Real-time glioblastoma tumor microenvironment assessment by SpiderMass for improved patient management.

Glioblastoma is a highly heterogeneous and infiltrative form of brain cancer associated with a poor outcome and limited therapeutic effectiveness. The extent of the surgery is related to survival. Reaching an accurate diagnosis and prognosis assessment by the time of the initial surgery is therefore paramount in the management of glioblastoma.

Cytotoxic innate intraepithelial lymphocytes control early stages of infection.

Background: Intraepithelial lymphocytes (IELs) are the first immune cells to contact and fight intestinal pathogens such as , a widespread parasite which infects the gut epithelium. IFN-γ producing CD4 T IELs provide an efficient and a long-term protection against cryptosporidiosis while intraepithelial type 1 innate lymphoid cells limits pathogen spreading during early stages of infection in immunodeficient individuals. Yet, the role of T-cell like innate IELs, the most frequent subset of innate lymphocytes in the gut, remains unknown.

Oncogenetic landscape of lymphomagenesis in coeliac disease.

Objective: Enteropathy-associated T-cell lymphoma (EATL) is a rare but severe complication of coeliac disease (CeD), often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCDII). Knowledge on underlying oncogenic mechanisms remains scarce. Here, we analysed and compared the mutational landscape of RCDII and EATL in order to identify genetic drivers of CeD-associated lymphomagenesis.

Severe SARS-CoV-2 patients develop a higher specific T-cell response.

Objectives: Assessment of the adaptive immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for studying long-term immunity and vaccine strategies. We quantified IFNγ-secreting T cells reactive against the main viral SARS-CoV-2 antigens using a standardised enzyme-linked immunospot assay (ELISpot).

Methods: Overlapping peptide pools built from the sequences of M, N and S viral proteins and a mix (MNS) were used as antigens.

NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study.

Objectives: Primary GI T-cell lymphoproliferative diseases (T-LPD) are heterogeneous entities, which raise difficult diagnosis and therapeutic challenges. We have recently provided evidences that lymphomas complicating coeliac disease (CD) arise from innate-like lymphocytes, which may carry NK receptors (NKRs).

Design: NKRs expression was compared by flow cytometry in intraepithelial lymphocytes (IEL) from CD, type I or type II refractory CD (RCD).

A locus at 7p14.3 predisposes to refractory celiac disease progression from celiac disease.

Background: Approximately 5% of patients with celiac disease (CeD) do not respond to a gluten-free diet and progress to refractory celiac disease (RCD), a severe progression that is characterized by infiltration of intraepithelial T lymphocytes. Patients with RCD type II (RCDII) show clonal expansions of intraepithelial T lymphocytes that result in a poor prognosis and a high mortality rate through development of aggressive enteropathy-associated T-cell lymphoma. It is not known whether genetic variations play a role in severe progression of CeD to RCDII.

Discovery and characterization of a novel humanized anti-IL-15 antibody and its relevance for the treatment of refractory celiac disease and eosinophilic esophagitis.

Interleukin-15 (IL-15) is a critical regulator of immune responses, especially at mucosal interfaces within the gastro-intestinal tract. Here, we describe the discovery and characterization of a humanized antibody to IL-15. Data from its epitope and mode of action, cell biology and primate pharmacology, as well as translational studies in human samples and in vivo proof-of-concept experiments in mouse models demonstrate the therapeutic potential of this new antibody targeting IL-15 for refractory celiac disease and eosinophilic esophagitis.

Interleukin-15-Dependent T-Cell-like Innate Intraepithelial Lymphocytes Develop in the Intestine and Transform into Lymphomas in Celiac Disease.

The nature of gut intraepithelial lymphocytes (IELs) lacking antigen receptors remains controversial. Herein we showed that, in humans and in mice, innate intestinal IELs expressing intracellular CD3 (iCD3(+)) differentiate along an Id2 transcription factor (TF)-independent pathway in response to TF NOTCH1, interleukin-15 (IL-15), and Granzyme B signals. In NOTCH1-activated human hematopoietic precursors, IL-15 induced Granzyme B, which cleaved NOTCH1 into a peptide lacking transcriptional activity.

Designing 3D Mesenchymal Stem Cell Sheets Merging Magnetic and Fluorescent Features: When Cell Sheet Technology Meets Image-Guided Cell Therapy.

