Comité National Français de Géodésie et de Géophysique : rapport quadriennal 1991-1994

Au cours de quatre campagnes successives (1990-1993), l'expérience EPSAT-Niger a permis d'acquérir un ensemble de données pluviographiques et radar sans équivalent à ce jour sur l'Afrique de l'Ouest. Un panorama rapide des données acquises et des conditions climatiques qui ont prévalu durant ces 4 années d'expérience est donné ici, permettant de dégager quelques éléments dominants de la climatologie des précipitations au Sahel. Il est suivi d'une description des travaux menés en vue d'obtenir des estimations de lames d'eau au sol plus fiables sur des surfaces dont la taille peut varier selon les besoins des hydrologues et des modélisateurs du climat. Une analyse des champs pluviométriques associés aux systèmes convectifs de méso-échelle est ensuite présentée, montrant qu'ils sont constitués de structures emboîtées dont la trace se retrouve jusque dans les cartes de cumuls saisonniers. Néanmoins la possibilité de calculer des statistiques pertinentes pour ces structures est limitée par la nature intégrée des données fournies aussi bien par le radar que par les pluviographes. Un effort majeur reste donc à accomplir pour prendre en compte la distorsion introduite par ces effets d'intégration et développer des procédures d'estimation des paramètres de modèles de champs pluviométriques sahéliens. (Résumé d'auteur

Precise mapping of the CD95 pre-ligand assembly domain.

International audiencePre-association of CD95 at the plasma membrane is mandatory for efficient death receptor signaling. This homotrimerization occurs through self-association of an extracellular domain called the pre-ligand assembly domain (PLAD). Using novel molecular and cellular tools, we confirmed that CD95-PLAD is necessary to promote CD95 multimerization and plays a pivotal role in the transmission of apoptotic signals. However, while a human CD95 mutant deleted of the previously described PLAD domain (amino acids 1 to 66) fails to interact with its wild-type counterpart and trigger autonomous cell death, deletion of amino acids 1 to 42 does not prevent homo- or hetero (human/mouse)-oligomerization of CD95, and thus does not alter transmission of the apoptotic signal. Overall, these findings indicate that the region between amino acids 43 to 66 corresponds to the minimal motif involved in CD95 homotypic interaction and is necessary to convey an efficient apoptotic signal. Interfering with this PLAD may represent a new therapeutic strategy for altering CD95-induced apoptotic and non-apoptotic signals

Tacrolimus pharmacodynamics and pharmacogenetics along the calcineurin pathway in human lymphocytes.

BACKGROUND: Although therapeutic drug monitoring has improved the clinical use of immunosuppressive drugs, there is still interpatient variability in efficacy and toxicity that pharmacodynamic monitoring may help to reduce. To select the best biomarkers of tacrolimus pharmacodynamics, we explored the strength and variability of signal transduction and the influence of polymorphisms along the calcineurin pathway. METHODS: Peripheral blood mononuclear cells from 35 healthy volunteers were incubated with tacrolimus (0.1-50 ng/mL) and stimulated ex vivo. Inhibition of NFAT1 (nuclear factor of activated T cells 1) translocation to the nucleus and intracellular expression of interleukin-2 in CD4(+) and CD8(+) T cells and the surface activation marker CD25 in CD3(+) cells were measured by flow cytometry. We sequenced the promoter regions of immunophilins and calcineurin subunits and characterized selected single nucleotide polymorphisms in the genes of the calcineurin pathway with allelic discrimination assays. RESULTS: All responses closely fitted an I/Imax sigmoid model. Large interindividual variability (n = 30) in I0 and IC50 was found for all biomarkers. Moreover, strong and statistically significant associations were found between tacrolimus pharmacodynamic parameters and polymorphisms in the genes coding cyclophilin A, the calcineurin catalytic subunit α isoenzyme, and CD25. CONCLUSIONS: This study demonstrates the consistency and large interindividual variability of signal transduction along the calcineurin pathway, as well as the strong influence of pharmacogenetic polymorphisms in the calcineurin cascade on both the physiological activity of this route and tacrolimus pharmacodynamics.Agencia Nacional de Investigación e InnovaciónUnidda de Biología Molecular, Facultad de Química, UdelarService de Coopération Sientífique et d´Action Culturelle de l´Ambassade de France en UruguayU1248 INSERM, IPPRITT (Individual Profiling and Preventions of Risks with Immunosuppressive Therapies and Transplantation) Université de Limoges, Franc

