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Biomedical subjects

A Capron

Publications and source records attributed to A Capron.

At least 19 recordsLinked to original sources
PubMed2003

Failure of a recombinant Schistosoma bovis-derived glutathione S-transferase to protect cattle against experimental Fasciola hepatica infection.

The potential of a recombinant Schistosoma bovis 28-kDa glutathione S-transferase (rSb28GST) to protect cattle against Fasciola hepatica was tested in a vaccination trial. Thirty two calves were randomly divided into four groups of eight animals. Calves of the three vaccine groups received two intramuscular injections at 3 weeks interval, of 0.250mg rSb28GST in either aluminium hydroxide (Al(OH)(3)), Quil A, or PBS emulsified in an equal volume of Freund's complete adjuvant (FCA).Animals of the control group received injections of Al(OH)(3)/PBS only. All animals were challenged orally with a total of 360 metacercariae of F. hepatica, spread over 6 weeks. All groups of vaccinated animals produced measurable IgG antibody titers to rSb28GST after vaccination. Animals immunised with FCA adjuvanted vaccine had the highest and more durable antibody titers and only sera from this group recognised an approximately 24kDa protein band from F. hepatica, that is thought to be a F. hepatica GST. Despite a good antibody response differences in cumulative faecal egg output between the groups were not statistically significant. In addition, no significant difference was found between groups in terms of total worm numbers or percentage of immature flukes recovered at necropsy. In conclusion, the recombinant S. bovis 28kDa GST was not found to adequately protect cattle against experimental F. hepatica challenge, using either aluminium hydroxide, Quil A or FCA as adjuvant.

Adjuvants, Immunologic↗
PubMed2003

Adjuvant activity of free Bordetella pertussis filamentous haemagglutinin delivered by mucosal routes.

The development of safe and potent mucosal adjuvants remains a major objective in vaccinology. The potential usefulness of filamentous haemagglutinin (FHA) of Bordetella pertussis as an adjuvant was assessed in a mouse model. The glutathione-S-transferase of Schistosoma mansoni (Sm28GST) was used for intranasal administration, while the gut-resistant keyhole limpet haemocyanin (KLH) was administrated by the oral route. For both antigens, coadministration with FHA increased antigen-specific immunoglobulin titres. This adjuvant effect did not require chemical cross-linking or direct interaction between FHA and the antigen tested. FHA also behaved as an adjuvant by the subcutaneous route, indicating that its adjuvanticity is not restricted to binding to mucosal surfaces. The FHA-induced adjuvanticity was also observed in mice with high anti-FHA antibody titres as a result of antipertussis vaccination, indicating that pre-existing anti-FHA antibodies do not impair FHA adjuvanticity. No mRNA coding for proinflammatory cytokines was induced in the lungs after intranasal FHA administration. However, an increase in the levels of mRNAs coding for B7-1, transforming growth factor (TGF)-beta and major histocompatibility complex (MHC)-II was detected in the lungs after FHA administration. Although the molecular mechanisms of the FHA-induced adjuvanticity remain to be elucidated, the data presented here indicate that this adhesin, already assessed for human use as a pertussis vaccine constituent, represents a promising adjuvant to improve the humoral immune response when given by mucosal routes.

Adhesins, Bacterial↗
PubMed2003

A novel cellular RNA helicase, RH116, differentially regulates cell growth, programmed cell death and human immunodeficiency virus type 1 replication.

