Ameliorated ConA-Induced Hepatitis in the Absence of PKC-theta

Severe liver injury that occurs when immune cells mistakenly attack an individual's own liver cells leads to autoimmune hepatitis. In mice, acute hepatitis can be induced by concanavalin A (ConA) treatment, which causes rapid activation of CD1d-positive natural killer (NK) T cells. These activated NKT cells produce large amounts of cytokines, which induce strong inflammation that damages liver tissues. Here we show that PKC-θ−/− mice were resistant to ConA-induced hepatitis due to essential function of PKC-θ in NKT cell development and activation. A dosage of ConA (25 mg/kg) that was lethal to wild-type (WT) mice failed to induce death resulting from liver injury in PKC-θ−/− mice. Correspondingly, ConA-induced production of cytokines such as IFNγ, IL-6, and TNFα, which mediate the inflammation responsible for liver injury, were significantly lower in PKC-θ−/− mice. Peripheral NKT cells had developmental defects at early stages in the thymus in PKC-θ−/− mice, and as a result their frequency and number were greatly reduced. Furthermore, PKC-θ−/− bone marrow adoptively transferred to WT mice displayed similar defects in NKT cell development, suggesting an intrinsic requirement for PKC-θ in NKT cell development. In addition, upon stimulation with NKT cell-specific lipid ligand, peripheral PKC-θ−/− NKT cells produced lower levels of inflammatory cytokines than that of WT NKT cells, suggesting that activation of NKT cells also requires PKC-θ. Our results suggest PKC-θ is an essential molecule required for activation of NKT cell to induce hepatitis, and thus, is a potential drug target for prevention of autoimmune hepatitis

Quality of life of children aged 5 to 11 years : conceptualisation, self-assessment and relations with schooling context among children with intellectual disability

Prenant appui sur l’étude de la qualité de vie des enfants au développement typique, cette thèse a pour objectifs d’appréhender la satisfaction de vie des enfants présentant une déficience intellectuelle âgés de 5 à 11 ans et d’étudier ses relations avec leur contexte de scolarisation. Pour y répondre, trois études complémentaires ont été réalisées. La première s’est attachée à examiner les perceptions relatives aux expériences de vie de 161 enfants scolarisés de la grande section de maternelle (GSM) au cours moyen deuxième année (CM2) afin d’identifier les dimensions constitutives de leur qualité de vie. Les résultats des focus groups montrent que ces jeunes accordent une importance particulière aux domaines des relations familiales et paritaires ainsi qu’à l’école. A partir de ces résultats, l’objectif principal de la deuxième étude était d’adapter et de valider la Multidimensional Student’s Life Satisfaction Scale (MSLSS) (Huebner, Zullig, & Runa, 2012) auprès de 340 enfants au développement typique et de 71 enfants présentant une déficience intellectuelle. De manière générale, les analyses indiquent que ce questionnaire présente des propriétés psychométriques satisfaisantes. Enfin, dans la troisième étude nous avons utilisé la MSLSS afin d’examiner prioritairement les relations entre la qualité de vie perçue de 66 élèves présentant une déficience intellectuelle et leur contexte de scolarisation (classes d’inclusion scolaire, CLIS versus instituts médico-éducatifs, IME). Les résultats montrent que chez les élèves de CLIS certains dispositifs visant à compenser leur handicap peuvent être source d’insatisfaction.Based on the study of the quality of life of children without disability, this thesis aims to examine the life satisfaction of children with intellectual disability aged 5 to 11 years and to study its associations with their schooling context. To this aim, three studies were conducted. The first study examined how children aged 5 to 11 years old conceive their quality of life through the dimensions contributing to their subjective well-being. The results show that family, friends, and school play an important role in children’s lives. On the basis of these results, the main objective of the second study was to validate a French adaptation of the Multidimensional Student’s Life Satisfaction Scale (MSLSS) (Huebner, Zullig, & Runa, 2012) with 340 children without disability and 71 children with intellectual disability. Overall, the analyses indicate that this questionnaire has satisfactory psychometric properties. Finally, in the third study we used the MSLSS to examine the relationships between the perceived quality of life of 66 students with intellectual disability and their schooling context (inclusive classrooms versus specialised institutions). The results show that among students in inclusive classrooms some interventions designed to compensate for their disability can be source of dissatisfaction

