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Biomedical subjects

V Geenen

Publications and source records attributed to V Geenen.

At least 55 records · Page 3Linked to original sources
PubMed1997

Identification of neurotensin-related peptides in human thymic epithelial cell membranes and relationship with major histocompatibility complex class I molecules.

This study shows the expression at the cell surface of human thymic epithelial cells (TEC) of a neurotensin (NT)-like immunoreactivity. NT radio-immunoassay (RIA) revealed that cultured human TEC contain +/-5 ng immunoreactive (ir) NT/10(6) cells, of which 5% is associated with plasma cell membranes. HPLC analysis of NT-ir present in human TEC showed a major peak of NT-ir corresponding to NT1-13. NT-ir was not detected in the supernatant of human TEC cultures. Using an affinity column prepared with a anti-MHC class I monoclonal antibody, NT-ir-related peptides were retained on the column and eluted together with MHC class I-related proteins. According to the elution time on HPLC of these peptides, they correspond to intact NT1-13, as well as to smaller fragments of NT1-13.

Cell Membrane↗
PubMed1997

Increase in cytokine production (IL-1 beta, IL-6, TNF-alpha but not IFN-gamma, GM-CSF or LIF) by stimulated whole blood cells in postmenopausal osteoporosis.

Postmenopausal osteoporosis is a progressive disorder characterized by a decreased bone mass and increased susceptibility to fractures. Several investigations have suggested that one of the mechanisms through which estrogen prevents bone loss was a modulation on secretion or release of various cytokines that are known to influence bone remodeling, even if some recent data have challenged this hypothesis. However, in established osteoporosis, the possibility that enhanced cytokines activity may account for the progression of this disease remains unclear and controversial. We sought here to determine whether production of IL-1 beta, IL-6, TNF-alpha, IFN-gamma, GM-CSF and LIF, after direct stimulation in whole blood, was different in healthy (n = 30) or osteoporotic postmenopausal women (n = 24) and whether lumbar bone density (1-BMD) correlated with the values of cytokine production observed in these conditions. A significant difference was observed between the osteoporotic and control subjects for IL-1 beta (p < 0.0001), IL-6 (p < 0.001) and TNF-alpha (p = 0.027) productions, the values being higher in the osteoporotic women. No significant differences between the groups were observed for IFN-gamma (p = 0.51), GM-CSF (p = 0.70) or LIF (p = 0.97). In the whole population, statistically significant negative correlations were observed between lumbar BMD and IL-1 beta (r = -0.46) (p < 0.0005), IL-6 (r = -0.50) (p < 0.0001) and TNF-alpha (r = -0.39) (p < 0.005) production while no such correlations were observed for IFN-gamma, GM-CSF or LIF. In conclusion, the study of cytokine production by immune cells cultured in autologous whole blood suggests that in women more than 10 years past the menopause and presenting a decrease in lumbar bone density corresponding to the new WHO definition of "osteoporosis', production of IL-1 beta, IL-6 and TNF-alpha is still increased compared to controls matched for age and ovarian function, while no differences are reported for IFN-gamma, GM-CSF or LIF production.

Bone Density↗
PubMed1997

Effects of meloxicam compared to acetylsalicylic acid in human articular chondrocytes.

Meloxicam is a new nonsteroidal anti-inflammatory drug (NSAID) derived from enolic acid, which has displayed potent anti-inflammatory properties in animal studies combined with low gastrointestinal toxicity. Other NSAIDs have been shown, in vitro, to have a variety of effects on cartilage repair processes in diseased articular cartilage. The aim of this study was to ascertain the effects of meloxicam on some of these processes using in vitro models. Acetylsalicylic acid, a NSAID whose characteristics have been previously elucidated in the models, was used as an active comparator. The effects of meloxicam were different from those of acetylsalicylic acid on chondrocyte clusters. At pharmacologically active concentrations, meloxicam was a potent inhibitor of prostaglandin-E2 production. However, all chondroformative processes were unaffected by meloxicam as indicated by a lack of effect on DNA synthesis and on type-II collagen and proteoglycan levels in chondrocyte culture medium and clusters, while acetylsalicylic acid decreased proteoglycan production and cell proliferation. Consequently, these in vitro findings suggest that meloxicam does not adversely affect the reparative processes active within the cartilage matrix of a diseased joint. This study represents a sound basis for future studies to establish the effects of meloxicam on osteoarthritis disease progression.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

Cytokine production by human thymic epithelial cells: control by the immune recognition of the neurohypophysial self-antigen.

