Éditeur(s) : HAL CCSD
Résumé : International audience
Leishmania parasites induce an immunomodulation by subverting the host immune response towards a CD4(+) Th2 lymphocytic cell response that favors parasite persistence. Here, we report that after successful treatment of visceral leishmaniasis due to Leishmania infantum, an immune reconstitution syndrome revealing hip septic arthritis was associated with a switch from Th2 towards a Th1 cytokine profile, and a decrease in the level of immunomodulating factors, such as soluble HLA-G and indoleamine 2,3-dioxygenase (IDO) activity. We then measured IDO activity in a cohort of 39 patients and uninfected control subjects. Results showed significantly enhanced IDO activity in patients with visceral Leishmania infection, compared with uninfected control subjects (P < 0.001), but also compared with treated patients (P < 0.05). A decrease in IDO activity could constitute a relevant biomarker for the restoration of the immune response during visceral leishmaniasis.
Innate Immunity

inserm-00818884
http://www.hal.inserm.fr/inserm-00818884
DOI : 10.1177/1753425912473170
PUBMED : 23413147

Éditeur(s) : Université de La Rochelle, Ecole doctorale Gay Lussac
Résumé : The thesis work is part of the very current issue on mass mortality outbreaks affecting Pacific oyster, C. gigas, spat and juveniles and questions about the involvement of pesticides in this phenomenon. The first part of this thesis was devoted to study the effects of pesticides on hemocyte parameters in the Pacific oyster (in vitro and in vivo). The immunomodulator effect of selected pesticides (alone or in mixture) has been explored principally through flow cytometry. The second part concerned the study of the effects of a pesticides mixture on OsHV-1 itself. No direct effects have been reported on the viral particles in presence of the pollutants. Moreover, pesticide effects on Pacific oysters were also explored through experimental pathology assays after treatment of animals with a polluant mixture. Results showed that pesticide treated oysters appeared more susceptible to the viral infection in experimental conditions. The third part concerned the study of autophagy in the Pacific oyster, C. gigas. The publication of the complete genome in 2012 has opened up new possibilities for the study of innate immunity in this species. The study of autophagy for the first time in oysters consisted in a first step in the in silico search for genes involved in this pathway and the corresponding proteins by Western blotting. Then, the role of this important process in innate immunity has been explored through reproduction infections tests with or without modulators of autophagy. Results showed that autophagy appeared as involved in defence mechanisms against viral and bacterial infection in Pacific oysters.
Le travail de thèse s’inscrit dans la problématique très actuelle des mortalités massives de naissain et de juvéniles d’huîtres creuses, C. gigas, et des questionnements autour de l’implication des pesticides dans ce phénomène. La première partie de la thèse a été consacrée à l’étude des effets de pesticides sur les capacités hémocytaires de l’huître creuse (in vitro et in vivo). L’effet immunomodulateur des xénobiotiques sélectionnés (seul ou en mélange) a été exploré principalement au travers de la cytométrie en flux. La deuxième partie de la thèse a concerné l’étude des effets d’un mélange de pesticides sélectionnés sur le virus OsHV-1 et l’infection qu’il induit chez l’huître creuse. Les effets des pesticides sur le virus lui-même ont été évalués. Les expériences réalisées non pas permis de mettre en évidence dans les conditions testées, de dégradation des particules virales en présence des polluants. D’autre part, leurs effets sur les huîtres elles-mêmes ont été explorés après traitement des animaux avec un mélange de pesticides lors d’essais de pathologie expérimentale. Il a ainsi pu être montré que des huîtres préalablement comtaminées par un mélange de pesticides à des concentrations retrouvées dans l’environnement semblaient être plus sensibles à l’infection virale. La troisième partie de la thèse a concerné l’étude de l’autophagie chez l’huître creuse, C. gigas. La publication du génome complet de cette espèce en 2012 a ouvert de nouvelles possibilités pour étudier l'immunité innée. L’étude de l’autophagie réalisée pour la première fois chez l’huître creuse a consisté lors d’une première étape en la recherche in silico de gènes impliqués dans cette voie et des protéines correspondantes par western blotting. Puis, le rôle de ce processus important dans l’immunité innée a été exploré au travers d’essais de reproduction d’infections en présence ou non de modulateurs de l’autophagie. Les résultats obtenus semblent montrer que l’autophagie soit un processus important pouvant être impliqué dans les capacités de défense de l’huître creuse vis-à-vis d’infections virales et bactériennes.

