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Biomedical subjects

H Valentin

Publications and source records attributed to H Valentin.

At least 19 recordsLinked to original sources
PubMed2003

Measles virus and dendritic cell functions: how specific response cohabits with immunosuppression.

Measles virus (MV) infection induces both an efficient MV-specific immune response and a transient but profound immunosuppression characterised by a panlymphopenia that occasionally results in opportunistic infections responsible for a high rate of mortality in children. On the basis of in vitro studies, the putative roles of dendritic cells (DCs) in MV infection are discussed. (1) DCs could participate in anti-MV innate immunity because MV turns on TNF-related apoptosis-inducing ligand (TRAIL)-mediated DC cytotoxicity. (2) Cross-priming by non-infected DCs might be the route of MV adaptive immune response. (3) After CD40-ligand activation in secondary lymphoid organs, MV-infected DCs could initiate the formation of Warthin-Finkeldey multinucleated giant cells, replicating MV and responsible for in vivo spreading of MV. (4) We review how integrated viral attack of the host immune system also targets DCs: Progress in understanding the immunobiology of MV-infected DCs that could account for MV-induced immunosuppression observed in vivo is presented and their potential role in lymphopenia is underlined. In conclusion, future research directions are proposed.

Apoptosis↗
PubMed2001

Mechanism of measles virus-induced suppression of inflammatory immune responses.

Measles virus (MV) causes profound immunosuppression, resulting in high infant mortality. The mechanisms are poorly understood, largely due to the lack of a suitable animal model. Here, we report that particular MV proteins, in the absence of MV replication, could generate a systemic immunosuppression in mice through two pathways: (1) via MV-nucleoprotein and its receptor FcgammaR on dendritic cells; and (2) via virus envelope glycoproteins and the MV-hemagglutinin cellular receptor, CD46. The effects comprise reduced hypersensitivity responses associated with impaired function of dendritic cells, decreased production of IL-12, and the loss of antigen-specific T cell proliferation. These results introduce a novel model for testing the immunosuppressive potential of anti-measles vaccines and reveal a specific mechanism of MV-induced modulation of inflammatory reactions.

Animals↗
PubMed2000

Productive measles virus brain infection and apoptosis in CD46 transgenic mice.

Measles virus (MV) infection causes acute childhood disease, associated in certain cases with infection of the central nervous system (CNS) and development of neurological disease. To develop a murine model of MV-induced pathology, we generated several lines of transgenic mice ubiquitously expressing as the MV receptor a human CD46 molecule with either a Cyt1 or Cyt2 cytoplasmic tail. All transgenic lines expressed CD46 protein in the brain. Newborn transgenic mice, in contrast to nontransgenic controls, were highly sensitive to intracerebral infection by the MV Edmonston strain. Signs of clinical illness (lack of mobility, tremors, and weight loss) appeared within 5 to 7 days after infection, followed by seizures, paralysis, and death of the infected animals. Virus replication was detected in neurons from infected mice, and virus was reproducibly isolated from transgenic brain tissue. MV-induced apoptosis observed in different brain regions preceded the death of infected animals. Similar results were obtained with mice expressing either a Cyt1 or Cyt2 cytoplasmic tail, demonstrating the ability of different isoforms of CD46 to function as MV receptors in vivo. In addition, maternally transferred immunity delayed death of offspring given a lethal dose of MV. These results document a novel CD46 transgenic murine model where MV neuronal infection is associated with the production of infectious virus, similarly to progressive infectious measles encephalitis seen in immunocompromised patients, and provide a new means to study pathogenesis of MV infection in the CNS.

Animals↗
PubMed1999

Measles virus infection induces terminal differentiation of human thymic epithelial cells.

