Highly Variable Sialylation Status of Donor-Specific Antibodies Does Not Impact Humoral Rejection Outcomes

Clinical outcome in antibody-mediated rejection (AMR) shows high inter-individual heterogeneity. Sialylation status of the Fc fragment of IgGs is variable, which could modulate their ability to bind to C1q and/or Fc receptors. In this translational study, we evaluated whether DSA sialylation influence AMR outcomes. Among 938 kidney transplant recipients for whom a graft biopsy was performed between 2004 and 2012 at Lyon University Hospitals, 69 fulfilled the diagnosis criteria for AMR and were enrolled. Sera banked at the time of the biopsy were screened for the presence of DSA by Luminex. The sialylation status of total IgG and DSA was quantified using Sambucus nigra agglutinin-based chromatography. All patients had similar levels of sialylation of serum IgGs (~2%). In contrast, the proportion of sialylated DSA were highly variable (median = 9%; range = 0–100%), allowing to distribute the patients in two groups: high DSA sialylation (n = 44; 64%) and low DSA sialylation (n = 25; 36%). The two groups differed neither on the intensity of rejection lesions (C4d, ptc, and g; p > 0.05) nor on graft survival rates (Log rank test, p = 0.99). in vitro models confirmed the lack of impact of Fc sialylation on the ability of a monoclonal antibody to trigger classical complement cascade and activate NK cells. We conclude that DSA sialylation status is highly variable but has not impact on DSA pathogenicity and AMR outcome

Inflammatory Disease Processes and Interactions with Nutrition

Inflammation is a stereotypical physiological response to infections and tissue injury; it initiates pathogen killing as well as tissue repair processes and helps to restore homeostasis at infected or damaged sites. Acute inflammatory reactions are usually self-limiting and resolve rapidly, due to the involvement of negative feedback mechanisms. Thus, regulated inflammatory responses are essential to remain healthy and maintain homeostasis. However, inflammatory responses that fail to regulate themselves can become chronic and contribute to the perpetuation and progression of disease. Characteristics typical of chronic inflammatory responses underlying the pathophysiology of several disorders include loss of barrier function, responsiveness to a normally benign stimulus, infiltration of inflammatory cells into compartments where they are not normally found in such high numbers, and overproduction of oxidants, cytokines, chemokines, eicosanoids and matrix metalloproteinases. The levels of these mediators amplify the inflammatory response, are destructive and contribute to the clinical symptoms. Various dietary components including long chain ω-3 fatty acids, antioxidant vitamins, plant flavonoids, prebiotics and probiotics have the potential to modulate predisposition to chronic inflammatory conditions and may have a role in their therapy. These components act through a variety of mechanisms including decreasing inflammatory mediator production through effects on cell signaling and gene expression (ω-3 fatty acids, vitamin E, plant flavonoids), reducing the production of damaging oxidants (vitamin E and other antioxidants), and promoting gut barrier function and anti-inflammatory responses (prebiotics and probiotics). However, in general really strong evidence of benefit to human health through anti-inflammatory actions is lacking for most of these dietary components. Thus, further studies addressing efficacy in humans linked to studies providing greater understanding of the mechanisms of action involved are require

Aldo Keto Reductase 1B7 and Prostaglandin F2α Are Regulators of Adrenal Endocrine Functions