Reduced structural flexibility of eplet amino acids in HLA proteins

International audienceThe proteins encoded in the HLA (Human Leukocyte Antigen) system are largely responsible for the compatibility in organ transplants. To date, the molecular determinants involved in recognizing HLA antigens by recipient antibodies are unknown. Here we explore flexibility as a potential determinant. For this purpose, we compare in terms of N-RMSF (Normalized Root Mean Square Fluctuation) amino acids labeled as confirmed eplets (regions defined around polymorphic amino acids) against amino acids that have not been reported as eplets. We found that eplet amino acids tend to be less flexible than non-eplet amino acids, which would indicate that the antibodies would have a preference for binding with less mobile regions

Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation : The 2019 Expert Consensus From the Transplantion Society Working Group

With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated. At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes were discussed. The evidence for different treatments was reviewed, and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented. While it was agreed that the aims of treatment are to preserve renal function, reduce histological injury, and reduce the titer of donor-specific antibody, there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes

Molecular Characterization of HIV-1 CRF01_AE in Mekong Delta, Vietnam, and Impact of T-Cell Epitope Mutations on HLA Recognition (ANRS 12159)

To date, 11 HIV-1 subtypes and 48 circulating recombinant forms have been described worldwide. The underlying reason why their distribution is so heterogeneous is not clear. Host genetic factors could partly explain this distribution. The aim of this study was to describe HIV-1 strains circulating in an unexplored area of Mekong Delta, Vietnam, and to assess the impact of optimal epitope mutations on HLA binding.We recruited 125 chronically antiretroviral-naive HIV-1-infected subjects from five cities in the Mekong Delta. We performed high-resolution DNA typing of HLA class I alleles, sequencing of Gag and RT-Prot genes and phylogenetic analysis of the strains. Epitope mutations were analyzed in patients bearing the HLA allele restricting the studied epitope. Optimal wild-type epitopes from the Los Alamos database were used as reference. T-cell epitope recognition was predicted using the immune epitope database tool according to three different scores involved in antigen processing (TAP and proteasome scores) and HLA binding (MHC score). with a Vietnamese specificity held by two different haplotypes. The percentage of homology between Mekong and B consensus HIV-1 sequences was above 85%. Divergent epitopes had TAP and proteasome scores comparable with wild-type epitopes. MHC scores were significantly lower in divergent epitopes with a mean of 2.4 (±0.9) versus 2 (±0.7) in non-divergent ones (p<0.0001).Our study confirms the wide predominance of CRF01_AE in the Mekong Delta where patients harbor a specific HLA pattern. Moreover, it demonstrates the lower MHC binding affinity among divergent epitopes. This weak immune pressure combined with a narrow genetic diversity favors immune escape and could explain why CRF01_AE is still predominant in Vietnam, particularly in the Mekong area

Early acute microvascular kidney transplant rejection in the absence of anti-HLA antibodies is associated with preformed IgG antibodies against diverse glomerular endothelial cell antigens

International audienceBACKGROUND: Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed.METHODS: We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs.RESULTS: We identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals.CONCLUSIONS: Our findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that cell-based assays are needed to improve risk assessments before transplant

