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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.

This phase 1b, open-label, dose-escalation study assessed the safety, efficacy, and pharmacokinetics of anti-CD38 monoclonal antibody isatuximab given in 2 schedules (3, 5, or 10 mg/kg every other week [Q2W] or 10 or 20 mg/kg weekly [QW] for 4 weeks and then Q2W thereafter [QW/Q2W]), in combination with lenalidomide 25 mg (days 1-21) and dexamethasone 40 mg (QW), in patients with relapsed/refractory multiple myeloma (RRMM). Patients received 28-day treatment cycles; the primary objective was to determine the maximum tolerated dose (MTD) of isatuximab with lenalidomide and dexamethasone. Fifty-seven patients (median 5 [range 1-12] prior regimens; 83% refractory to previous lenalidomide therapy) were treated. Median duration of dosing was 36.4 weeks; 15 patients remained on treatment at data cutoff. Isatuximab-lenalidomide-dexamethasone was generally well tolerated with only 1 dose-limiting toxicity reported (grade 3 pneumonia at 20 mg/kg QW/Q2W); the MTD was not reached. The most common isatuximab-related adverse events were infusion-associated reactions (IARs) (56%), which were grade 1/2 in 84% of patients who had an IAR and predominantly occurred during the first infusion. In the efficacy-evaluable population, the overall response rate (ORR) was 56% (29/52) and was similar between the 10 mg/kg Q2W and 10 and 20 mg/kg QW/Q2W cohorts. The ORR was 52% in 42 evaluable lenalidomide-refractory patients. Overall median progression-free survival was 8.5 months. Isatuximab exposure increased in a greater than dose-proportional manner; isatuximab and lenalidomide pharmacokinetic parameters appeared independent. These data suggest that isatuximab combined with lenalidomide and dexamethasone is active and tolerated in heavily pretreated patients with RRMM. This trial was registered at www.clinicaltrials.gov as #NCT01749969.

WOS: 000491229800404, [No abstract available]

Introduction In the heart, several transcription factors (TF) are powerful regulators of cardiac cell fate and organogenesis. Less well studied are the roles of TF in physiological functions. Several studies on animal models have shown that the Iroquois homeobox (Irx) TFs are key patterning and differentiation regulators that confer cell type-specific properties to specialized cardiac lineages. Importantly, studies in mice have shown that IRX5 is expressed very early during cardiogenesis and maintained in adult heart where it regulates ventricular electrophysiological properties, the repolarizing gradient. It has also been shown that IRX5 target-genes regulation occurs through recruitment of histone modifiers. Objective/Method In order to study IRX5 in human, we used cardiomyocytes differentiated from induced pluripotent stem cells (hiPS-CMs) generated from patients carrying loss of function mutations in IRX5 (IRX5Mut) and control individuals. As we detected IRX5 protein as early as in the pluripotent state, we also analyzed cells at hiPS stage in our experiments. High-throughput transcriptomic and epigenetic analyses were performed to obtain a global understanding of IRX5 function. Results The transcriptomic experiments allowed us to determine the entire set of differentially expressed genes in hiPS and hiPS-CMs IRX5Mut cells as compared to control cells. The epigenetic experiments, performed by ChIPseq, suggested that IRX5 binds to already open chromatin, and preferentially, to enhancer rich regions rather than proximal promoters. Combining these high-throughput experiments, we found direct target genes of IRX5 at hiPS-CM stage, and some of them are relevant to cardiac function. Notably, we showed that this TF regulates the expression of several actors of electrical conduction, such as SCN5A, at hiPS-CM stage. Conclusion IRX5 seems to be an important factor for the regulation of human cardiac function, and more specifically of its electrical function.

The paper extends the two‐dimensional bosonization formulas on a Riemann surface to the case with Abelian gauge field. The result is used to bosonize the massless Thirring model and as an alternative route to the chiral bosonization.