later in pregnancy. This may reflect the loss of steroid-sensitive thymocytes from the cortex. The influence of sex-steroids, neurological impulses and immune activity in causing the changes are discussed, as are the possible consequences in pregnancy of a reduced, thymocyte-depleted cortex and an enlarged medulla that shows great complexity and activity.

Animals↗
PubMed1994

The thymus in pregnancy: the interplay of neural, endocrine and immune influences.

This article discusses the dramatic events that accompany thymic involution during pregnancy, and traces the possible immune, neural and endocrine interactions that may occur. Ann Clarke and Marion Kendall present accumulating evidence that activity, not inactivity, is a feature of the thymus at this time. Whilst the cortex shrinks, the medulla enlarges and rearranges to create a microenvironment containing increased numbers of mature thymocytes. It is suggested that these recently derived T cells may contribute to the unique populations of cells with suppressive function that appear during pregnancy, and thereby contribute to the immune suppression of the mother to paternal and fetal antigens. In addition, the pregnancy-associated cortical involution of the thymus may reflect the deletion of clones with potential reactivity to paternal and/or fetal antigens.

Animals↗
PubMed1994

The noradrenergic innervation of the rat thymus during pregnancy and in the post partum period.

The noradrenergic innervation of the rat thymus during pregnancy and the post partum period was examined by a sucrose glyoxylic acid method for catecholamines, and by high pressure liquid chromatography. Fluorescent nerves decreased in number throughout pregnancy when there was an overall loss in thymic weight due to cortical involution. These changes are maximal by parturition. There was a dramatic increase in nerves between d 21 of pregnancy and d 1 after parturition, especially in the capsule and around blood vessels in the connective tissue septa. The neonates were removed at parturition and thymic weight was rapidly regained. The increased numbers of nerves remained throughout this post partum period. Noradrenaline levels in the thymus altered in a similar pattern throughout pregnancy and the post partum period, but did not parallel thymic weight changes. The mean noradrenaline concentration in the virgin thymus was 1063 +/- 107 pg/mg protein. Levels remained similar during early pregnancy and increased significantly at d 16. Virgin levels were regained by d 21. Values peaked after parturition but rapidly decreased over the next 3 days, and remained at or below virgin levels to d 28 except for a transient rise at d 10 post partum. Adrenaline values were consistently below detection levels. This study shows that there are variations in both nerves visualised, and in neurotransmitter (noradrenaline) content in the thymus during the course of pregnancy and the post partum period. Thus thymic function could be influenced by central events (levels of catecholamines in peripheral blood) as well as local events mediated by transmitter changes in nerves.

Animals↗
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↗
PubMed1992

The thymus: new views of an old gland.

The existence of the thymus was recognised by ancient scientists and doctors, although its vital role in the development and maintenance of the competent T cell repertoire has been fully appreciated only comparatively recently. Current research is now moving on to explore the role of the thymus in interactions between the brain, the nervous system and the immune response. This is an exciting new field which should lead to advances in the management, treatment and prognosis of disease in man and animals.

Receptors, Antigen, T-Cell↗
PubMed1992

Thymulin and its role in immunomodulation.

Even though thymulin was isolated, sequenced and characterised some 20 years ago and later identified as a thymic hormone involved in immunomodulation, much more work is still required to further understanding of the mechanisms of action(s) of this peptide. Since the observation, by a semiquantitative bioassay, of diminished levels of thymulin in immunodeficiency and autoimmune disease, new data obtained by radioimmunoassay have not only confirmed previous observations but also demonstrated that thymulin plays a role in the interaction between the immune system and the neuro-endocrine system. In this paper we give an up to date account of recent developments in research into the role of thymulin in immunomodulation.

Amino Acid Sequence↗