Protection from inflammatory organ damage in a murine model of hemophagocytic lymphohistiocytosis using treatment with IL-18 binding protein

Hemophagocytic lymphohistiocytosis (HLH) is a life threatening condition due to the association of an infectious agent with lymphocyte cytotoxicity defects, either of congenital genetic origin in children or presumably acquired in adults. In HLH patients, an excess of lymphocyte or macrophage cytokines, such as IFN-gamma and TN Fu is present in serum. In animal models of the disease, IFN-gamma and INF-alpha have been shown to play a central pathogenic role. In humans, unusually high concentrations of IL-18, an inducer of IFN-gamma, and INF-alpha have been reported, and are associated with an imbalance between IL-18 and its natural inhibitor IL18 binding protein (IL18BP) resulting in an excess of free IL18 Here we studied whether IL-18B P could reduce disease severity in an animal model of HLH. Mouse cytomegalovirus infection in perforin-1 knock out mice induced a lethal condition similar to human HLH characterized by cytopenia with marked inflammatory lesions in the liver and spleen as well as the presence of hemophagocytosis in bone marrow. IL-18B P treatment decreased hemophagocytosis and reversed liver as well as spleen damage. IL-18BP treatment also reduced both IFN-gamma and TNF-alpha production by CD8+ T and NK cells, as well as Fas ligand expression on NK cell surface. These data suggest that IL-18B P is beneficial in an animal model of HLH and in combination with anti infectious therapy may be a promising strategy to treat HLH patients

Emerging concepts about NAIP/NLIRC4 inflammasomes

Neuronal apoptosis inhibitory protein (NAIP)/NOD-like receptor (NLR) containing a caspase activating and recruitment domain (CARD) 4 (NLRC4) inflammasome complexes are activated in response to proteins from virulent bacteria that reach the cell cytosol. Specific NAIP proteins bind to the agonists and then physically associate with NLRC4 to form an inflammasome complex able to recruit and activate pro-caspase-1. NAIP5 and NAIP6 sense flagellin, component of flagella from motile bacteria, whereas NAIP1 and NAIP2 detect needle and rod components from bacterial type III secretion systems, respectively. Active caspase-1 mediates the maturation and secretion of the pro-inflammatory cytokines, 11,113 and 11,18, and is responsible for the induction of pyroptosis, a pro-inflammatory form of cell death. in addition to these well-known effector mechanisms, novel roles have been described for NAIP/NLRC4 inflammasomes, such as phagosomal maturation, activation of inducible nitric oxide synthase, regulation of autophagy, secretion of inflammatory mediators, antibody production, activation of T cells, among others. These effector mechanisms mediated by NAIP/NLRC4 inflammasomes have been extensively studied in the context of resistance of infections and the potential of their agonists has been exploited in therapeutic strategies to non-infectious pathologies, such as tumor protection. Thus, this review will discuss current knowledge about the activation of NAIP/NLRC4 inflammasomes and their effector mechanisms.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)INCTVUniversidade Federal de São Paulo, Ctr Terapia Celulare & Mol CTC Mol, BR-04044010 São Paulo, SP, BrazilUniversidade Federal de São Paulo, Dept Ciencias Biol, BR-04044010 São Paulo, SP, BrazilUniversidade Federal de São Paulo, Ctr Terapia Celulare & Mol CTC Mol, BR-04044010 São Paulo, SP, BrazilUniversidade Federal de São Paulo, Dept Ciencias Biol, BR-04044010 São Paulo, SP, BrazilFAPESP: 2013/16010-5Web of Scienc

Les lymphocytoses B monoclonale ou MBL (10 ans de suivi au CHU Conception)

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Is R-CHOP Therapy a Lymphoma Growth Factor?

International audienceThis article describes the first reported case of dramatic lymphocytosis flare after initiation of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy for an indolent lymphoma. The study patient exhibited a marginal zone lymphoma with mild nodal involvement but packed infiltration of the bone marrow. After initiation of RCHOP therapy, lymphocyte count increased from 329 to 707 x 10(9)/L at day 7. Patient exhibited grade III infusion-related side effect during rituximab therapy. Lymphocyte flare was not accompanied with other clinical manifestation such as lymph node enlargement. Because patient's bone marrow aspirate showed a packed infiltration, it was hypothesized that lymphocytosis flare was a link to lymphocyte release from bone marrow and lymphocyte demargination. This report highlights the necessity to be vigilant after initiation of RCHOP therapy for lymphoma when pathologist notified a pack infiltration of the bone marrow

Mean Platelet Volume Predicts Vascular Access Events in Hemodialysis Patients

Arteriovenous fistula (AVF) and arteriovenous graft (AVG) is the vascular access (VA) of 78% of hemodialysis patients (HD) in France. VA dysfunction corresponding to either stenosis requiring angioplasty or acute thrombosis is responsible for 30% of hospitalizations. Mean platelet volume (MPV) is a biological marker of cardiovascular events. We studied MPV in a cohort of HD patients as a predictive marker of VA dysfunction. We conducted a prospective monocentric cohort study that included patients with AVF or AVG on chronic HD (n = 153). The primary outcome was the incidence of VA dysfunction regarding MPV value. The median MPV was 10.8 fL (7.8−13.5), and four groups were designed according to MPV quartiles. Fifty-four patients experienced the first event of VA dysfunction. The incidence of VA dysfunction was higher in patients with the highest MPV: 59% (23 events), 34% (14 events), 27% (11 events), and 18% (6 events), respectively, for the fourth, third, second, and first quartiles (p = 0.001). Multivariate analysis confirmed an independent association between MPV and VA dysfunction—OR 1.52 (1.13−2.07), p < 0.001. VA dysfunction is predicted by MPV level. Patients with the highest MPV have the highest risk of VA events

CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine

International audienceKey Points Ara-C is the mainstay of treatment for patients with AML, and life-threatening toxicities are common. We demonstrated that cytidine deaminase downregulation predicts severe/lethal toxicities with cytarabine