Droits : 2014 Université de La Rochelle
http://archimer.ifremer.fr/doc/00226/33740/32149.pdf
http://archimer.ifremer.fr/doc/00226/33740/

Éditeur(s) : HAL CCSD Paris, Masson et Cie
Résumé : National audience
Decreased frequency of pulmonary exacerbations, mainly related to immunomodulatory effects of macrolide antibiotics, has been demonstrated in bronchiectasis and chronic obstructive pulmonary diseases (COPD). Due to its tolerance, azithromycin is the antibiotic of choice for maintenance therapy at the dose of 250 mg per day or 500 mg × 3 per week (for body weight >55 kg). Maintenance therapy with macrolide could be proposed in selected patients with bronchiectasis or COPD with more than 3 acute exacerbations in the previous year or decreased lung function despite compliance with optimum treatment. The risk of sudden cardiac death with azithromycin is rare and controversial. It should be avoided in patients with a high baseline risk of cardiovascular disease, QT>450 msec, pulse rate>100 bpm and potential drug interactions, particularly those known to cause QT prolongation. It is recommended to search for hearing deficit (audiometry) and sputum culture positive for mycobacteria. Patients must also be aware that it can rapidly lead to macrolide resistance in commensal or pathogenic flora. Follow-up evaluation every 3 month can be proposed with medical history (hearing deficit) and electrocardiography. After one year, the treatment should be stopped in the absence of reduction in the frequency of exacerbations.
Points essentielsLes macrolides administrés au long cours permettent, grâce en partie à leurs propriétés anti-inflammatoires, de diminuer la fréquence des exacerbations dans la DDB et la BPCO.Du fait de sa tolérance, l’azithromycine est le macrolide de choix, pouvant être utilisé à la dose de 250 mg/j ou 500 mg 3 fois par semaine chez les patients de plus de 55 kg.Un traitement par macrolides au long cours pourrait être proposé à des patients atteints de DDB ou de BPCO ayant eu plus de 3 exacerbations l’année précédente ou ayant une dégradation de leur fonction respiratoire malgré un traitement de fond bien conduit.Du fait d’un risque rare et controversé de mort subite d’origine cardiaque, il ne doit pas être proposé en cas de pathologie cardiovasculaire évoluée, d’intervalle QT > 450 ms, de traitement pouvant allonger l’intervalle QT, de tachycardie > 100/min.Il est recommandé de s’assurer de l’absence de troubles auditifs (audiogramme) et de mycobactérie atypique dans les cultures des expectorations. Les patients doivent aussi être informés du risque d’apparition de résistance aux macrolides de la flore commensale et pathogène.Une surveillance clinique, avec en particulier la recherche de troubles auditifs et électrocardiographique, peut être proposée tous les 3 mois. L’absence de diminution de la fréquence des exacerbations, lors du bilan annuel, justifie l’arrêt du traitement.
ISSN: 0032-7867

hal-01073027
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01073027
DOI : 10.1016/j.lpm.2013.08.006
PUBMED : 24631048

Éditeur(s) : HAL CCSD
Résumé : International audience
Decreased frequency of pulmonary exacerbations, mainly related to immunomodulatory effects of macrolide antibiotics, has been demonstrated in bronchiectasis and chronic obstructive pulmonary diseases (COPD). Due to its tolerance, azithromycin is the antibiotic of choice for maintenance therapy at the dose of 250 mg per day or 500 mg × 3 per week (for body weight extgreater55 kg). Maintenance therapy with macrolide could be proposed in selected patients with bronchiectasis or COPD with more than 3 acute exacerbations in the previous year or decreased lung function despite compliance with optimum treatment. The risk of sudden cardiac death with azithromycin is rare and controversial. It should be avoided in patients with a high baseline risk of cardiovascular disease, QT extgreater450 msec, pulse rate extgreater100 bpm and potential drug interactions, particularly those known to cause QT prolongation. It is recommended to search for hearing deficit (audiometry) and sputum culture positive for mycobacteria. Patients must also be aware that it can rapidly lead to macrolide resistance in commensal or pathogenic flora. Follow-up evaluation every 3 month can be proposed with medical history (hearing deficit) and electrocardiography. After one year, the treatment should be stopped in the absence of reduction in the frequency of exacerbations.
Presse Médicale (Paris, France: 1983)

hal-01063927
https://hal.archives-ouvertes.fr/hal-01063927
DOI : 10.1016/j.lpm.2013.08.006

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The transcription factor nuclear factor-erythroid 2-related-2 (Nrf2) controls cellular redox homeostasis and displays immunomodulatory properties. Nrf2 alters cytokine expression in murine T cells, but its effects in human T lymphocytes are unknown. This study investigated the expression and activity of Nrf2 in human activated CD4(+) T helper lymphocytes (Th cells) that mediate the adaptive immune response. Th cells were isolated from peripheral blood mononuclear cells and activated with antibodies against CD3 and CD28, mimicking physiologic Th cell stimulation by dendritic cells. Nrf2 is hardly detectable in unstimulated Th cells. Activation of Th cells rapidly and strongly increases the levels of Nrf2 protein by increasing NRF2 gene transcription. Th cell activation also enhances mRNA and protein levels of Nrf2 target genes encoding antioxidant enzymes. Blocking Nrf2 expression using chemical inhibitors or siRNAs prevents these gene inductions. Pretreatment with inorganic arsenic, a Nrf2 inducer that does not alter NRF2 gene expression, increases protein level and transcriptional activity of Nrf2 induced by Th cell stimulation. Inorganic arsenic enhances nuclear translocation of Nrf2, its interaction with the coactivator protein p300, and its DNA binding activity. Inhibition of Nrf2 expression abrogates the effects of inorganic arsenic on mRNA levels of antioxidant genes, but does not alter the expression of IL-2, TNF-α, interferon-γ, or IL-17 in Th cells activated in the absence or presence of the metalloid. In conclusion, this study demonstrates for the first time that stimulation of human Th cells increases transcription of the NRF2 gene and activity of the Nrf2 protein. However, modulation of Nrf2 levels does not modify the secretion of inflammatory cytokines from these T lymphocytes.
ISSN: 0891-5849

hal-01018643
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01018643
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01018643/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01018643/file/Nrf2_expression_and_activity_in_human_T_lymphocytes_accepted.pdf
DOI : 10.1016/j.freeradbiomed.2014.03.006