Measles virus infection induces a profound immunosuppression that may lead to serious secondary infections and mortality. In this report, we show that the human cortical thymic epithelial cell line is highly susceptible to measles virus infection in vitro, resulting in infectious viral particle production and syncytium formation. Measles virus inhibits thymic epithelial cell growth and induces an arrest in the G0/G1 phases of the cell cycle. Moreover, we show that measles virus induces a progressive thymic epithelial cell differentiation process: attached measles virus-infected epithelial cells correspond to an intermediate state of differentiation while floating cells, recovered from cell culture supernatants, are fully differentiated. Measles virus-induced thymic epithelial cell differentiation is characterized by morphological and phenotypic changes. Measles virus-infected attached cells present fusiform and stellate shapes followed by a loss of cell-cell contacts and a shift from low- to high-molecular-weight keratin expression. Measles virus infection induces thymic epithelial cell apoptosis in terminally differentiated cells, revealed by the condensation and degradation of DNA in measles virus-infected floating thymic epithelial cells. Because thymic epithelial cells are required for the generation of immunocompetent T lymphocytes, our results suggest that measles virus-induced terminal differentiation of thymic epithelial cells may contribute to immunosuppression, particularly in children, in whom the thymic microenvironment is of critical importance for the development and maturation of a functional immune system.

Apoptosis↗
PubMed1997

Transcriptional activation of the vascular cell adhesion molecule-1 gene in T lymphocytes expressing human T-cell leukemia virus type 1 Tax protein.

Recruitment and extravasation of T cells through the blood-brain barrier are favored by adhesion molecule-mediated interactions of circulating T cells with endothelial cells. Since a common pathological finding in human T-cell leukemia virus type 1 (HTLV-1)-associated diseases is the infiltration of HTLV-1-infected T lymphocytes into various organs, we have looked for the profile of adhesion molecules expressed by HTLV-1-transformed T cells. Flow cytometry analysis indicated that these cells were expressing high levels of vascular cell adhesion molecule 1 (VCAM-1 [CD106]), a 110-kDa member of the immunoglobulin gene superfamily, first identified on endothelial cells stimulated with inflammatory cytokines. This adhesion molecule was also expressed by T cells obtained from one patient with HTLV-1-associated myelopathy/tropical spastic paraparesis but not by activated T cells isolated from one normal blood donor. The role of the viral trans-activator Tax protein in the induction of VCAM-1 was first indicated by the detection of this adhesion molecule on Jurkat T-cell clones stably expressing the tax gene. The effect of Tax on VCAM-1 gene transcription was next confirmed in JPX-9 cells, a subclone of Jurkat cells, carrying the tax sequences under the control of an inducible promoter. Furthermore, deletion and mutation analyses of the VCAM-1 promoter performed with chloramphenicol acetyltransferase constructs revealed that Tax was trans activating the VCAM-1 promoter via two NF-kappaB sites present at bp -72 and -57 in the VCAM-1 gene promoter, with both of them being required for the Tax-induced expression of this adhesion molecule. Finally, gel mobility shift assays demonstrated the nuclear translocation of proteins specifically bound to these two NF-kappaB motifs, confirming that VCAM-1 was induced on Tax-expressing cells in a kappaB-dependent manner. Collectively, these results therefore suggest that the exclusive Tax-induced expression of VCAM-1 on T cells may represent a pivotal event in the progression of HTLV-1-associated diseases.

Gene Expression Regulation, Viral↗
PubMed1997

Electronic measurements of relative tongue-palate contact time. Development and testing for orthodontic functional analysis.

The importance of the tongue to the form of the jaws and dental arches has long been accepted. Clear-cut differences in arch width and arch height are observed between mouth and nasal breathing. Course measurements, e.g. duration of tongue contact with the gum, are not feasible with traditional measuring methods. The palatal measuring appliance presented here together with the purpose-developed storage and evaluation equipment permits for the first time continuous 24-hour measurement of tongue contact with the palate. The clinical observation is confirmed by the presented results. Nasal obstruction is associated with lower tongue-palate contact times. In our probands, these times fell by an average of 72% after forced mouth breathing. Since complex movements within the mouth cavity cannot be directly observed, functional analysis relating to the tongue position was previously impossible, at least over a longer period. The measuring device presented here is suitable for analyzing in more detail the diagnostically difficult complex of tongue movements and breathing habits. It might therefore conceivably be used to assess myofunctional disturbances and therapeutic methods.

Child↗
PubMed1996

Productive and persistent infection of human thymic epithelial cells in vitro with HIV-1.