Oxytocin (OT) has been shown to be the dominant peptide of the neurohypophysial family expressed by thymic epithelial and nurse cells (TEC/TNC) in various species. Thymic OT is not secreted but, after translocation of a hybrid neurophysin/MHC class I protein, is integrated within the plasma membrane of TEC, thus allowing its presentation to pre-T cells. In order to further demonstrate that thymic OT behaves like a membrane antigen, we assessed the effect of mAbs to OT on cytokine productions by cultures enriched in human TEC. 75-85% pure TEC cultures were prepared from human thymic fragments. Using immunofluorescence and confocal microscopy, ir-OT, ir-interleukin-1 beta (IL-1 beta), ir-interleukin-6 (IL-6) and ir-leukemia inhibitory factor (LIF) could be detected in these TEC cultures. ir-OT was restricted to TEC, while some ir-IL-6 and ir-LIF were also seen in occasional fibroblasts. In basal conditions, ir-IL-6 and ir-LIF (but not ir-OT and ir-IL-1 beta) were detected in the supernatants of human TEC cultures. MAbs to OT induced a marked increase of ir-IL-6 and ir-LIF secretion in TEC cultures. No significant effect was observed using mAbs against vasopressin, mouse immunoglobulins, or control ascitic fluid controls. These data show that OT is fully processed and recognized by specific mAbs at the outer surface of TEC plasma membrane. They further support that thymic OT behaves as the self-antigen of the neurohypophysial family.

Antibodies, Monoclonal↗
PubMed1996

Neurophysins in central diabetes insipidus.

When they were discovered by Acher and co-workers, neurophysins were thought to act as carriers for the active nonapeptides vasopressin (AVP) and oxytocin (OT) and were then recognized as the inactive fragment of a precursor with a higher molecular weight (propressophysin). The role of neurophysins in the hypothalamo-neurohypophyseal system is now being reconsidered in the light of crystallographic and molecular biology research and the recent definition of the different deletions or substitutions that cause central diabetes insipidus in rats (Brattleboro) or human beings. Apparently, any disruption of the structure and/or conformation of neurophysins (by genic substitution or deletion) may cause a decline in the binding and the activity of the endopeptidase responsible for the cleavage of the AVP. The disruption may also produce a change in the polymerization of neurophysins and salt bridges relating this to the neuropeptides, with the result that there is an accelerated aspecific enzymatic degradation of the hormone revealing clinical symptomatology. So, rather than being a mere inactive part of the precursor, neurophysins are now equally regarded as a system for carrying and protecting nonapeptides.

Animals↗
PubMed1996

Development and evolutionary aspects of thymic T cell education to neuroendocrine self.

Thymic epithelial cells, including nurse cells (TECs/TNCs), from various species synthesize neuroendocrine-related precursors belonging to neurohypophysial, tachykinin and insulin hormone families. The thymic repertoire of neuroendocrine-related polypeptides illustrates at the molecular level the paradoxical role of the thymus in both T cell positive and negative selection. On the one hand, these precursors are a source of signals which interact with neuroendocrine-type receptors expressed by target pre-T cells according to the cryptocrine type of cell-to-cell signaling. On the other hand, the same precursors constitute a source of self-antigens which are presented to pre-T cells by the thymic major histocompatibility complex system. Basically, the model of thymic T cell education to neuroendocrine self was established by the identification in TECs/TNCs of immunoreactive (ir) oxytocin as the self-antigen of the neurohypophysial family. Nevertheless, through the expression in TECs/TNCs of ir-neurokinin A and ir-insulin-like growth factor-II, the model also applies to the tachykinin and insulin hormone families.

Animals↗
PubMed1996

Ex vivo cytokine production by whole blood cells from cancer patients.

It has been hypothesized that the development of cancer might partially result from a diminution of immunocompetence. Using ex vivo cytokine production by whole blood (WB) cells after polyclonal activation, we compared cytokine production levels of cancer patients to those of healthy controls. Seventeen patients without any prior treatment and attending the hospital for oncological surgery (for cancers of several origins) were enrolled in the study. WB was collected in heparinized tubes, diluted 1/10 in RPMI 1640 and incubated for 2, 4, 24, 48, and 72 h at 37 degrees C in the presence of 5 micrograms/ml PHA and 25 micrograms/ml LPS. Cytokine levels in the supernatant were measured by specific immunoassay kits. IL-10 levels after 24 h of culture, IFN-gamma and GM-CSF levels after 24 and 72 h of culture, and LIF levels after 72 h of culture were significantly lower in cancer patients than in healthy controls. No significant difference was observed for IL-1 beta, IL-2, IL-4, IL-8, and TNF-alpha production at any culture time. Our results suggest that the putative immunosuppression of cancer patients might be reflected by their reduced production of immunostimulated cytokines.

Adult↗
PubMed1995

Messenger RNA expression for a TSH receptor variant in the thymus of a two-year-old child.

We recently described the presence of a thyroid-stimulating hormone receptor (TSH-R) variant in orbital tissues. Although the presence of this TSH-R variant could provide the antigenic link between the thyroid and the orbit in Graves' disease and thyroid-associated ophthalmopathy (TAO), the etiopathophysiological significance of this finding remains to be elucidated. Graves' disease and TAO are autoimmune diseases which are likely to be caused by a breakdown of tolerance. We therefore investigated the presence of this variant TSH-R transcript in human thymus. Using primers specific for this variant in reverse polymerase chain reaction (PCR) experiments, Southern blotting, and sequencing of the PCR products we demonstrate the presence of this transcript in RNA extracted from normal human thymus of a 2-year-old child. We were also able to amplify this variant TSH-R transcript from a normal human thyroid cDNA library, but not from an epithelial thymus library. The presence of the variant TSH-R transcript in RNA prepared from normal human thymus suggests that induction of immunological tolerance against this variant TSH-R transcript in the thymus is possible. A lack of tolerance induction for this variant TSH-R transcript could provide an explanation for a possible antigenic link between Graves' disease and TAO.

Blotting, Southern↗
PubMed1995

Cryptocrine signaling in the thymus network and T cell education to neuroendocrine self-antigens.

Both during phylogeny and ontogeny the thymus appears as a nodal point between the two major systems of cell-to-cell signaling, the neuroendocrine and immune systems. This review presents the experimental observations which support a dual role in T cell selection played by the thymic repertoire of neuroendocrine polypeptide precursors. Through the mode of cryptocrine intercellular signaling thymic neuroendocrine-related precursors synthesized in thymic epithelial cells have been shown to influence the early steps in T cell differentiation. In addition, thymic neuroendocrine-related polypeptides are a source of self-antigens which are presented by the major histocompatibility system of the thymic epithelium. Preliminary data also suggest that the intrathymic T cell education to neuroendocrine self-antigens is not strictly superimposible to the antigen presentation by dedicated presenting cells. Insulin-like growth factor-II (IGF-II) was identified as one dominant member of the insulin family expressed by thymic epithelial and nurse cells. The intrathymic presentation of IGF-II or IGF-II derived self-antigens is under current investigation. If further confirmed, the central tolerogenic properties of IGF-II could be considered in the elaboration of a strategy for an efficient and safe prevention of insulin-dependent diabetes.

Amino Acid Sequence↗
PubMed1993

Multiple ways to cellular immune tolerance.

Both central and peripheral pathways leading to T-cell tolerance were discussed at a recent meeting. The mechanisms that maintain self tolerance, as well as the conditions in which self-reactive T cells launch an autoaggressive attack, were specially emphasized.

Animals↗
PubMed1993

Membrane translocation and relationship with MHC class I of a human thymic neurophysin-like protein.

Thymic epithelial and nurse cells (TEC/TNC) synthesize an oxytocin (OT)-like peptide in association with a neurophysin (NP)-related protein in a way similar to in the hypothalamo-neurohypophysial (NHP) system. The central T-cell tolerance of the NHP neuroendocrine functions have been proposed to be mediated through these thymic NHP-related peptides due to their close homology with the NHP neurohormones OT and vasopressin (VP). In order to investigate their putative presentation by proteins of the major histocompatibility complex (MHC), human thymic membranes were purified and passed through an immunoaffinity column using mAb B9.12 directed to the monomorphic determinant of human MHC class I proteins. This methodology provided the following observations: (1) a NP-like protein is translocated in human thymic membranes and is retained by B9.12 on the column; (2) the MW of this NP-like material (50-55 kD) is quite different from the MW of hypothalamic NP proteins (10 kD), and (3) this thymic NP-like protein could be identified on Western blots with mAb B9.12. The precise extent of this relationship between the thymic NP-like protein and the Ig/MHC superfamily is actually investigated through the characterization of the genetic mechanisms responsible for the thymic expression of NHP-related peptides. Given the physiological importance of OT and of its binding to NP for transport along the axonal processes of the NHP tract, we postulate that, somewhat analogously, the thymic NP-/MHC class I-related protein could be involved in the presentation of the OT-like peptide to immature T-cells.

Amino Acid Sequence↗