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
ABSTRACT: Eclipsed by the debates about malaria incidence and severity in individual patients, malaria transmission in helminth-infected persons has so far received very little attention. Studies in humans have shown increased malaria incidence and prevalence, and a trend for a reduction of symptoms in patients with malaria. This suggests that such patients could possibly be less likely to seek treatment thus carrying malaria parasites and their gametocytes for longer durations, therefore, being a greater potential source of transmission. In addition, in humans, a study showed increased gametocyte carriage, and in an animal model of helminth-malaria co-infection, there was increased malaria transmission. These elements converge towards the hypothesis that patients co-infected with worms and malaria may represent a hub of malaria transmission. The test of this hypothesis requires verifying, in different epidemiological settings, that helminth-infected patients have more gametocytes, that they have less symptomatic malaria and longer-lasting infections, and that they are more attractive for the vectors. The negative outcome in one setting of one of the above aspects does not necessarily mean that the other two aspects may suffice to increase transmission. If it is verified that patients co-infected by worms and malaria could be a transmission hub, this would be an interesting piece of strategic information in the context of the spread of anti-malarial resistance and the malaria eradication attempts.
ISSN: 1475-2875

inserm-00758017
http://www.hal.inserm.fr/inserm-00758017
http://www.hal.inserm.fr/inserm-00758017/document
http://www.hal.inserm.fr/inserm-00758017/file/1475-2875-11-376.pdf
DOI : 10.1186/1475-2875-11-376

Éditeur(s) : HAL CCSD
Résumé : International audience
Introduction: Type 1 diabetes mellitus, a T cell-mediated autoimmune disease, is a complex process that results from the loss of tolerance to insulin and other beta-cell-specific antigens. Diabetes is associated with an increased risk of death from infectious disease. Hyperglycaemia, oxidative stress and inflammation have been identified as the main factor contributing to the development of diseases associated with diabetes mellitus. However, experimental evidence indicates individual susceptibility to develop complications of diabetes. Various genetic and environmental factors have been studied so far, but precise causation has yet to be established. Numerous studies in rodents and human subjects have been performed in order to elucidate the role of B and T cells, which determine the risk of development and progression of diabetes. Moreover, the therapy management of diabetes includes nutritional recommendations and exercise training. The effects of exercise training on glycemia, oxidative stress, inflammation and immune response are well known and favorable to limit the development of diabetes and its complications. More interestingly, ?-galacto-oligosaccharides (?-GOS) are prebiotics that selectively alter the composition of gut microbiota and exhibit strong antioxidant, anti- inflammatory and insulin-sensitive effects in vitro (Efstathiou and Fathi 2010) and in vivo (Boucher J et al. 2003). Thus, ? -GOS is a potential functional food for the treatment of diabetes. But, less is known about the effect of training and ? –GOS on immune response in diabetes. In this context, the aim of this work was to study the immune response in a streptozotocin-induced type 1 diabetes with two therapeutic means: training and ?-galacto-oligosaccharides (?-GOS) alone or combined. Methods: Forty-two male Wistar rats were divided into control placebo, streptozotocin-diabetic rat (STZ) groups supplemented or not with ?-GOS (20 mg/kg/day) for 8 weeks and/or following endurance training. The training program was individualized and consisted in a 1h/day, 5days/week running during 8 weeks on a motor-driven treadmill. At the end of the protocol, blood was obtained by venous puncture into heparin-containing tubes for further analyses (glucose, insulin, fructosamine and immune responses) Results: Relative to the control group, STZ rats exhibited hyperglycemia, insulin deficiency and a trend to higher plasma fructosamine levels, a marker of glycated proteins. They also exhibited a decrease in T and B cells and an increase in natural killers (NK). ?-GOS treatment reduced plasma fructosamine levels and increased B cells compared to STZ rats. Training induced a decrease in plasma glucose, T cells and an increase in B cells in STZ rats. The combined effect of ?-GOS and training didn’t potentiate the immune response on B and T cells but inhibited the effects of training on NK. Discussion: Our results suggest that training and ?-GOS alter positively plasma glucose and/or fructosamine and the immune response. But the effects of combined treatments only concern limited parameters. ? -GOS effects could be partly attributable to its immunomodulating activity. Keywords: ?-GOS, training, immune cells, diabetes. References Efstathiou, T. and D. Fathi. Sojasun Technologies. 2010 Boucher J et al. J Physiol Biochem. 59(3):169-73, 2003
18th Annual Congress of the European College of Sport Sciences, Barcelone, Spain, 26-29 juin.
Barcelone, Spain

hal-01159378
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01159378