L' Apoptose induite par fas et sa modulation par des co-récepteurs membranaires

Le Fas (CD95/Apo1) est un récepteur membranaire appartenant à la superfamille du récepteur au TNF (tumor necrosis factor). Le ligand naturel FasL ou les anticorps agonistes agrègent ce récepteur et déclenchent un signal de mort par apoptose. Le Fas possède dans sa région intracellulaire un domaine de mort indispensable au signal apoptotique. Dans le but d'obtenir un mutant dominant négatif, la région extracellulaire du Fas a été fusionnée avec une séquence d'ancrage membranaire GPI (glycosylphosphatidylinositol). Ce Fas-GPI, transfecté dans des lignées lymphomateuses T exprimant du Fas endogène, n'inhibait pas le signal apoptotique mais au contraire l'amplifiait. Le Fas-GPI était localisé dans les microdomaines,. Ces domaines sont des radeaux lipidiques compacts qui flottent dans la membrane cytoplasmique plus fluide. Les microdomaines concentrent des protéines extracellulaires (protéines-GPI), transmembranaires et intracellulaires (protéines de signalisation intracellulaire). Des récepteurs naturels comme le CD28 ou le CD59 localisés aussi dans ces microdomaines induisaient respectivement une amplification ou une inhibition du signal apoptotique Fas et la destruction de ces structures lipidiques par un chélateur de cholestérol (méthyl-b-cyclodextrine) annulait ces signaux modulateurs. Donc le recrutement des microdomaines avec la protéine Fas module son signal apoptotique. De plus nos résultats mettent en évidence une hétérogénéité dans ces microdomaines qui peuvent induire des signaux intracellulaires opposés. Lors de l'activation du Fas par l'anticorps agoniste, il se forme des agrégats Fas résistant au SDS et aux réducteurs de ponts di-sulfures. Nous avons démontré dans nos travaux que ces agrégats n'apparaissaient pas en présence du FasL soluble ou membranaire. De plus la formation de ces agrégats était indépendante du signal apoptotique car des lignées cellulaires résistantes à la mort cellulaire produisaient toujours ces complexes de Fas.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Etude structure-fonction du lif et de son récepteur de basse affinité, la gp 190

Les sept cytokines de la famille de l'interleukine-6 (IL-6) utilisent toutes la chaîne gp130 comme chaîne transductrice du signal. Le LIF (Leukemia Inhibitory Factor) se fixe à la chaîne gp190 avec une basse affinité avant de recruter la gp130 pour former le récepteur de haute affinité fonctionnel. Ces deux chaînes sont des récepteurs hématopoiétiques qui existent aussi sous des formes solubles inhibitrices des effets des cytokines. La gp190 possède dans sa région extracellulaire deux domaines CRH (Cytokine Receptor Homology domain), D1 à l'extrémité N-terminale de la protéine et D2 séparés par un domaine de type immunoglobuline (Ig). Trois modules de type fibronectine de type III séparent D2 de la région transmembranaire. Afin d'éclaircir les différentes étapes aboutissant à l'activation du récepteur au LIF, nous avons construit des mutants ponctuels de la gp190 et analysé leur capacité de liaison au LIF ainsi que leur capacité d'activation de la prolifération cellulaire. Nos résultats indiquent que le LIF se fixe à l'extrémité C-terminale Ig de la gp190. D'autre part, nous avons créé un récepteur gp190 ayant une plus haute affinité pour le LIF en mutant seulement deux acides aminés. La forme soluble de ce mutant pourrait constituer un meilleur inhibiteur des effets du LIF que le récepteur sauvage. De nombreux récepteurs hématopoiétiques existent à l'état prédimérique en l'absence de ligand. Nous avons montré que la gp190 ne dérogeait pas à cette règle et qu'aussi bien sous sa forme soluble que membranaire elle était dimérique. L'analyse des mutants de délétion et l'utilisation d'anticorps monoclonaux ont permis de mettre en évidence les rôles spécifiques des deux domaines CRH. Le domaine D2 contient l'information nécessaire à l'activation du récepteur alors que le domaine D1 jouerait plutôt un rôle dans le maintien de la conformation globale de la protéine.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF