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International audience; BACKGROUND AND PURPOSE: Incubation of craving, the progressive increase in drug seeking over the first weeks of abstinence, is associated with temporal changes during abstinence in the activity of several structures involved in drug-seeking behavior. Decrease of dopamine (DA) release and decrease in DA neurons’ activity (hypodopaminergic state) have been reported in the ventral tegmental area (VTA) during cocaine abstinence but the mechanisms underlying these neuroadaptations are not well understood. Here, we investigated the potential involvement of a VTA inhibiting circuit (basolateral amygdala (BLA)-ventral pallidum (VP) pathway) in the hypodopaminergic state associated with abstinence from chronic cocaine. EXPERIMENTAL APPROACH: In a model of cocaine self-administration, we performed in vivo electrophysiological recordings of DA VTA neurons and BLA neurons from anesthetized rats during early and protracted abstinence and evaluated the involvement of the BLA-VP pathway using a pharmacological approach. KEY RESULTS: We found significant decreases in VTA DA population activity and significant increases in BLA activity after protracted but not after short-term abstinence from chronic cocaine. The decrease in VTA DA activity was restored by pharmacological inhibition of the activity of either the BLA or the VP, suggesting that these regions exert a negative influence on DA activity. CONCLUSION AND IMPLICATIONS: Our study sheds new lights on neuroadaptations occurring during incubation of craving leading to relapse. In particular, we describe the involvement of the BLA-VP pathway in cocaine-induced decreases of DA activity in the VTA. This study adds important information about the specific brain network dysfunctions underlying hypodopaminergic activity during abstinence.

Multiple sclerosis is an autoimmune disease of the central nervous system. Yet, the autoimmune targets are still undefined. The extracellular e1 sequence of KCNJ10, the inwardly rectifying potassium channel 4.1, has been subject to fierce debate for its role as a candidate autoantigen in multiple sclerosis. Inwardly rectifying potassium channel 4.1 is expressed in the central nervous system but also in peripheral tissues, raising concerns about the central nervous system-specificity of such autoreactivity. Immunization of C57Bl6/J female mice with the e1 peptide (amino acids 83–120 of Kir4.1) induced anti-e1 immunoglobulin G- and T-cell responses and promoted demyelinating encephalomyelitis with B cell central nervous system enrichment in leptomeninges and T cells/macrophages in central nervous system parenchyma from forebrain to spinal cord, mostly in the white matter. Within our cohort of multiple sclerosis patients (n = 252), 6% exhibited high anti-e1 immunoglobulin G levels in serum as compared to 0.7% in the control cohort (n = 127; P = 0.015). Immunolabelling of inwardly rectifying potassium channel 4.1-expressing white matter glia with the anti-e1 serum from immunized mice increased during murine autoimmune neuroinflammation and in multiple sclerosis white matter as compared with controls. Strikingly, the mouse and human anti-e1 sera labelled astrocytoma cells when N-glycosylation was blocked with tunicamycin. Western blot confirmed that neuroinflammation induces Kir4.1 expression, including its shorter aglycosylated form in murine experimental autoencephalomyelitis and multiple sclerosis. In addition, recognition of inwardly rectifying potassium channel 4.1 using mouse anti-e1 serum in Western blot experiments under unreduced conditions or in cells transfected with the N-glycosylation defective N104Q mutant as compared to the wild type further suggests that autoantibodies target an e1 conformational epitope in its aglycosylated form. These data highlight the e1 sequence of inwardly rectifying potassium channel 4.1 as a valid central nervous system autoantigen with a disease/tissue-specific post-translational antigen modification as potential contributor to autoimmunity in some multiple sclerosis patients.

Background and ObjectivesOcrelizumab (OCR), a humanized anti-CD20 monoclonal antibody, is highly efficient in patients with relapsing-remitting multiple sclerosis (RR-MS). We assessed early cellular immune profiles and their association with disease activity at treatment start and under therapy, which may provide new clues on the mechanisms of action of OCR and on the disease pathophysiology.MethodsA first group of 42 patients with an early RR-MS, never exposed to disease-modifying therapy, was included in 11 centers participating to an ancillary study of the ENSEMBLE trial (NCT03085810) to evaluate the effectiveness and safety of OCR. The phenotypic immune profile was comprehensively assessed by multiparametric spectral flow cytometry at baseline and after 24 and 48 weeks of OCR treatment on cryopreserved peripheral blood mononuclear cells and analyzed in relation to disease clinical activity. A second group of 13 untreated patients with RR-MS was included for comparative analysis of peripheral blood and CSF. The transcriptomic profile was assessed by single-cell qPCRs of 96 genes of immunologic interest.ResultsUsing an unbiased analysis, we found that OCR as an effect on 4 clusters of CD4+T cells: one corresponding to naive CD4+T cells was increased, the other clusters corresponded to effector memory (EM) CD4+CCR6−T cells expressing homing and migration markers, 2 of them also expressing CCR5 and were decreased by the treatment. Of interest, one CD8+T-cell cluster was decreased by OCR corresponding to EM CCR5-expressing T cells with high expression of the brain homing markers CD49d and CD11a and correlated with the time elapsed since the last relapse. These EM CD8+CCR5+T cells were enriched in the CSF of patients with RR-MS and corresponded to activated and cytotoxic cells.DiscussionOur study provides novel insights into the mode of action of anti-CD20, pointing toward the role of EM T cells, particularly a subset of CD8 T cells expressing CCR5.

International audience; Multiple sclerosis is a chronic and inflammatory disease of the central nervous system. Although this disease is widely studied, many of the precise mechanisms involved are still not well known. Numerous studies currently focusing on multiple sclerosis highlight the involvement of many major immune cell subsets, such as CD4+ T cells, CD8+ T cells and more recently B cells. However, our vision of its pathology has remained too broad to allow the proper use of targeted therapeutics. This past decade, new technologies have emerged, enabling deeper research into the different cell subsets at the single-cell level both in the periphery and in the central nervous system. These technologies could allow us to identify new cell populations involved in the disease process and new therapeutic targets. In this review, we briefly introduce the major single-cell technologies currently used in studies before diving into the major findings from the multiple sclerosis research from the past 5 years. We focus on results that were obtained using single-cell technologies to study immune cells and cells from the central nervous system.

International audience; Rationale: In rodents, environmental enrichment (EE) produces both preventive and curative effects on drug addiction, and this effect is believed to depend at least in part on EE's actions on the stress system.Objectives: This study investigated whether exposure to EE during abstinence reduces methamphetamine seeking after extended self-administration. In addition, we investigated whether these effects are associated with alterations in the levels of glucocorticoid receptors (GR) in the brain and whether administration of GR antagonists blocks methamphetamine relapse.Methods: We allowed rats to self-administer methamphetamine for twenty 14-h sessions. After 3 weeks of abstinence either in standard (SE) or EE conditions, we measured methamphetamine seeking in a single 3-h session. Then, we used western blot techniques to measure GR levels in several brain areas. Finally, in an independent group of rats, after methamphetamine self-administration and abstinence in SE, we administered the GR antagonist mifepristone, and we investigated methamphetamine seeking.Results: Exposure to EE reduced methamphetamine seeking and reversed methamphetamine-induced increases in GR levels in the ventral and dorsal hippocampus. In addition, EE decreased GR levels in the amygdala in drug-naive animals, but this effect was prevented by previous exposure to methamphetamine. Administration of mifepristone significantly decreased methamphetamine seeking.Conclusions: The anti-craving effects of EE are paralleled by restoration of methamphetamine-induced dysregulation of GR in the hippocampus. These results provide support for the hypothesis that the effect of EE on methamphetamine relapse is at least in part mediated by EE's action on the brain stress system.

International audience; Several lines of evidence support a key role for CD8+ T cells in central nervous system tissue damage of patients with multiple sclerosis. However, the precise phenotype of the circulating CD8+ T cells that may be recruited from the peripheral blood to invade the CNS remains largely undefined to date. It has been suggested that IL-17 secreting CD8 (Tc17) T cells may be involved, and in humans these cells are characterized by the expression of CD161. We focused our study on a unique and recently described subset of CD8 T cells characterized by an intermediate expression of CD161 as its role in neuroinflammation has not been investigated to date. The frequency, phenotype, and function of CD8+ T cells with an intermediate CD161 expression level were characterized ex-vivo, in vitro, and in situ using RNAseq, RT-PCR, flow cytometry, TCR sequencing, and immunohistofluorescence of cells derived from healthy volunteers (n = 61), MS subjects (n = 90), as well as inflammatory (n = 15) and non-inflammatory controls (n = 6). We report here that CD8+CD161int T cells present characteristics of effector cells, up-regulate cell-adhesion molecules and have an increased ability to cross the blood-brain barrier and to secrete IL-17, IFNγ, GM-CSF, and IL-22. We further demonstrate that these cells are recruited and enriched in the CNS of MS subjects where they produce IL-17. In the peripheral blood, RNAseq, RT-PCR, high-throughput TCR repertoire analyses, and flow cytometry confirmed an increased effector and transmigration pattern of these cells in MS patients, with the presence of supernumerary clones compared to healthy controls. Our data demonstrate that intermediate levels of CD161 expression identifies activated and effector CD8+ T cells with pathogenic properties that are recruited to MS lesions. This suggests that CD161 may represent a biomarker and a valid target for the treatment of neuroinflammation.

International audience; A recent pre-clinical study has shown that brain-penetrating statins can reduce risks of relapse to cocaine and nicotine addiction in rats. Based on this information, we conducted a randomized, double-blind, placebo-controlled, proof-of-concept trial to assess the efficacy of simvastatin in smoking cessation. After informed consent, 118 participants received behavioral cessation support and were randomly assigned to a 3-month treatment with simvastatin or placebo. The primary outcome was biochemically verified abstinence or smoking reduction at 3-month post-target quit date (TQD). Secondary outcomes were abstinence during weeks 9-12 post-TQD, prolonged abstinence or reduction at months 6 and 12 post-TQD, safety and craving assessed at each visit during the 3-month period of treatment. Simvastatin treatment was not associated with higher 3-month abstinence or smoking reduction compared to placebo. There was no significant difference in any of the secondary outcomes. Simvastatin was well tolerated. Over 3 and 9 months follow-up period, 78% simvastatin and 69% placebo participants were retained in the study. At 6 and 12 months, smoking remained significantly reduced from baseline in both groups. Our results demonstrate that a 3-month simvastatin treatment (40 mg/day), added to individual behavioral cessation support, does not improve significantly smoking cessation compared to placebo in humans. According to the World Health Organization, smoking is the largest preventable cause of disease and death in the world 1. Although the prevalence of everyday tobacco use has dropped in most nations since 1990, the total number of smokers has increased 2. In 2015, 6.4 million deaths worldwide were attributable to smoking, representing a 4.7% increase in smoking-attributable deaths since 2005. This number is likely to reach 8 to 10 millions a year by 2030 1,2. The benefits of smoking cessation have been clearly proven in terms of morbidity and mortality for different diseases related to tobacco, especially for lung cancer 3,4. Although over 70% of smokers want to quit, less than 5% of quit attempts are successful annually 5. Currently, there are only 3 first-line approved medications in the USA and Europe for smoking-cessation: nicotine replacement therapy (NRT), sustained release bupropion, and varenicline, which are widely recommended in many national guidelines. Nevertheless, the therapeutic effectiveness of NRT is relatively modest, bupropion is not widely used because of its safety profile and varenicline's use is limited because of fear of potential cardio-vascular or neuropsychiatric adverse effects 6,7. Therefore, the discovery of new medications that could facilitate abstinence and reduce relapse to cigarette use represents a pressing necessity to reduce risks associated with tobacco smoking. We recently reported in rats that brain-penetrating statins-simvastatin and atorvastatin-can reduce risks of relapse to addiction 8. In fact, chronic treatment with low doses of statins daily during a 21-day period of abstinence , significantly reduced cocaine or nicotine seeking compared with placebo without altering seeking for food. Based on this information, we hypothesized that simvastatin could have beneficial effects on smoking cessation in

Renal operationally tolerant patients (TOL) display a defect in B cell differentiation, with a deficiency in plasma cells. Recently described, T follicular helper cells (Tfh) play a critical role in B cell differentiation. We analyzed blood Tfh subsets in TOL and transplanted patients with stable graft function under immunosuppression (STA). We observed a reduced proportion of blood activated and highly functional Tfh subsets in TOL, without affecting Tfh absolute numbers. Functionally, Tfh from TOL displayed a modified gene expression profile, failed to produce IL-21 and were unable to induce IgG production by naive B cells. This Tfh defect is linked to a low incidence of post graft de novo DSA (dnDSA) immunization, suggesting that the lack of Tfh in TOL may induce a pro-tolerogenic environment with reduced risk of developing dnDSA. Finally, we showed that elevated Tfh in STA precedes the occurrence of dnDSA during an alloresponse. These data provide new insights into the mechanisms of antibody response in operational tolerance. Disrupted homeostasis and impaired Tfh function in TOL could lead to a reduced risk of developing dnDSA and suggest a predictive role of blood Tfh on the occurrence of dnDSA in transplant recipients. This article is protected by copyright. All rights reserved.

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Mandibular osteoradionecrosis is a severe side effect of radiotherapy after the treatment of squamous cell carcinomas of the upper aerodigestive tract. As an alternative to its treatment by micro-anastomosed free-flaps, preclinical tissular engineering studies have been developed. Total bone marrow (TBM) associated with biphasic calcium phosphate (BCP) significantly enhanced bone formation in irradiated bone. One mechanism, explaining how bone marrow cells can help regenerate tissues like this, is the paracrine effect. The bone marrow cell extract (BMCE) makes use of this paracrine mechanism by keeping only the soluble factors such as growth factors and cytokines. It has provided significant results in repairing various tissues, but has not yet been studied in irradiated bone reconstruction. The purpose of this study was to evaluate the effect of BMCE via an intraosseous or intravenous delivery, with a calcium phosphate scaffold, in irradiated bone reconstruction. Twenty rats were irradiated on their hind limbs with a single 80-Gy dose. Three weeks later, surgery was performed to create osseous defects. The intraosseous group (n = 12) studied the effect of BMCE in situ, with six combinations (empty defect, BCP, TBM, BCP-TBM, lysate only, BCP-lysate). After four different combinations of implantation (empty defect, BCP, TBM, BCP-TBM), the intravenous group (n = 8) received four intravenous injections of BMCE for 2 weeks. Five weeks after implantation, samples were explanted for histological and scanning electron microscopy analysis. Lysate immunogenicity was studied with various mixed lymphocyte reactions. Intravenous injections of BMCE led to a significant new bone formation compared to the intraosseous group. The BCP-TBM mixture remained the most effective in the intraosseous group. However, intravenous injections were more effective, with TBM placed in the defect, with or without biomaterials. Histologically, highly cellularized bone marrow was observed in the defects after intravenous injections, and not after an in situ use of the lysate. The mixed lymphocyte reactions did not show any proliferation after 3, 5, or 7 days of lysate incubation with lymphocytes from another species. This study evaluated the role of BMCE in irradiated bone reconstruction. There were significant results arguing in favor of BMCE intravenous injections. This could open new perspectives to irradiated bone reconstruction.

Introduction Le rejet medie par les anticorps (AMR) est une cause majeure de perte d’organe en transplantation. Pourtant, certains patients conservent une bonne fonction du greffon au long cours, malgre la presence d’anticorps specifiques du donneur (DSA) dans leur circulation. L’identification des parametres associes a la pathogenicite des DSA est donc aussi importante que la detection de leur presence. Des etudes experimentales recentes ont montre que la teneur en sucre, en particulier l’etat de sialylation du fragment Fc des IgG, est variable. Cela pourrait modifier la capacite des IgG a se lier au recepteur C1q et au recepteur Fc, modulant ainsi les fonctions effectrices des IgG. Dans cette etude, le statut de sialylation des DSA a ete analyse et sa relation avec la physiopathologie de l’AMR evaluee. Methodes Parmi les 938 greffes renaux ayant beneficie d’une biopsie du greffon entre 2004 et 2012 au CHU de Lyon, 69 remplissaient les criteres diagnostiques d’AMR. Les serums collectes au moment de la biopsie ont ete testes pour la presence de DSA par luminex. Le niveau de sialylation des DSA presents dans chaque serum a ete determine par chromatographie avec l’agglutinine de Sambucus nigra. Resultats obtenus ou attendus Tous les patients avaient des niveaux de sialylation des IgG seriques remarquablement similaires (∼ 2 %). Cependant, le statut de sialylation des DSA etait tres variable (mediane = 9 % ; range = 0–100 %), permettant de repartir les patients en deux groupes : DSA fortement sialyles : n = 44 (64 %) et faiblement sialyles : n = 25 (36 %). Les deux groupes ne differaient ni par l’intensite des lesions de rejet (C4d, ptc et g ; p > 0,05), ni par les taux de survie du greffon (Log rank test ; p = 0,99). Ces resultats cliniques ont ete confirmes in vitro dans les tests de cytotoxicite dependante du complement et de l’ADCC ( Fig. 1 ). Conclusion Le statut de sialylation des DSA est tres variable mais ne correle pas avec leur pathogenicite.

International audience; Whereas a B cell-transcriptional profile has been recorded for operationally tolerant kidney graft patients, the role that B cells have in this tolerance has not been reported. In this study, we analyzed the role of B cells from operationally tolerant patients, healthy volunteers, and kidney transplant recipients with stable graft function on T cell suppression. Proliferation, apoptosis, and type I proinflammatory cytokine production by effector CD4 + CD25 2 T cells were measured after anti-CD3/anti-CD28 stimulation with or without autologous B cells. We report that B cells inhibit CD4 + CD25 2 effector T cell response in a dose-dependent manner. This effect required B cells to interact with T-cell targets and was achieved through a granzyme B (GzmB)-dependent pathway. Tolerant recipients harbored a higher number of B cells expressing GzmB and displaying a plasma cell phenotype. Finally, GzmB + B-cell number was dependent on IL-21 production , and B cells from tolerant recipients but not from other patients positively regulated both the number of IL-21 + T cells and IL-21 production, suggesting a feedback loop in tolerant recipients that increases excessive B cell activation and allows regulation to take place. These data provide insights into the characterization of B cell-mediated immunoregulation in clinical tolerance and show a potential regulatory effect of B cells on effector T cells in blood from patients with operationally tolerant kidney grafts.

Several lines of evidence support a key role for CD8

International audience

Summary A small number of patients do not reject their graft after weaning from immunosuppressive treatment. Here, we analyze the studies carried out to try to understand the mechanisms involved in this operational transplant tolerance and evaluate the hypotheses proffered on these potential mechanisms.

Background DSA are associated with reduced long-term transplant function and increased prevalence of chronic rejection in some patients, whereas others do not: our goal was to determine whether the sialylation of IgG and DSA could help to explain in these last cases their “non-aggressive” and/or “protective” biological activity. Methods The sialylation level of total IgG in blood from two groups of kidney-transplant patients with de novo DSA, one with an AMR (DSA + AMR + ), and the other without were studied. Results In the DSA + AMR − patients total IgG were more sialylated at time of transplant, and at the first detection of DSA, class I DSA were 2.6-fold more sialylated (mean 9.943 ± 1.801 versus 3.898 ± 2.475, p = 0.058); DSA + AMR + patients exhibited higher levels of class II DSA. Conclusions In our study, higher levels of sialylated IgG are detectable on day of transplant in patients who do not develop AMR, they have higher sialylated class I DSA at the initial detection of DSA, whereas class II DSA are significantly higher in patients who develop AMR. This is the first report suggesting that transplant outcome, and particularly AMR, is associated with levels of sialylated IgG antibodies. Our data suggest that DSA are functionally heterogeneous and that further studies with an enlarged cohort may improve our understanding of their clinical impact.

Summary Despite their utility, immunosuppressive treatments have numerous side effects, including infectious complications, malignancies and metabolic disorders, all of which contribute to long-term graft loss. In addition to the development of new pharmaceutical products with reduced toxicity and more comfortable modes of administration, tailoring immunosuppression according to the immune status of each patient would represent a significant breakthrough. Gene expression profiling has been shown to be a clinically relevant monitoring tool. In this paper, we have assessed the overall long-term kidney transplant outcome and attempted to identify operationally tolerant-like patients among recipients with stable clinical status at least 5 years post-transplantation. We thus measured a combination of noninvasive blood biomarkers of operational tolerance in a cohort of 144 stable patients and showed that only 3.5% exhibited a gene expression profile of operational tolerance, suggesting that such a profile can be detected under immunosuppressive therapy but that its frequency is low in kidney transplant recipients when compared with liver transplant recipients. We suggest that a rational approach to patient selection, based on a combination of clinical and biological characteristics, may help to provide a safer method for identification of patients potentially suitable for immunosuppressive drug weaning procedures.

Chronic active antibody-mediated rejection is a form of late rejection with a poor prognosis. To identify specific markers of this, we analyzed several microarray studies in the literature and performed mRNA profiling of 65 biopsies and 165 blood samples of a large cohort of renal transplant patients with precisely characterized pathologies. Immunoproteasome beta subunit 10 was found to be specifically increased in the graft and blood samples during chronic active antibody-mediated rejection and was also significantly increased in rat cardiac allografts undergoing acute rejection as well as chronic active antibody-mediated rejection. This syndrome is characterized by chronic transplant vasculopathy associated with diffuse C4d staining and circulating donor-specific antibodies. Using this animal model, we found that administration of the proteasome inhibitor, Bortezomib, delayed acute rejection and attenuated the humoral response in both the acute phase and established state of this syndrome in a dose-dependent manner. Following treatment with this reagent, donor-specific antibodies and C4d deposition were reduced. These studies highlight the role of the proteasome in chronic rejection and identify this molecule as a marker of this syndrome.

International audience; The role of regulatory T-cells (Tregs) is crucial to maintain immune homoeostasis by controlling peripheral tolerance. A better understanding in the molecular mechanisms involved in the biology of these Tregs could improve their expansion and selection to treat immune-related diseases, achieve immunosuppression-free organ transplantation and to specifically target them in cancer. We reported on the overexpression of tribbles-1 (TRIB1) in Tregs compared with their counterpart naive T-cells and that TRIB1 interacts with the master molecule of Tregs, forkhead box P3 (FOXP3), a transcription factor essential for Treg suppressive activity. We demonstrated that these two molecules interact together in the nucleus of Tregs and TRIB1 overexpression is associated with a decrease in their proliferative capacities. Since TRIB1 was reported to be overexpressed in the blood of renal transplanted patients with chronic antibody-mediated rejection (CAMR), altogether, these results suggest TRIB1 could be linked to the decrease proportion of Tregs in patients exhibiting CAMR and a key player in Tregs through its FOXP3 interaction. In addition, yeast two-hybrid screening experiments highlighted that TRIB1 potentially interacts with molecules playing roles in intracellular events following T-cell activation and particularly cluster of differentiation (CD)4+ T-cells. This suggests still non explored potential links between TRIB1 in Tregs. Our goal is thus to decipher the role of TRIB1 in the Treg biology, notably in pathways known to involved its partner and main transcriptional factor of Tregs, FOXP3 and to determine the role of TRIB1 in immune pathologies.

International audience; Besides the neurofibrillary tangles and amyloid plaques, an inflammatory process is involved at central and peripheral levels in Alzheimer's disease (AD). We aimed to determine whether peripheral inflammatory parameter levels, in plasma and in peripheral blood mononuclear cells (PBMCs), could be correlated with the cognitive status at the time of AD diagnosis. Patients were included at diagnosis with MMSE score between 16 and 25 and were naive of symptomatic treatment for AD. C-reactive protein >10 mg/L and any acute or chronic inflammation were considered as exclusion criteria. Cognitive assessment also included the ADAScog scale. Plasma interleukins (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and the chemokine ligand 5 (CCL5) were measured using Luminex(®) X-MAP(®) technology. A subgroup of patients also underwent measures of these parameters in extracellular and intracellular compartments of PBMCs (ancillary study). One hundred and nine patients were included; mean age 79.4 ± 6.8 years with 37 patients in the ancillary study. The mean values of IL-1β, TNF-α, IL-6 and CCL5 values were 1.49, 7.18, 3.09 and 69,615.81 pg/mL, respectively. No correlation between plasma cytokines or chemokine levels and cognitive scores was found. In PBMCs, the levels of cytokines were detectable but did not either show any correlation with cognitive scores. Our data indicate that at diagnosis, peripheral levels of cytokines and CCL5 display low values without any correlation with the cognitive status. Further results of our study will show if these circulating markers are related to the progression of AD.

Background The factors contributing to the development and severity of obsessive-compulsive spectrum disorders such as obsessive-compulsive disorder, Tourette’s syndrome, pathological gambling, and addictions remain poorly understood, limiting the development of therapeutic and preventive strategies. Recent evidence indicates that impulse-control deficits may contribute to the severity of compulsivity in several of these disorders. This suggests that impulsivity may be a transnosological endophenotype of vulnerability to compulsivity. However, the precise nature of the link between impulsivity and compulsivity in anxiety-related compulsive disorders remains unknown. Methods We investigated the relationship between impulsivity and the development of a compulsive behavior in rats, which captures the hallmarks of compulsivity as defined in the DSM-IV—namely, that it is maladaptive, excessive, repetitive, and anxiolytic. Results We demonstrate that a high-impulsivity trait, as measured in the five-choice serial reaction time task, predicts an increased propensity to develop compulsivity as measured in a schedule-induced polydipsia procedure. Trait impulsivity and compulsivity were nonlinearly related. This impulsivity–compulsivity relationship was lost after the development of compulsivity or under chronic treatment with atomoxetine, a noradrenergic reuptake inhibitor used to treat attention-deficit/hyperactivity disorder. Atomoxetine treatment both decreased impulsivity and prevented the development of compulsivity in high-impulsive animals. Conclusions These observations provide insight into the reciprocal influence of impulsivity and compulsivity in compulsive disorders and suggest that atomoxetine may be a useful treatment for patients suffering from obsessive-compulsive spectrum disorders with high impulsivity.

This review describes the key role of the serine-threonine kinase like protein Tribbles-1 in health as well as in diverse human pathologies. Tribbles-1 is a homolog protein of the Drosophila Tribbles. In Drosophila, the Tribbles protein is involved in the cell-cycle progression during mitosis and in mammals initial data showed TRIB1 to be involved in cell proliferation. In mammals, TRIB1 lacks a catalytic domain and thus acts as an adaptor protein by interacting with several partners. The activity of TRIB1 seems to be very specific to the environment and the cells type in which it is expressed, and a role for this molecule has been mainly described in several pathological states including various cancers such as acute myeloid leukemia and ovarian cancer. Further evidence has also linked TRIB1 to the control of plasmalipid homeostasis thus indicating the role of this molecule as a risk factor for myocardial infarction. Finally, TRIB1 is shown to be up-regulated during inflammatory events such as chronic inflammation of atherosclerotic arteries or chronic antibody-mediated rejection of transplanted organs. Here we provide a review of the current state of the scientific literature for TRIB1, highlighting its role in diverse pathologies and inflammatory states. A better understanding of the role of this protein as both a target as well as a biological marker in diseases should drive the development of new therapeutic strategies.

Adult neurogenesis occurs in the dentate gyrus of the hippocampus, which is a key structure in learning and memory. It is believed that adult-born neurons exert their unique role in information processing due to their high plasticity during immature stage that renders them malleable in response to environmental demands. Here, we demonstrate that, in rats, there is no critical time window for experience-induced dendritic plasticity of adult-born neurons as spatial learning in the water maze sculpts the dendritic arbor of adult-born neurons even when they are several months of age. By ablating neurogenesis within a specific period of time, we found that learning was disrupted when the delay between ablation and learning was extended to several months. Together, these results show that mature adult-born neurons are still plastic when they are functionally integrated into dentate network. Our results suggest a new perspective with regard to the role of neo-neurons by highlighting that even mature ones can provide an additional source of plasticity to the brain to process memory information.

Animal studies have suggested a potential role for regulatory T cells (Tregs) in allograft tolerance, but these FOXP3+ cells seem to be an inherent component of acute rejection (AR) in human recipients of renal transplants. The balance between regulatory cells and effector/cytotoxic cells may determine graft outcome; this balance has not been described for chronic allograft injury. We investigated the expression of key regulatory, effector, and cytotoxic transcripts (i.e., FOXP3, T-bet, and granzyme B, respectively) in the grafts and peripheral blood of long-term-surviving renal transplant patients. We found that, whereas neither intragraft nor peripheral blood FOXP3 or T-bet mRNA could distinguish between rejection and nonrejection status, granzyme B (GrzB) mRNA could: It was significantly increased in the graft and significantly decreased in the peripheral blood of patients with chronic antibody-mediated rejection (CAMR). Quantifying peripheral blood GrzB mRNA demonstrated potential to aid in the noninvasive diagnosis of CAMR. In summary, these data affirm GrzB as a marker not only for AR but also for CAMR. In addition, we identified several previously unreported clinical or demographic factors influencing regulatory/effector/cytotoxic profiles in the peripheral blood, highlighting the necessity to consider confounding variables when considering the use of potential biomarkers, such as FOXP3, for diagnosis or prognosis in kidney transplantation.