Infection with HIV-1 results in a disruption of the thymic microenvironment and the presence of HIV-1 in thymic epithelial cells has been demonstrated in vivo. In the present study, we examined the susceptibility of a highly enriched culture of thymic epithelial cells (TEC) to infection in vitro by HIV-1 laboratory strains and primary isolates. Replication in TEC is shown to depend on the virus and on the expression of CD4 molecules that are found to be expressed at a low density on the plasma membrane. Our results are consistent with infection of TEC controlled by the efficiency of the interactions between the envelope glycoprotein of the virus and the cell surface molecules. As a consequence, certain HIV-1 viruses induce a productive and persistent infection in TEC without damaging the cells. Altogether these results support the idea that TEC may act as a reservoir for HIV-1 in the thymus but are probably destroyed by an indirect mechanism involving infection of thymocytes.

Cells, Cultured↗
PubMed1994

Two subpopulations of human triple-negative thymic cells are susceptible to infection by human immunodeficiency virus type 1 in vitro.

Some infants infected with human immunodeficiency virus type 1 (HIV-1) rapidly develop a fatal disease characterized by a severe lymphopenia. To explain the immune dysfunction, we proposed a mechanism by which a nongeneration of CD4+ T cells is caused by HIV-1 infection of thymic cells. To examine this hypothesis, we infected primary triple-negative (TN; phenotypically CD3- CD4- CD8-), CD1a- TN, or CD1a+ TN thymic cell subsets. Our data indicate that by flow cytometry, TN, CD1a- TN, and CD1a+ TN cells remain CD4 negative throughout the culture period. We demonstrated that TN and CD1a+ TN thymic cell subsets are susceptible to HIV-1 as is the entire thymic cell population, whereas CD1a- TN cells are not. A limited number of infected TN cells are expressing HIV-1 but the level of transcription is very high in permissive cells, as detected by in situ hybridization. We then performed blocking experiments on TN cells to examine the mechanism of HIV-1 entry into these cells. CD4 (OKT4a) monoclonal antibody blocks their infection. Finally, infection experiments on two subpopulations of TN cells (CD2+ CD7+ and CD2- CD7-) indicate that infected TN cells may correspond to both immature thymocytes and thymic dendritic cells. These data are of particular interest since infection of thymic stromal cells might result in an impairment of T-cell differentiation, which may explain a nongeneration of functional CD4+ T-cell population in the thymus. This phenomenon may play a role in AIDS pathogenesis, in particular in infants born from seropositive mothers.

Antibodies, Monoclonal↗
PubMed1993

Identification and prevention of work-related diseases and premature incapacity.

In many cases, the increasing knowledge about the causes of occupational diseases has led to improved preventive actions at the working place. This made it possible to achieve a general decrease in the incidence of occupational diseases--except for some illnesses such as asbestos-related and obstructive lung diseases. An opposite trend can be noticed in the field of work-related illnesses, which especially includes cardiovascular, psychiatric and psychovegetative diseases, and musculoskeletal disorders. In contrast to the occupational diseases, in this context work factors are only of less importance and interact with intrapersonal, social and environmental aspects. Since the associations between the working world and the disease are normally too weak due to the multiple causes involved, what is therefore required for researching these multifactorial relationships are most sensitive epidemiological examination methods including large populations and at the same time avoiding or controlling bias and confounding. Most of the recent studies are based on secondary evaluations of already existing data (premature incapacity, inability to work, results from special preventive checks at the working place). Although this leads to large populations, a considerable bias is caused at the same time since these data in most cases are collected for administrative purpose rather than for epidemiological reasons. Moreover, when looking at the different load factors, only the work aspects are mainly taken into consideration, which leads to considerable confounding due to the omitted other concurring causes. Thus, most of the associations discovered so far are not strong enough to allow for a general deduction of special preventive measures at the working place. For further investigation of these relationships, prospective cohort and intervention studies are therefore required.

Coronary Disease↗
PubMed1992

The distribution of the CDW52 molecule on blood cells and characterization of its involvement in T cell activation.

The O97 mouse mAb was used to define, together with the CAMPATH-1 mAb series, the CDw52 in the course of the Fourth International Workshop on Human Leucocyte Differentiation Antigens. O97 and CAMPATH-1M produce full competitive inhibition and react with an epitope dependent on O-linked sugar residues. The two mAb, however, display significant differences in reactivity with leukocyte populations--in fact the reactivity of O97, which also exerts a powerful cytotoxic effect with human C', is similar to mAb from the CAM-PATH-1 series having the broadest one. Noteworthy, O97 spares PBL, NK, and LAK precursors, permitting an easy purification of these cells; O97 is able to kill long-term colony-forming cells in bone marrow culture and characteristically reacts, in contrast to CAMPATH-1M, with erythrocytes. Western blotting has revealed a strikingly different molecular size on red cells, since CDw52 mAb revealed a broad band ranging from 6-16 kDa, instead of the 21-28 kDa revealed from leukocyte extracts. In agreement with immunofluorescence data, O97 revealed abundant material from red cells in Western blotting, while reactivity of CAMPATH-1M was very faint. Overall, these results show that distinct molecular forms of the CDw52 molecules are present on different blood cells. We have also characterized an activation signal that can be delivered to T cells via the CDw52 molecule by CAMPATH-1M but not by O97. This is an accessory signal that can complement a primary activation signal delivered via the CD2 pathway but not via the CD3-TcR pathway. This is similar to the effects obtained with the CD45R (2H4) mAb, 2H4 and CAMPATH-1M mAb having additive effects on T cell activation via CD2.

Antibodies, Monoclonal↗
PubMed1992

Molecular basis for biosynthesis and accumulation of polyhydroxyalkanoic acids in bacteria.

The current knowledge on the structure and on the organization of polyhydroxyalkanoic acid (PHA)-biosynthetic genes from a wide range of different bacteria, which rely on different pathways for biosynthesis of this storage polyesters, is provided. Molecular data will be shown for genes of Alcaligenes eutrophus, purple non-sulfur bacteria, such as Rhodospirillum rubrum, purple sulfur bacteria, such as Chromatium vinosum, pseudomonads belonging to rRNA homology group I, such as Pseudomonas aeruginosa, Methylobacterium extorquens, and for the Gram-positive bacterium Rhodococcus ruber. Three different types of PHA synthases can be distinguished with respect to their substrate specificity and structure. Strategies for the cloning of PHA synthase structural genes will be outlined which are based on the knowledge of conserved regions of PHA synthase structural genes and of the PHA-biosynthetic routes in bacteria as well as on the heterologous expression of these genes and on the availability of mutants impaired in the accumulation of PHA. In addition, a terminology for the designation of PHAs and of proteins and genes relevant for the metabolism of PHA is suggested.

Acyltransferases↗
PubMed1991

Isoforms of the E2 molecule: D44 monoclonal antibody defines an epitope on E2 and reacts differentially with T cell subsets.

Human T cell rosetting with erythrocytes is clearly dependent on the CD2-CD58 interaction. We have previously demonstrated that other T cell molecules are involved in the rosette phenomenon, including the E2 molecule, a 32-kDa transmembrane glycoprotein. In this report we show that the D44 monoclonal antibody (mAb), previously shown to subdivide T cells into subpopulations with distinct functional repertoires and to identify 70% of lymphocytes from bronchoalveolar lavage from HIV+ patients, defined a new epitope on the E2 molecule. This was illustrated by the reactivity of the D44 mAb in Western blot experiments performed with the immunoaffinity purified E2 molecule. Moreover, double-labeling experiments showed that the E2 molecule exhibited varying epitopes when expressed in different cell types. The D44 and 12E7 epitopes were restricted to distinct subpopulations of T cells and, more importantly, the D44 expression was limited to the CD29+ population including the memory subset. The O662 and L129 epitopes are present on all T cells. Thus, the E2 molecule has both common and variable epitopes in its extracellular domain, and only the common epitopes seem to be involved in T cell adhesion processes.

12E7 Antigen↗
PubMed1991

[Current situation of occupational diseases in physicians and medical personnel].