Prostaglandin F2α (PGF2α), represses ovarian steroidogenesis and initiates parturition in mammals but its impact on adrenal gland is unknown. Prostaglandins biosynthesis depends on the sequential action of upstream cyclooxygenases (COX) and terminal synthases but no PGF2α synthases (PGFS) were functionally identified in mammalian cells. In vitro, the most efficient mammalian PGFS belong to aldo-keto reductase 1B (AKR1B) family. The adrenal gland is a major site of AKR1B expression in both human (AKR1B1) and mouse (AKR1B3, AKR1B7). Thus, we examined the PGF2α biosynthetic pathway and its functional impact on both cortical and medullary zones. Both compartments produced PGF2α but expressed different biosynthetic isozymes. In chromaffin cells, PGF2α secretion appeared constitutive and correlated to continuous expression of COX1 and AKR1B3. In steroidogenic cells, PGF2α secretion was stimulated by adrenocorticotropic hormone (ACTH) and correlated to ACTH-responsiveness of both COX2 and AKR1B7/B1. The pivotal role of AKR1B7 in ACTH-induced PGF2α release and functional coupling with COX2 was demonstrated using over- and down-expression in cell lines. PGF2α receptor was only detected in chromaffin cells, making medulla the primary target of PGF2α action. By comparing PGF2α-responsiveness of isolated cells and whole adrenal cultures, we demonstrated that PGF2α repressed glucocorticoid secretion by an indirect mechanism involving a decrease in catecholamine release which in turn decreased adrenal steroidogenesis. PGF2α may be regarded as a negative autocrine/paracrine regulator within a novel intra-adrenal feedback loop. The coordinated cell-specific regulation of COX2 and AKR1B7 ensures the generation of this stress-induced corticostatic signal

B cells loaded with synthetic particulate antigens : an alternative platform to generate antigen-specific regulatory T cells for adoptive cell therapy

Dans des modèles expérimentaux, une tolérance d'allogreffe a pu être induite en transférant des lymphocytes T CD4+ régulateurs (Treg) spécifiques d'antigènes (Ag) du donneur expandus ex vivo. Les données ont démontré l'importance des Treg d'allospécificité indirecte (Treg indirects) dans l'induction d'une tolérance à long terme. L'expansion de Treg indirects ex vivo est problématique, principalement à cause de la difficulté d'obtenir en grand nombre des cellules présentatrices d'antigène autologues (CPA)pour stimuler les Treg. Les lymphocytes B (LB) sont des APC accessibles, présentes en grand nombre et ont un fort potentiel régulateur. Cependant, l'utilisation de LB autologues comme APC est rendue problématique par leur incapacité à présenter les Ag dont ils ne sont pas spécifiques.Dans ce travail de thèse, nous avons développé une approche nanobiotechnologique permettant de transformer des LB polyclonaux autologues en puissants stimulateurs de Treg spécifiques de l'Ag.Des Ag particulaires synthétiques (SPAg) ont été générés en fixant sur des nanosphères fluorescentes de 400 nm de diamètre : (i) des anticorps monoclonaux dirigés contre un domaine constant de la chaine légère kappa du récepteur des LB, et (ii) des Ag modèles.Les SPAg se comportent comme des Ag particulaires naturels lorsqu'ils sont incubés in vitro avec des LB murins ou humains. Les SPAg se lient à la surface des LB kappa+, déclenchent un signal d'activation et sont internalisés dans leur endosomes. Les LB chargés en SPAg induisent l'activation et la prolifération des lymphocytes T CD4+ spécifiques de l'Ag in vitro.Des propriétés régulatrices peuvent être conférées aux LB chargés en SPAg en les stimulant avec du CpG. Les LB régulateurs générés n'induisent pas de prolifération des T CD4+ effecteurs mais, au contraire, entrainent une prolifération importante des Treg.Cette approche apparait comme une alternative innovante pour expandre des Treg spécifiques de l'Ag ex vivoAllograft tolerance has been obtained in experimental models with adoptive transfer of ex vivo-expanded regulatory T cells (Treg) specific for donor antigens. Preclinical data have shown that Treg specific for indirectly presented alloantigens (indirect Treg) are mandatory for long-term tolerance. However, the ex vivo expansion of indirect Treg faces limitations,related essentially to the source of autologous antigen-presenting cells (APCs) used to stimulate T cells in vitro. B cells are (i) potent regulatory cells and (ii) APCs able to establish a privileged crosstalk with CD4+ T cells. However, the use of B cells as APCs is made problematic due to their inability to internalize and present non-cognate antigens. We have developed a novel nanobiotechnology-based approach to turn autologous polyclonal B cells into potent stimulators of antigen-specific T reg.Synthetic particulate antigens (SPAg) were generated by immobilizing (i) monoclonal antibodies directed against a framework region of B cell receptor (BCR) kappa-light chains and (ii) model antigens on fluorescent nanospheres of 400 nm in diameter.SPAg behaved like genuine particulate antigens when incubated in vitro with polyclonal murine B cells. SPAg bound to surface BCR of any kappa-positive B cells, triggered activation signal and were internalized in late endosomal compartment of B cells. SPAgloaded B cells induced activation and proliferation of antigen-specific T cells. This approach was transposable to humans’ cells. Importantly, regulatory properties could be conferred toSPAg-loaded B cells by CpG stimulation. SPAg-loaded regulatory B cells prevented proliferation of effector CD4+ T cells and induced proliferation of antigen-specific Treg in vitro.Autologous polyclonal B cells loaded with SPAg appear as an innovative platform to expand Treg ex vivo. This approach may improve the efficiency and costs of current procedure