Background. Deciphering the mechanisms of tolerance and chronic rejection (CR) remains a major goal in transplantation. Data in rodents suggest that Toll-like receptors (TLR), regulators of innate immune responses, play a role in determining graft outcome. However, few studies have focused on TLR expression in human kidney transplant recipients. Methods. Here, we analyzed the expression ofTLR4 in peripheral blood mononuclear cells from kidney recipients with contrasted clinical situations: operational tolerance and CR, compared with patients with stable graft function, nontransplant patients with renal failure and healthy volunteers. Results. We report that myeloid differentiation factor 88 and TLR4 are significantly contrasted in the peripheral blood mononuclear cells, and in particular in monocytes, of patients with CR versus operational tolerance. Chronic rejection patients have significantly increased TLR4 and myeloid differentiation factor 88 compared with operationally tolerant patients, who resemble healthy volunteers and nontransplant patients with renal failure. Interestingly, analysis of TLR4 transcripts in graft biopsies from patients with normal histology or CR reflected the blood findings, with a significant increase of TLR4 in CR. Conclusions. These data support a link between TLR4 expression and long-term graft outcome. Moreover, whereas absence of TLR signaling may be a feature of tolerance, increased TLR4 signaling may be implicated in CR.

Diagnosis of the specific cause of late allograft injury is necessary if more personalized and efficient immunosuppressive regimens are to be introduced. This study sought previously unrecognized biomarkers for specific histologic diagnoses of late graft scarring by comparison of gene sets from published microarray studies. Tribbles-1 (TRIB1), a human homolog of Drosophila tribbles, was identified to be a potentially informative biomarker. For testing this, mRNA expression in 76 graft biopsies, 71 blood samples, and 11 urine samples were profiled from independent cohorts of renal transplant patients with different histologic diagnoses recruited at two European centers. TRIB1 but not TRIB2 or TRIB3 was found to be a potential blood and tissue biomarker of chronic antibody-mediated rejection, an active immune-mediated form of chronic allograft failure associated with a poor prognosis. TRIB1 mRNA levels in peripheral blood mononuclear cells discriminated patients with chronic antibody-mediated rejection from those with other types of late allograft injury with high sensitivity and specificity. TRIB1 was also upregulated in a rodent model of chronic cardiac vasculopathy, suggesting that this biomarker may be useful in other solid-organ transplants and across species. It was determined that TRIB1 is expressed primarily by antigen-presenting cells and activated endothelial cells. Overall, these data support the potential use of TRIB1 as a biomarker of chronic antibody-mediated allograft failure.

Several transplant patients maintain stable kidney graft function in the absence of immunosuppression. Here we compared the characteristics of their peripheral B cells to that of others who had stable graft function but were under pharmacologic immunosuppression, to patients with chronic rejection and to healthy volunteers. In drug-free long-term graft function (DF) there was a significant increase in both absolute cell number and frequency of total B cells; particularly activated, memory and early memory B cells. These increased B-cell numbers were associated with a significantly enriched transcriptional B-cell profile. Costimulatory/migratory molecules (B7-2/CD80, CD40, and CD62L) were upregulated in B cells; particularly in memory CD19(+)IgD(-)CD38(+/-)CD27(+) B cells in these patients. Their purified B cells, however, responded normally to a polyclonal stimulation and did not have cytokine polarization. This phenotype was associated with the following specific characteristics which include an inhibitory signal (decreased FcgammaRIIA/FcgammaRIIB ratio); a preventive signal of hyperactive B-cell response (an increase in BANK1, which negatively modulates CD40-mediated AKT activation); an increased number of B cells expressing CD1d and CD5; an increased BAFF-R/BAFF ratio that could explain why these patients have more peripheral B cells; and a specific autoantibody profile. Thus, our findings show that patients with DF have a particular blood B-cell phenotype that may contribute to the maintenance of long-term graft function.