Cell sheet technology opens new perspectives in tissue regeneration therapy by providing readily implantable, scaffold-free 3D tissue constructs. Many studies have focused on the therapeutic effects of cell sheet implantation while relatively little attention has concerned the fate of the implanted cells in vivo. The aim of the present study was to track longitudinally the cells implanted in the cell sheets in vivo in target tissues.

Gastrointestinal Disorder Associated with Olmesartan Mimics Autoimmune Enteropathy.

Background And Objectives: Anti-hypertensive treatment with the angiotensin II receptor antagonist olmesartan is a rare cause of severe Sprue-like enteropathy. To substantiate the hypothesis that olmesartan interferes with gut immune homeostasis, clinical, histopathological and immune features were compared in olmesartan-induced-enteropathy (OIE) and in autoimmune enteropathy (AIE).

Methods: Medical files of seven patients with OIE and 4 patients with AIE enrolled during the same period were retrospectively reviewed.

The role of animal models in unravelling therapeutic targets in coeliac disease.

Coeliac disease is a complex small intestinal enteropathy that develops consequently to a breach of tolerance to gliadin, a storage protein abundantly found in cereals such as wheat, rye and barley. The understanding of the mechanisms underlying the development of coeliac disease in HLA-DQ2 and HLA-DQ8 genetically susceptible individuals has greatly improved during the last decades but so far did not allow to develop curative therapeutics, leaving a long-life gluten free diet as the only treatment option for the patients. In order to bring new therapeutic targets to light and to test the safety and efficacy of putative drugs, animal models recapitulating features of the disease are needed.

Interleukin-15, a master piece in the immunological jigsaw of celiac disease.

Background: The immune response causing celiac disease (CD) depends on the activation of intestinal CD4+ T cells by gluten-derived peptides presented by HLA-DQ2 or HLA-DQ8 molecules, the main genetic risk factor. However, additional factors are necessary to impair immune tolerance to dietary gluten, to stimulate intraepithelial lymphocytes (IEL) and to induce intestinal damage.

Key Messages: Current data point to a central role of interleukin-15 (IL-15).

Small intestinal CD4+ T-cell lymphoma is a heterogenous entity with common pathology features.

Background & Aims: Little is known about intestinal CD4+ T-cell lymphoma; this rare malignancy is misdiagnosed frequently. We evaluated diagnostic criteria and factors that might affect its development and outcome.

Methods: In a retrospective analysis, we analyzed medical records and intestinal specimens from 10 patients diagnosed with intestinal CD4+ T-cell lymphoma among 115 consecutive patients examined for severe enteropathy with villous atrophy.

Enteropathy associated T cell lymphoma in celiac disease: a large retrospective study.

Introduction: Prognosis of enteropathy-associated T cell lymphoma is poor but predictors of survival remain ill-defined. How clinical presentation, pathological features and therapies influence outcome was evaluated in 37 thoroughly characterized patients with celiac disease and T-cell lymphoma.

Patients And Methods: Medical files were studied retrospectively.

Large granular lymphocytic leukemia: a treatable form of refractory celiac disease.

Large granular lymphocyte leukemia (LGL) is characterized by clonal expansion of CD3+ T cells or CD3(-) natural killer cells and frequently is associated with autoimmune diseases. We describe 2 patients with celiac disease who no longer responded to gluten-free diets after they developed T-cell LGL, with intestinal localization of malignant lymphocytes. Flow cytometry phenotyping of isolated intestinal intraepithelial and lamina propria cells eliminated type II refractory celiac disease, identifying large-sized CD8(+)CD57(+) T cells.

Refractory celiac disease: from bench to bedside.

Refractory celiac disease is defined by the persistence of symptoms of malnutrition and intestinal villous atrophy for more than 6-12 months despite strict gluten-free diet in celiac patients. Diagnosis of this rare condition is made after excluding other causes of chronic small intestinal inflammation and villous atrophy and inadvertent intake of gluten. Over the past 15 years, multidisciplinary approaches have been developed to assess the mechanism of resistance to the diet, and two distinct entities have been delineated.

Celiac disease: an immunological jigsaw.

Celiac disease (CD) is a chronic enteropathy induced by dietary gluten in genetically predisposed people. The keystone of CD pathogenesis is an adaptive immune response orchestrated by the interplay between gluten and MHC class II HLA-DQ2 and DQ8 molecules. Yet, other factors that impair immunoregulatory mechanisms and/or activate the large population of intestinal intraepithelial lymphocytes (IEL) are indispensable for driving tissue damage.