In an effort to define novel cellular factors regulating human immunodeficiency virus type 1 (HIV-1) replication, a differential display analysis has been performed on endogenously infected cells stimulated with the HIV-suppressive immunomodulator Murabutide. In this study, the cloning and identification of a Murabutide-downregulated gene, named RH116, bearing classical motifs that are characteristic of the DExH family of RNA helicases, are reported. The 116 kDa encoded protein shares 99.9 % similarity with MDA-5, an inducible RNA helicase described recently. Ectopic expression of RH116 in HeLa-CD4 cells inhibited cell growth and cell proliferation but had no measurable effect on programmed cell death. RH116 presented steady state cytoplasmic localization and could translocate to the nucleus following HIV-1 infection. Moreover, the endogenous expression of RH116, at both the transcript and protein levels, was found to be considerably upregulated after infection. Overexpression of RH116 in HIV-1-infected HeLa-CD4 cells also resulted in a dramatic increase in the level of secreted viral p24 protein. This enhancement in virus replication did not stem from upregulated proviral DNA levels but correlated with increased unspliced and singly spliced viral mRNA transcripts. These findings implicate RH116 in the regulation of HIV-1 replication and point to an apoptosis-independent role for this novel helicase in inducing cell growth arrest.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2002

The transcriptional response of human macrophages to murabutide reflects a spectrum of biological effects for the synthetic immunomodulator.

The synthetic immunomodulator murabutide (MB) presents multiple biological activities with minimal toxicity in animals and in man. Although MB is known to target cells of the reticuloendothelial system and to regulate cytokine synthesis, the molecular mechanisms underlying several of its biological effects are still largely unknown. In an effort to define cellular factors implicated in the immunomodulatory and HIV-suppressive activities of MB, we have undertaken profiling the regulated expression of genes in human monocyte-derived macrophages (MDM) following a 6-h stimulation with this synthetic glycopeptide. Oligonucleotide microarray analysis was performed on RNA samples of differentiated MDM from four separate donors, using probe sets corresponding to 1081 genes. We have identified, in a reproducible fashion, the enhanced expression of 40 genes and the inhibition of 16 others in MB-treated MDM. These regulated genes belonged to different families of immune mediators or their receptors, transcription factors and kinases, matrix proteins and their inhibitors, ion channels and transporters, and proteins involved in cell metabolic pathways. Additional verification of the regulated expression of selected genes was carried out using Northern blots or the quantification of released proteins in MDM cultures. The profile of MB-regulated genes in MDM provides a molecular basis for some of its previously reported biological activities, and reveals new set of genes targeted by the immunomodulator suggesting potential application in novel therapeutic indications.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2001

Cloning of the rat IL-5Ralpha gene: analysis of 5'-upstream region and expression by B cells.

Although rats are widely used for the analysis of allergic reactions and parasitic infections where IL-5 is involved, nothing is currently known of the expression of IL-5 receptor in this species. In this study, the cDNA sequence, genomic structure and the transcriptional regulation of the rat IL-5Ralpha were analyzed. The rat IL-5Ralpha gene, which we localized to chromosome 4q34-q41, spans more than 25 kb and consists of 12 exons. Promoter activity was seen in different cell lines and analysis by deletion experiments allowed to identify two negative regulatory regions which did not differ when tested either with IL-5Ralpha-negative or positive cells. Finally, the investigation of the expression of IL-5Ralpha showed that it is expressed in lung, spleen, liver, and purified rat B cells from normal rat. This can provide an explanation for the role of rat IL-5 as B-cell growth factor and a relevant model in order to better understand the activity of IL-5 on human B cells.

5' Untranslated Regions↗
PubMed2001

Features of the antibody response attributable to plasmid backbone adjuvanticity after DNA immunization.

DNA vaccination induces antigen-specific immune responses with characteristics distinct from other vaccination modes. In the present study, the contribution of the plasmid backbone adjuvant effect to the quality of the DNA-raised antibody response was investigated. For this purpose, three intradermal primings were compared in mice using: (1) the recombinant Schistosoma haematobium glutathione S-transferase antigen (rSh28GST): (2) rSh28GST supplemented with a non-coding plasmid; and (3) a Sh28GST-encoding plasmid. In contrast to immunization with the protein, DNA immunization elicited a very stable antibody (Ab) response over a prolonged period of time. This feature was attributed to the plasmid backbone, because co-administration of the non-coding plasmid with rSh28GST allowed the maintenance of the specific Ab response. A strong anamnestic Ab response was induced after intradermal boost with rSh28GST only in the mice primed with pMSh. This indicated that the selective ability of DNA vaccination to induce memory humoral response was independent of the plasmid backbone. In contrast the plasmid backbone was found to strongly participate in the preferential IgG2a Ab production observed. These results suggest that, following DNA immunization, the Th1-biased profile and the maintenance of the long-lived Ab response could be attributed to an adjuvant effect of the plasmid backbone during priming, whereas the strength of B-cell memory was independent of this effect.

Adjuvants, Immunologic↗
PubMed2001

Role of the parasite-derived prostaglandin D2 in the inhibition of epidermal Langerhans cell migration during schistosomiasis infection.

Epidermal Langerhans cells (LCs) play a key role in immune defense mechanisms and in numerous immunological disorders. In this report, we show that percutaneous infection of C57BL/6 mice with the helminth parasite Schistosoma mansoni leads to the activation of LCs but, surprisingly, to their retention in the epidermis. Moreover, using an experimental model of LC migration induced by tumor necrosis factor (TNF)-alpha, we show that parasites transiently impair the departure of LCs from the epidermis and their subsequent accumulation as dendritic cells in the draining lymph nodes. The inhibitory effect is mediated by soluble lipophilic factors released by the parasites and not by host-derived antiinflammatory cytokines, such as interleukin-10. We find that prostaglandin (PG)D2, but not the other major eicosanoids produced by the parasites, specifically impedes the TNF-alpha-triggered migration of LCs through the adenylate cyclase-coupled PGD2 receptor (DP receptor). Moreover, the potent DP receptor antagonist BW A868C restores LC migration in infected mice. Finally, in a model of contact allergen-induced LC migration, we show that activation of the DP receptor not only inhibits LC emigration but also dramatically reduces the contact hypersensitivity responses after challenge. Taken together, we propose that the inhibition of LC migration could represent an additional stratagem for the schistosomes to escape the host immune system and that PGD2 may play a key role in the control of cutaneous immune responses.

Animals↗
PubMed2001

Modulation of cellular and humoral immune responses to a multiepitopic HIV-1 DNA vaccine by interleukin-18 DNA immunization/viral protein boost.

In this study, the impact of Th1-inducing cytokine gene co-delivery and antigen boosting on humoral and cellular responses induced by multiepitopic DNA immunization in mice have been investigated. Intramuscular injection of mixed DNA constructs encoding for HIV-1 Gag, Tat and Nef proteins, co-administered with the DNA encoding for interleukin-18 (IL-18) have been used. The effect of boosting with the recombinant proteins was also evaluated on the outcome of the responses in DNA-primed mice. It was demonstrated that at least two DNA immunizations were necessary to generate virus specific Th-1 responses detected by the presence of cytotoxic T lymphocyte (CTL) and by the secretion of IL-2 and IFN-gamma, but not IL-4 and IL-10, in antigen-stimulated splenocyte cultures. Interestingly, co-delivery of Th-1-inducing IL-18 gene was able to shorten by 2 weeks, the CTL induction time, and to increase the antigen-induced secretion of IL-2 and IFN-gamma. Furthermore, IL-18 co-delivery enhanced antigen-specific lymphoproliferative responses, and this was most evident in mice that were primed and boosted with plasmid DNA. However, the induction of detectable antibodies in mice required two DNA vaccinations and a protein boost. In contrast to the effects on cell-mediated immunity, co-administration of IL-18-plasmid resulted in decreased antibody titers against viral proteins.

AIDS Vaccines↗
PubMed2001

Immunostimulatory effect of IL-18-encoding plasmid in DNA vaccination against murine Schistosoma mansoni infection.

In vivo delivery of DNA encoding antigens is a simple tool to induce immune responses against pathogens. This approach to vaccination also offers the possibility to codeliver plasmids encoding immunomodulatory molecules in order to drive immune responses towards optimal protective effects. In the murine model of Schistosoma mansoni infection, vaccination inducing a Th1 profile has been shown to be protective. In this study, we used a plasmid encoding the Th1-promoting cytokine IL-18, since we observed that percutaneous infection of Balb/c mice strongly induced the production of IL-18 mRNA in the skin. Intradermal injection of the IL-18-encoding plasmid prior to infection did not interfere with parasite migration through the skin although it led to a local and transient cellular infiltration. When the IL-18-encoding plasmid was codelivered with a S. mansoni glutathione S-transferase (Sm28GST)-encoding plasmid, a 30-fold increase of antigen-specific IFN-gamma secretion by spleen cells was observed in comparison to spleen cells from mice that had received only the Sm28GST-encoding plasmid. This immunostimulatory effect was related to a significant protective effect (28% reduction in egg laying and 23% reduction in worm burden) which was attributed to a cooperative effect between both plasmids. Therefore, this study shows that codelivery of an IL-18-encoding plasmid with an antigen-encoding plasmid can stimulate specific cellular responses and induce protective effects against S. mansoni infection.

Animals↗
PubMed2001

Macrophage stimulation with Murabutide, an HIV-suppressive muramyl peptide derivative, selectively activates extracellular signal-regulated kinases 1 and 2, C/EBPbeta and STAT1: role of CD14 and Toll-like receptors 2 and 4.

The smallest unit of bacterial peptidoglycans known to be endowed with biological activities is muramyl dipeptide (MDP). A clinically acceptable synthetic derivative of MDP, namely murabutide (MB), has been found to present interesting pharmacological properties and to suppress HIV-1 replication in monocyte-derived macrophages (MDM). We have addressed the signaling events activated in MDM following stimulation with either MB or the potent immunostimulant LPS. We also examined whether signaling by muramyl peptides involves the use of cell surface receptors, including CD14 and Toll-like receptor 2 (TLR2) or TLR4 that are known to be signal-transducing receptors for other bacterial cell wall components. We demonstrate that, unlike LPS, the safe immunomodulator MB selectively activates extracellular signal-regulated kinases (Erk) 1/2, in the absence of detectable Jun N-terminal kinase (JNK) or p38 mitogen-activated kinase activation. Furthermore, STAT1 activation but weak or no activation of STAT3 or STAT5 respectively, could be detected in MB-stimulated MDM. Using MonoMac6 cells, we observed high C/EBPbeta and AP-1 but weaker and transient NF-kappaB activation by MB.Moreover, the truncated form of C/EBPbeta, known to repress HIV-1 transcription, was detected in extracts from MB-treated THP-1 cells. Surprisingly, neither MB nor MDP were able to transduce signals via CD14 and TLR2 or 4. These findings present major differences in the early cell activation process between LPS and muramyl peptides, and strongly argue for the implication of co-receptors other than TLR2 and TLR4 in mediating the signaling events induced by defined subunits of bacterial peptidoglycans.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2001

[Contribution of experimental models to the understanding of immunity to schistosomiasis].

The discovery of a functional division in T helper cells on the basis of their cytokine secretion patterns has changed our vision of immunological responses. This dichotomy has equally shown the complexity of immune responses since there is a well orchestrated cross-regulation of cytokine production induced by viral, bacterial or parasitic pathogens. In the context of type 1-type 2 cytokine pattern, mice has been universally and extensively used to associate an infectious disease according to each category in order to better understand human infections. However, with respect to schistosomiasis, immunological observations in mice have not been confirmed in humans and particularly the nature of the protective immune response. This report will consider the relevance of extrapolating from immunological studies on schistosome in experimentally infected rats to studies on naturally infected humans.

Animals↗
PubMed2001

Seasonality in the transmission of schistosomiasis and in populations of its snail intermediate hosts in and around a sugar irrigation scheme at Richard Toll, Senegal.

Irrigation for intensive sugar cultivation started in the early 1980s at Richard Toll, some 100 km from the mouth of the Senegal River. Infections with Schistosoma mansoni were first seen in late 1988. This study records quantitative snail surveys for over 3 years from 1992 at sites representing different habitats in and around the irrigation scheme. Populations of both Biomphalaria pfeifferi (the intermediate host of S. mansoni) and Bulinus spp. (mainly B. truncatus, the local host of S. boris) peaked in late 'spring' or early 'summer', depending on the habitat, and then remained low until the following spring', B. pfeifferi favoured smaller, man-made habitats with most transmission between May and August each year. The less abundant Bulinus spp. favoured larger natural and man-made habitats with most S. bovis transmission between April and July. S. mansoni infections were more, but S. bovis infections were less abundant than other trematodes in their respective snail hosts. Ecological changes in the early 1980s due to sugar irrigation pre-dated similar, more widespread changes in the late 1980s when the completion of dams across the Senegal River prevented seasonal rain fed floods and sea water intrusion. S. mansoni has since spread rapidly around Richard Toll. The incompatibility of the local S. haematobium strains with the dominant bulinid snails has so far prevented an epidemic of urinary schistosomiasis at Richard Toll, but the invasion of similar downstream habitats by susceptible B. globosus is worrying. The principal control measure, chemotherapy, given in the 'winter' would minimise the rate of reinfection. It could be reinforced by judicious mollusciciding within the sugar irrigation scheme but not elsewhere.

Animals↗
PubMed2001

Gender-dependent specific immune response during chronic human Schistosomiasis haematobia.

The cellular and humoral acquired immune responses to Schistosoma haematobium 28 kD gluthathione S-Transferase (Sh28GST) antigen were evaluated in a Senegalese population chronically infected with S. haematobium parasite. We show a gender-dependent immune response in adult individuals presenting similar intensities of infection. Indeed, the specific IgA response and production of TGF-beta and IL-10 were found significantly higher in females compared to males. In addition, we showed that this profile was combined with a weak production of Th1-related cytokines (TNFalpha and IFNgamma) and was associated with an absence of proliferation to the antigen. A significantly higher Nuclear Matrix Protein 41/7 secretion, an apoptosis marker, was specifically observed in mononuclear blood cell cultures of females suggesting that a specific cell death process was engaged in a gender-dependent manner. This specific profile could be associated with the so-called T helper type-3 (Th3) immune response specifically promoting the production of IgA and would be developed upon the down-regulation of the specific Type-1 response by a probable cell death mechanism. This gender-dependent immune regulation, which may be under the influence of nonimmunological factors like sexual hormones, may be related to the chronicity of the infection.

Adult↗
PubMed2001

Sub-cellular localisation of GFP-tagged tobacco mitotic cyclins during the cell cycle and after spindle checkpoint activation.

We have previously shown that the tobacco cyclin B1;1 protein accumulates during the G2 phase of the cell cycle and is subsequently destroyed during mitosis. Here, we investigated the sub-cellular localisation of two different B1-types and one A3-type cyclin during the cell cycle by using confocal imaging and differential interference contrast (DIC) microscopy. The cyclins were visualised as GFP-tagged fusion proteins in living tobacco cells. Both B1-type cyclins were found in the cytoplasm and in the nucleus during G2 but when cells entered into prophase, both cyclins became associated with condensing chromatin and remained on chromosomes until metaphase. As cells exited metaphase, the B1-type cyclins became degraded, as shown by time-lapse images. A stable variant of cyclin B1;1-GFP fusion protein, in which the destruction box had been mutated, maintained its association with the nuclear material at later phases of mitosis such as anaphase and telophase. Furthermore, we demonstrated that cyclin B1;1 protein is stabilised in metaphase-arrested cells after microtubule destabilising drug treatments. In contrast to the B1-type cyclins, the cyclin A3;1 was found exclusively in the nucleus in interphase cells and disappeared earlier than the cyclin B1 proteins during mitosis.

Base Sequence↗
PubMed2001

Selective regulation of human immunodeficiency virus-infected CD4(+) lymphocytes by a synthetic immunomodulator leads to potent virus suppression in vitro and in hu-PBL-SCID mice.

We have previously observed that the synthetic immunomodulator Murabutide inhibits human immunodeficiency virus type 1 (HIV-1) replication at multiple levels in macrophages and dendritic cells. The present study was designed to profile the activity of Murabutide on CD8-depleted phytohemagglutinin-activated lymphocytes from HIV-1-infected subjects and on the outcome of HIV-1 infection in severe combined immunodeficiency mice reconstituted with human peripheral blood leukocytes (hu-PBL-SCID mice). Maintaining cultures of CD8-depleted blasts from 36 patients in the presence of Murabutide produced dramatically reduced levels of viral p24 protein in the supernatants. This activity correlated with reduced viral transcripts and proviral DNA, was evident in cultures harboring R5, X4-R5, or X4 HIV-1 isolates, was not linked to inhibition of cellular DNA synthesis, and did not correlate with beta-chemokine release. Moreover, c-myc mRNA expression was down-regulated in Murabutide-treated cells, suggesting potential interference of the immunomodulator with the nuclear transport of viral preintegration complexes. On the other hand, daily treatment of HIV-1-infected hu-PBL-SCID mice with Murabutide significantly reduced the viral loads in plasma and the proviral DNA content in human peritoneal cells. These results are the first to demonstrate that a clinically acceptable synthetic immunomodulator with an ability to enhance the host's nonspecific immune defense mechanisms against infections can directly regulate cellular factors in infected lymphocytes, leading to controlled HIV-1 replication.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2001

SS-56, a novel cellular target of autoantibody responses in Sjögren syndrome and systemic lupus erythematosus.

Certain autoimmune disorders, including Sjögren syndrome (SS) and systemic lupus erythematosus (SLE), are characterized by autoantibodies against the Ro/SSA and La/SSB cellular antigens. Although the implication of these autoantibodies in disease pathogenesis is still unclear, it is believed that the aberrant responses against autoantigens may extend to other proteins that are not yet well defined. In an attempt to analyze the regulated gene expression in lymphocytes by an HIV-suppressive immunomodulator, we have identified and cloned a novel gene encoding a 56-kDa protein, named SS-56, which is structurally related to the 52-kDa Ro/SSA antigen. The new protein showed primarily perinuclear cytoplasmic localization, and recombinant SS-56 was found to react in ELISA with sera from most patients with SS or SLE. Western blot analysis confirmed the autoantigenic nature of native SS-56 in extracts from HeLa cells. Interestingly, the incidence of antibodies to SS-56 was associated with visceral complications in SLE, and roughly half of the 17 SS or SLE patients with no detectable antibodies to SSA and SSB antigens presented measurable antibodies against recombinant SS-56. Thus, SS-56 represents a new member of the SS family of autoantigens and could become an additional and important diagnostic marker for SS and SLE.

Adult↗
PubMed2000

Interleukin-18 modulates immune responses induced by HIV-1 Nef DNA prime/protein boost vaccine.

Many different HIV-1 vaccine strategies have been developed, but as yet none has been completely successful. Promising results from combined DNA prime/protein boost vaccines have been reported. Specific immune responses generated by DNA vaccines can be modulated by the co-delivery of genes coding for cytokines. In this study, we have used the intradermal route by needle injection of a plasmid coding for the HIV-1 Nef accessory protein. We show that DNA prime/protein boost vaccine combinations increase the humoral and cellular immune responses against HIV-1 Nef and that the co-injection of DNA encoding Interleukin-18 (IL-18) modulates the specific immune response towards a Th1 type.

AIDS Vaccines↗