In the introduction the social law bias of occupational diseases, the current list of occupational diseases and the importance of injuries to health by work and occupation are presented. Regarding physicians as a whole and the medical staff it refers to a numerically important occupational group. It has different scope of duties, it is not homogeneous structured and shows different potentials of danger. It is therefore appropriate to separate into three spheres of danger. The occupational hazards of physicians and the medical staff are wellknown. The existing statistics from the period 1978 to 1983 and the documentation of occupational diseases from 1984 to 1988 are discussed. In the three spheres of danger the infectious diseases and the skin diseases are numerically important. In the last ten years a considerable reduction of job related infectious diseases can be recorded, the number of toxic and allergic skin diseases remains constant. Improved hygienic conditions, health surveillance examinations has created positive influences on the process of occupational diseases in the field of medical health care occupations.

Allied Health Personnel↗
PubMed1990

Modulation of lymphokine release and cytolytic activities by activating peripheral blood lymphocytes via CD2.

We had previously shown that the signal of activation delivered via CD2 varies according to the mitogenic pair of CD2 mAb used. We had selected two typical mAb pairs, D66 + T11(1) and GT2 + T11(1), the former delivering the "richest" signal, the latter the poorest. Here we analyzed the cytolytic activities generated within PBL-stimulated by these two pairs. When purified CD2+,3- cells were cultured with either one of these two pairs, no significant lymphokine-activated killer (LAK) activity--namely the activity exerted on NK-resistant malignant cell lines or fresh tumor cells--was detected, thereby demonstrating the inability of CD2 mAb pairs to directly trigger the LAK precursors. By contrast, when purified CD2+,3+ cells were cultured, only D66 + T11(1) was able to trigger a potent CTL activity, as judged by targeting their activity, at the effector phase, with a bridging CD3 mAb on a FcR+ target cell or by using heteroaggregates on FcR- malignant cells. When whole PBL were used, a similar and moderate LAK activity was generated after culture with either one of the 2 CD2 mAb pairs. This, in fact, masked quite different events. The amounts of endogeneous IL-2 released in PBL cultures with GT2 + T11(1) was rather low, although it was sufficiently high in PBL cultures with D66 + T11(1) to generate a potent LAK activity. Yet, PBL stimulated with D66 + T11(1) released concomitantly a high amount of IL-4 which inhibited the development of the LAK activity, as demonstrated by unmasking this activity with an anti-IL4 antiserum and which did not inhibit the T CTL activity; this IL-4 secretion was not seen with GT2 + T11(1). Therefore, stimulation by these two typical CD2 mAb pairs induce a striking different pattern of IL synthesis.

Antigen-Antibody Reactions↗
PubMed1990

Immunoregulatory functions of paf-acether. VI. Inhibition of T cell activation via CD3 and potentiation of T cell activation via CD2.

In the present report we further explored the role of paf-acether (paf), a phospholipid cytokine, in the modulation of T cell activation induced via the CD2 and the CD3 pathways. Evidence was obtained that paf inhibited T cell proliferation induced by immobilized CD3 mAb (OKT3i), but potentiated that induced by a combination with the CD2 mAb, anti-(T11.1 + D66). Both effects were dose-dependent between 2 and 10 microM paf, and specific in that lysoPC, a phospholipid closely related to paf, had no effect. The inhibition became apparent after 48 h and was maintained up to 144 h of culture, whereas the enhancement was observed only by 96 h of culture. Interestingly, paf was able to inhibit OKT3i mAb response when added to cultures as late as 24-48 h after the initiation of a 96 h incubation. By contrast, paf enhanced the proliferative response only when added concomitantly with anti-(T11.1 + D66) mAb, suggesting that it modulates an early event of T cell activation. paf, which enhanced T cell proliferation induced via the CD2 pathway, also led to a substantial up-regulation of IL-2 secretion and CD25 expression. Moreover, paf markedly augmented IL-4 secretion upon CD2 mAb stimulation. Finally, when T cells were triggered via the CD3 molecule, paf inhibited the proliferative response but also down-modulated CD25 expression without impairing IL-2 secretion. When considered together, these data demonstrate that paf, a phospholipid cytokine released during inflammatory reactions, play a differential regulatory role in T cell activation induced via the CD3 and CD2 (T11.1 + D66) pathways.

Antibodies, Monoclonal↗