Novel Antileukemic Compound Ingenol 3-Angelate Inhibits T Cell Apoptosis by Activating Protein Kinase Cθ*

Members of the protein kinase C (PKC) family of serine-threonine kinases are important regulators of immune cell survival. Ingenol 3-angelate (PEP005) activates a broad range of PKC isoforms and induces apoptosis in acute myeloid leukemia cells by activating the PKC isoform PKCδ. We show here that, in contrast to its effect on leukemic cells, PEP005 provides a strong survival signal to resting and activated human T cells. The antiapoptotic effect depends upon the activation of PKCθ. This PKC isoform is expressed in T cells but is absent in myeloid cells. Further studies of the mechanism involved in this process showed that PEP005 inhibited activated CD8+ T cell apoptosis through the activation of NFκB downstream of PKCθ, leading to increased expression of the antiapoptotic proteins Mcl-1 and Bcl-xL. Transfection of CD8+ T cells with dominant-negative PKCθ diminished the prosurvival effect of PEP005 significantly. Ectopic expression of PKCθ in the acute myeloid leukemia cell line NB4 turned their response to PEP005 from an increased to decreased rate of apoptosis. Therefore, in contrast to myeloid leukemia cells, PEP005 provides a strong survival signal to T cells, and the expression of functional PKCθ influences whether PKC activation leads to an anti- or proapoptotic outcome in the cell types tested

Protein Kinase Cθ Is a Specific Target for Inhibition of the HIV Type 1 Replication in CD4+T Lymphocytes

Integration of HIV-1 genome in CD4(+) T cells produces latent reservoirs with long half-life that impedes the eradication of the infection. Control of viral replication is essential to reduce the size of latent reservoirs, mainly during primary infection when HIV-1 infects CD4(+) T cells massively. The addition of immunosuppressive agents to highly active antiretroviral therapy during primary infection would suppress HIV-1 replication by limiting T cell activation, but these agents show potential risk for causing lymphoproliferative disorders. Selective inhibition of PKC, crucial for T cell function, would limit T cell activation and HIV-1 replication without causing general immunosuppression due to PKC being mostly expressed in T cells. Accordingly, the effect of rottlerin, a dose-dependent PKC inhibitor, on HIV-1 replication was analyzed in T cells. Rottlerin was able to reduce HIV-1 replication more than 20-fold in MT-2 (IC(50) = 5.2 μM) and Jurkat (IC(50) = 2.2 μM) cells and more than 4-fold in peripheral blood lymphocytes (IC(50) = 4.4 μM). Selective inhibition of PKC, but not PKCδ or -ζ, was observed at <6.0 μM, decreasing the phosphorylation at residue Thr(538) on the kinase catalytic domain activation loop and avoiding PKC translocation to the lipid rafts. Consequently, the main effector at the end of PKC pathway, NF-κB, was repressed. Rottlerin also caused a significant inhibition of HIV-1 integration. Recently, several specific PKC inhibitors have been designed for the treatment of autoimmune diseases. Using these inhibitors in combination with highly active antiretroviral therapy during primary infection could be helpful to avoid massive viral infection and replication from infected CD4(+) T cells, reducing the reservoir size at early stages of the infection.This work was supported by Instituto de Salud Carlos III, Spanish Ministry of Health (FIS PI080752); AIDS Network ISCIII-RETIC (RD06/0006); VIRHORST Network from Comunidad de Madrid (Spain), Network of Excellence EUROPRISE; FIPSE (36584/06, 36633/07, and 360924/10).S