A GMP-Compliant Procedure for the Generation of Gene-Modified T cells.

The field of Adoptive Cell Therapy (ACT) has been revolutionized by the development of genetically modified cells, specifically Chimeric Antigen Receptor (CAR)-T cells. These modified cells have shown remarkable clinical responses in patients with hematologic malignancies. However, the high cost of producing these therapies and conducting extensive quality control assessments has limited their accessibility to a broader range of patients.

Study protocol: Phase I/II trial of induced HLA-G regulatory T cells in patients undergoing allogeneic hematopoietic cell transplantation from an HLA-matched sibling donor.

Regulatory T-cell (Treg) immunotherapy has emerged as a promising and highly effective strategy to combat graft-versus-host disease (GvHD) after allogeneic hematopoietic cell transplantation (allo-HCT). Both naturally occurring Treg and induced Treg populations have been successfully evaluated in trials illustrating the feasibility, safety, and efficacy required for clinical translation. Using a non-mobilized leukapheresis, we have developed a good manufacturing practice (GMP)-compatible induced Treg product, termed iG-Tregs, that is enriched in cells expressing the potent immunosuppressive human leucocyte antigen-G molecule (HLA-G).

The regenerating family member 3 β instigates IL-17A-mediated neutrophil recruitment downstream of NOD1/2 signalling for controlling colonisation resistance independently of microbiota community structure.

Objective: Loss of the Crohn's disease predisposing gene results in an intestinal microenvironment conducive for colonisation by attaching-and-effacing enteropathogens. However, it remains elusive whether it relies on the intracellular recruitment of the serine-threonine kinase RIPK2 by NOD2, a step that is required for its activation of the transcription factor NF-κB.

Design: Colonisation resistance was evaluated in wild type and mutant mice, as well as in ex-germ-free (ex-GF) mice which were colonised either with faeces from -deficient mice or with bacteria with similar preferences for carbohydrates to those acquired by the pathogen.

Card9 mediates susceptibility to intestinal pathogens through microbiota modulation and control of bacterial virulence.

Objective: In association with innate and adaptive immunity, the microbiota controls the colonisation resistance against intestinal pathogens. Caspase recruitment domain 9 (), a key innate immunity gene, is required to shape a normal gut microbiota. mice are more susceptible to the enteric mouse pathogen that mimics human infections with enteropathogenic and enterohaemorrhagic .

Epigenetic and Transcriptional Regulation of IRAK-M Expression in Macrophages.

During macrophage activation, expression of IL-1R-associated kinase (IRAK)-M is induced to suppress TLR-mediated responses and is a hallmark of endotoxin tolerance. Endotoxin tolerance requires tight regulation of genes occurring at the transcriptional and epigenetic levels. To identify novel regulators of IRAK-M, we used RAW 264.

The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs.

MicroRNAs regulated by lipopolysaccharide (LPS) target genes that contribute to the inflammatory phenotype. Here, we showed that the protein kinase Akt1, which is activated by LPS, positively regulated miRNAs let-7e and miR-181c but negatively regulated miR-155 and miR-125b. In silico analyses and transfection studies revealed that let-7e repressed Toll-like receptor 4 (TLR4), whereas miR-155 repressed SOCS1, two proteins critical for LPS-driven TLR signaling, which regulate endotoxin sensitivity and tolerance.

Adiponectin promotes endotoxin tolerance in macrophages by inducing IRAK-M expression.

High levels of plasma adiponectin are associated with low levels of inflammatory markers and cardioprotection. The mechanism via which adiponectin exerts its anti-inflammatory effect is yet unknown. In the present study, we demonstrate that globular adiponectin (gAd) induces the expression of the inactive isoform of IL-1R-associated kinases (IRAK), IRAK-M.

Distinct roles of TLR4 and CD14 in LPS-induced inflammatory responses of neonates.

During infections, pathogens bind to toll-like receptor (TLR)4 and CD14 receptors and induce cytokine release, leading to inflammation. Here, we investigated TLR4 and CD14 expression on peripheral blood leukocytes (PBLs) and their roles in lipopolysaccharide (LPS)-induced cytokine and chemokine release. Full-term and preterm neonates and adults were studied.

Vasoactive intestinal peptide suppresses toll-like receptor 4 expression in macrophages via Akt1 reducing their responsiveness to lipopolysaccharide.

Toll-like receptor 4 (TLR4) recognizes and initiates signals from Gram-negative bacterial lipopolysaccharide (LPS) triggering the inflammatory response. Expression levels of TLR4 on macrophages partly regulate the magnitude of the response to LPS. Vasoactive Intestinal Peptide (VIP) is known to block inflammatory responses by inhibiting pro-inflammatory cytokine production from activated macrophages.

Tpl2 and ERK transduce antiproliferative T cell receptor signals and inhibit transformation of chronically stimulated T cells.

The protein kinase encoded by the Tpl2 protooncogene plays an obligatory role in the transduction of Toll-like receptor and death receptor signals in macrophages, B cells, mouse embryo fibroblasts, and epithelial cells in culture and promotes inflammatory responses in animals. To address its role in T cell activation, we crossed the T cell receptor (TCR) transgene 2C, which recognizes class I MHC presented peptides, into the Tpl2(-/-) genetic background. Surprisingly, the TCR2C(tg/tg)/Tpl2(-/-) mice developed T cell lymphomas with a latency of 4-6 months.

Peripheral factors in the metabolic syndrome: the pivotal role of adiponectin.

Several recently published reports, including ours, suggest that adiponectin is a strong proinflammatory agent. Indeed, exposure of human placenta and adipose tissue to adiponectin induces the production of interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor alpha (TNF-alpha), and prostaglandin E2 (PGE2). We have previously shown that adiponectin is a powerful inducer of proinflammatory cytokines production by macrophages.

Adiponectin induces TNF-alpha and IL-6 in macrophages and promotes tolerance to itself and other pro-inflammatory stimuli.

Adiponectin exerts anti-inflammatory effects via macrophages, suppressing the production of pro-inflammatory cytokines in response to bacterial lipopolysaccharide (LPS). Here, we provide experimental evidence that the "anti-inflammatory" effect of adiponectin may be due to an induction of macrophage tolerance: globular adiponectin (gAd) is a powerful inducer of TNF-alpha and IL-6 secretion in primary human peripheral macrophages, in the THP-1 human macrophage cell line, and in primary mouse peritoneal macrophages. Pre-exposure of macrophages to 10 microg/ml gAd rendered them tolerant to further gAd exposure or to other pro-inflammatory stimuli such as TLR3 ligand polyI:C and TLR4 ligand LPS, while pre-exposure to 1 microg/ml of and re-exposure to 10 microg/ml gAd unmasked its pro-inflammatory properties.