Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level

International audience; TNF-related apoptosis-inducing ligand or Apo2L (Apo2L/TRAIL) is a promising anti-cancer drug owing to its ability to trigger apoptosis by binding to TRAIL-R1 or TRAIL-R2, two membrane-bound receptors that are often expressed by tumor cells. TRAIL can also bind non-functional receptors such as TRAIL-R4, but controversies still exist regarding their potential to inhibit TRAIL-induced apoptosis. We show here that TRAIL-R4, expressed either endogenously or ectopically, inhibits TRAIL-induced apoptosis. Interestingly, the combination of chemotherapeutic drugs with TRAIL restores tumor cell sensitivity to apoptosis in TRAIL-R4-expressing cells. This sensitization, which ma…

Circulating levels of 3-hydroxymyristate, a direct quantification of endotoxaemia in noninfected cirrhotic patients

IF 4.5; International audience; Background & AimsThe quantification of lipopolysaccharide (LPS) in biological fluids is challenging. We aimed to measure plasma LPS concentration using a new method of direct quantification of 3‐hydroxymyristate (3‐HM), a lipid component of LPS, and to evaluate correlations between 3‐HM and markers of liver function, endothelial activation, portal hypertension and enterocyte damage.MethodsPlasma from 90 noninfected cirrhotic patients (30 Child‐Pugh [CP]‐A, 30 CP‐B, 30 CP‐C) was prospectively collected. The concentration of 3‐HM was determined by high‐performance liquid chromatography coupled with mass spectrometry.Results3‐HM levels were higher in CP‐C patien…

Biological Description of 109 Cases of Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) from the French Network of BPDCN

Abstract Blastic plasmacytoid dendritic cell neoplasm is a clonal disease derived from precursors of plasmacytoid dendritic cells (pDC). It is a rare neoplasm involving the skin which may or may not be associated from the outset with a leukemic component. The disease invariably progresses to aggressive leukemic dissemination, leading to a differential diagnosis with acute leukemia. In 2004, we set up a French network to recruit biological data at diagnosis. Diagnosis was according to recommendations (Swerdlow et al, 2008), with, in addition, a mandatory panel of pDC markers (Garnache-Ottou et al, 2009) detected by flow cytometry or by immunohistochemistry on infiltrated blood, bone marrow o…

Tips and tricks for flow cytometry-based analysis and counting of microparticles

Submicron-sized extra-cellular vesicles generated by budding from the external cell membranes, microparticles (MPs) are important actors in transfusion as well as in other medical specialties. After briefly positioning their role in the characterization of labile blood products, this technically oriented chapter aims to review practical points that need to be considered when trying to use flow cytometry for the analysis, characterization and absolute counting of MP subsets. Subjects of active discussions relative to instrumentation will include the choice of the trigger parameter, possible standardization approaches requiring instrument quality-control, origin and control of non-specific ba…

Altered distribution and function of splenic innate lymphoid cells in adult chronic immune thrombocytopenia

IF 7.607; International audience; Innate lymphoid cells (ILCs) have been characterized as innate immune cells capable to modulate the immune response in the mucosae. Human ILCs have been rarely described in secondary lymphoid organs except in tonsils. Moreover, their function and phenotype in human secondary lymphoid organs during autoimmune diseases have never been studied. We took advantage of splenectomy as a treatment of immune thrombocytopenia (ITP) to describe and compare splenic ILC from 18 ITP patients to 11 controls. We first confirmed that ILC3 represented the most abundant ILC subset in human non-inflamed spleens, accounting for 90% of total ILC, and that they were mostly constit…

Interleukine 22

In vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to SL-401, an interleukin-3 receptor targeted biologic agent.

International audience; Blastic plasmacytoid dendritic cell neoplasm is an aggressive malignancy derived from plasmacytoid dendritic cells. There is currently no accepted standard of care for treating this neoplasm, and therapeutic strategies have never been prospectively evaluated. Since blastic plasmacytoid dendritic cell neoplasm cells express high levels of interleukin-3 receptor α chain (IL3-Rα or CD123), antitumor effects of the interleukin-3 receptor-targeted drug SL-401 against blastic plasmacytoid dendritic cell neoplasm were evaluated in vitro and in vivo. The cytotoxicity of SL-401 was assessed in patient-derived blastic plasmacytoid dendritic cell neoplasm cell lines (CAL-1 and …

Th1 and Th17 lymphocytes expressing CD161 are implicated in giant cell arteritis and polymyalgia rheumatica pathogenesis.

International audience; OBJECTIVE: Giant cell arteritis (GCA) is the most frequently occurring vasculitis in elderly individuals, and its pathogenesis is not fully understood. The objective of this study was to decipher the role of the major CD4+ T cell subsets in GCA and its rheumatologic form, polymyalgia rheumatica (PMR). METHODS: A prospective study of the phenotype and the function of major CD4+ T cell subsets (Th1, Th17, and Treg cells) was performed in 34 untreated patients with GCA or PMR, in comparison with 31 healthy control subjects and with the 27 treated patients who remained after the 7 others withdrew. RESULTS: Compared with control subjects, patients with GCA and patients wi…

LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis

International audience; Blastic plasmacytoid dendritic cell (PDC) neoplasm (BPDCN) is an aggressive hematological malignancy with a poor prognosis that derives from PDCs. No consensus for optimal treatment modalities is available today and the full characterization of this leukemia is still emerging. We identified here a BPDCN-specific transcriptomic profile when compared with those of acute myeloid leukemia and T-acute lymphoblastic leukemia, as well as the transcriptomic signature of primary PDCs. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes. LXR agonist treatment of primary BPDCN …

A new method for the direct quantification of lipopolysaccharide by High Performance Liquid Chromatography coupled with Mass Spectrometry in non-infected cirrhotic patients (The MICROCIR cohort)

IF 13.246; International audience

Preferential splenic CD8+ T-cell activation in rituximab-nonresponder patients with immune thrombocytopenia

The pathogenic role of B cells in immune thrombocytopenia (ITP) has justified the therapeutic use of anti-CD20 antibodies such as rituximab (RTX). However, 60% of ITP patients do not respond to RTX. To decipher the mechanisms implicated in the failure of RTX, and because the spleen plays a well-recognized role in ITP pathogenesis, 12 spleens from ITP patients who had been nonresponders to RTX therapy were compared with 11 spleens from RTX-untreated ITP patients and 9 controls. We here demonstrate that in RTX-nonresponder ITP patients, preferential Th1 and Tc1 T lymphocyte polarizations occur, associated with an increase in splenic effector memory CD8(+) T-cell frequency. Moreover, in the RT…

Donor interleukin-22 and host type I interferon signaling pathway participate in intestinal graft-versus-host disease via STAT1 activation and CXCL10.

Acute graft-versus-host disease (aGVHD) remains a major complication following allogeneic hematopoietic cell transplantation, limiting the success of this therapy. We previously reported that interleukin-22 (IL-22) participates to aGVHD development, but the underlying mechanisms of its contribution remain poorly understood. In this study, we analyzed the mechanism of the pathological function of IL-22 in intestinal aGVHD. Ex-vivo colon culture experiments indicated that IL-22 was able to induce Th1-like inflammation via signal transducer and activator of transcription factor-1 (STAT1) and CXCL10 induction in the presence of type I interferon (IFN). To evaluate a potential synergy between IL…