Les médecines non conventionnelles (enquête sur leur définition et appropriation par 25 professionnels de santé de la presqu'ile guérandaise en 2009)

Après une tentative de définition des médecines non conventionnelles (MNC), une enquête menée sur le territoire rural de la presqu'ile de Guérande interview 25 professionnels de santé sur leur ressenti concernant les pratiques de MNC de leurs patients. Médecins et infirmiers reconnaissent le développement actuel des MNC, et leur recours en cas de défaillance avec la médecine académique (échec de traitement, toxicité médecine d'organe très technique). Mais les MNC sont également utilisées d'emblée ou en complément, offrant aux patients une autre façon de se soigner dans un contexte où se développe la recherche du bien-être et de nouvelles attentes sociales. Les professionnels de santé se sont montrés dans l'ensemble très ouverts à ces pratiques dès lors qu'elles rentrent dans un parcours de soins coordonnés, reconnaissant qu'elles remplissent des fonctions complémentaires à la médecine académique. Une difficulté apparaît pour les médecins généralistes concernant leurs indications dans un contexte d'absence de formations universitaires et de manque de consensus des recommandations officielles.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Vuë de la Ville de Nismes du côté de la Tour-magne / J. P. Ant. Sicard delin. ; Claude Lucas sculp.

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Data collection and analysis of usages from connected objects: some lessons

The emergence of widely available connected devices is perceived as the promise of new added-value services. Companies can now gather, often in real time, huge amounts of data about their customers’ habits. Seemingly, all they have to do is to mine these raw data in order to discover the profiles of their users and their needs. Stemming from an industrial experience, this paper, however, shows that things are not that simple. It appears that, even in an exploratory data mining phase, the usual data cleaning and preprocessing steps are a long shot from being adequate. The rapid deployment of connected devices indeed introduces its own series of problems. The paper shares the pitfalls encountered in a project aiming at enhancing the cooking habits and presents some hard learnt lessons of general import

Alloimmune-induced intragraft lymphoid neogenesis promotes B-cell tolerance breakdown that accelerates chronic rejection

International audiencePURPOSE OF REVIEW: Antibody-mediated rejection (AMR) has emerged as a leading cause of allograft loss in solid organ transplantation. A better understanding of AMR immunopathology is a prerequisite to improve its management. RECENT FINDINGS: The prevalent dogma considers that AMR is the consequence of a thymo-dependent B-cell response against donor-specific polymorphic antigens (mainly mismatched human leukocyte antigen molecules).Nevertheless, antibodies directed against nonpolymorphic antigens expressed by the graft are also generated during chronic rejection and can contribute to allograft destruction. This implies that a breakdown of self-tolerance occurs during chronic rejection. Accumulating evidence suggests that this event occurs inside the ectopic 'tertiary' lymphoid tissue that develops within rejected allografts.Thus, AMR should be viewed as a complex interplay between allo- and autoimmune humoral responses. SUMMARY: The interplay between allo- and autoimmune humoral responses in chronic rejection highlights several unmet medical issues like better diagnosis tools are needed to screen recipients for nonhuman leukocyte antigen alloantibodies and autoantibodies, therapeutic strategies shall aim at blocking the response against alloantigens but also the breakdown of self-tolerance that occurs within tertiary lymphoid tissue