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Somatic mTOR mutation in clonally expanded T lymphocytes associated with chronic graft versus host disease.

ABSTRACT: Graft versus host disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). Here we report studies of a patient with chronic GvHD (cGvHD) carrying persistent CD4+ T cell clonal expansion harboring somatic mTOR, NFKB2, and TLR2 mutations. In the screening cohort (n = 134), we detect the mTOR P2229R kinase domain mutation in two additional cGvHD patients, but not in healthy or HSCT patients without cGvHD. Functional analyses of the mTOR mutation indicate a gain-of-function alteration and activation of both mTORC1 and mTORC2 signaling pathways, leading to increased cell proliferation and decreased apoptosis. Single-cell RNA sequencing and real-time impedance measurements support increased cytotoxicity of mutated CD4+ T cells. High throughput drug-sensitivity testing suggests that mutations induce resistance to mTOR inhibitors, but increase sensitivity for HSP90 inhibitors. Our findings imply that somatic mutations may contribute to aberrant T cell proliferations and persistent immune activation in cGvHD, thereby paving the way for targeted therapies.

SUBMITTER: Kim D

PROVIDER: S-EPMC7206083 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Somatic Gain-of-Function mTOR mutation in Clonally Expanded T-lymphocytes Associated with Chronic Graft-Versus-Host Disease

Project description:Graft-versus-host-disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). Here we report studies of a patient with chronic GVHD (cGVHD) carrying persistent CD4+ T cell clonal expansion which harbored somatic mTOR, NFKB2, and TLR2 mutations. Functional analysis of the discovered mTOR mutation indicated a gain-of-function alteration and activation of both mTORC1 and mTORC2 signaling pathways leading to increased cell proliferation and decreased apoptosis. Single-cell RNA sequencing and real-time impedance measurements supported increased cytotoxicity of mutated CD4+ T cells. High throughput drug-sensitivity testing suggested mutations induce resistance to mTOR inhibitors but increase sensitivity for HSP90 inhibitors. Our findings suggest that somatic mutations may contribute to aberrant T cell proliferations and participate in the persistent immune activation in cGVHD paving the way for novel targeted therapies.

2020-04-12 | E-MTAB-8911 | biostudies-arrayexpress

Somatic Gain-of-Function mTOR mutation in Clonally Expanded T-lymphocytes Associated with Chronic Graft-Versus-Host Disease

Project description:Somatic Gain-of-Function mTOR mutation in Clonally Expanded T-lymphocytes Associated with Chronic Graft-Versus-Host Disease

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Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis.

Project description:Somatic mutations contribute to tumorigenesis. Although these mutations occur in all proliferating cells, their accumulation under non-malignant conditions, such as in autoimmune disorders, has not been investigated. Here, we show that patients with newly diagnosed rheumatoid arthritis have expanded CD8+ T-cell clones; in 20% (5/25) of patients CD8+ T cells, but not CD4+ T cells, harbour somatic mutations. In healthy controls (n=20), only one mutation is identified in the CD8+ T-cell pool. Mutations exist exclusively in the expanded CD8+ effector-memory subset, persist during follow-up, and are predicted to change protein functions. Some of the mutated genes (SLAMF6, IRF1) have previously been associated with autoimmunity. RNA sequencing of mutation-harbouring cells shows signatures corresponding to cell proliferation. Our data provide evidence of accumulation of somatic mutations in expanded CD8+ T cells, which may have pathogenic significance for RA and other autoimmune diseases.

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Human CD4- invariant NKT lymphocytes regulate graft versus host disease.

Project description:Despite increasing evidence for a protective role of invariant (i) NKT cells in the control of graft-versus-host disease (GVHD), the mechanisms underpinning regulation of the allogeneic immune response in humans are not known. In this study, we evaluated the distinct effects of human in vitro expanded and flow-sorted human CD4+ and CD4- iNKT subsets on human T cell activation in a pre-clinical humanized NSG mouse model of xenogeneic GVHD. We demonstrate that human CD4- but not CD4+ iNKT cells could control xenogeneic GVHD, allowing significantly prolonged overall survival and reduced pathological GVHD scores without impairing human T cell engraftment. Human CD4- iNKT cells reduced the activation of human T cells and their Th1 and Th17 differentiation in vivo. CD4- and CD4+ iNKT cells had distinct effects upon DC maturation and survival. Compared to their CD4+ counterparts, in co-culture experiments in vitro, human CD4- iNKT cells had a higher ability to make contacts and degranulate in the presence of mouse bone marrow-derived DCs, inducing their apoptosis. In vivo we observed that infusion of PBMC and CD4- iNKT cells was associated with decreased numbers of splenic mouse CD11c+ DCs. Similar differential effects of the iNKT cell subsets were observed on the maturation and in the induction of apoptosis of human monocyte-derived dendritic cells in vitro. These results highlight the increased immunosuppressive functions of CD4- versus CD4+ human iNKT cells in the context of alloreactivity, and provide a rationale for CD4- iNKT selective expansion or transfer to prevent GVHD in clinical trials.

| S-EPMC6204997 | biostudies-literature

Biomarkers in chronic graft-versus-host disease.

Project description:Chronic graft-versus-host disease (cGVHD ) is a leading cause of allogeneic hematopoietic stem-cell transplantation-related mortality and morbidity. It is an immune-mediated disorder that can target almost any organ in the body, often with devastating consequences. The immune-suppressive medications currently used to treat it are equally toxic and are often not very effective. At this time, our understanding of its pathophysiology is limited. The discovery of potential biomarkers offers new possibilities in the clinical management of cGVHD. They could potentially be used for diagnosing cGVHD, for predicting or evaluating response to therapy and for unique insights into the pathophysiology underlying the clinical manifestations of cGVHD. Understanding the biological origins of these biomarkers can help us construct a more comprehensive and clinically relevant model for the pathogenesis of this disease. In this article, we review existing evidence for candidate biomarkers that have been identified in the framework of how they may contribute to the pathophysiology of cGVHD. Issues regarding the discovery and application of biomarkers are discussed.

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Updates in chronic graft-versus-host disease.

Project description:Chronic graft-versus-host disease (GVHD) is the leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. Symptoms and manifestations of chronic GVHD are heterogeneous and pleomorphic, and there are no standard treatments beyond corticosteroids. Therapy is typically prolonged, and chronic GVHD and its treatment are associated with adverse effects that have a significant impact on long-term quality of life and functional status. Several advances have been made over the last 2 decades to define the diagnosis of chronic GVHD as well as its severity and response criteria for clinical trials. Further understanding into the biologic mechanisms of the development of chronic GVHD has led to the investigation of several novel immunomodulatory and targeted therapies. Multi-institutional collaboration and pharmaceutical support in the development of therapies based on sound biologic mechanisms and clinical trials with defined end points and responses have led to several promising agents on the horizon of approval for treatment of chronic GVHD. This article reviews advances in our knowledge of chronic GVHD and its biologic framework to improve approaches to prevention and treatment.

| S-EPMC8791178 | biostudies-literature

A Biomarker Panel for Chronic Graft-versus-Host Disease

Project description:Using a quantitative proteomics approach, we compared pooled plasma samples from 35 patients with cGVHD obtained at a median of 103 days post-HCT and 18 patients without cGVHD obtained at matched timepoints to identify biomarkers for cGVHD.

2016-05-27 | PXD002762 | Pride

Oral Complications of Chronic Graft-Versus-Host Disease.

Project description:The increasing clinical indications for hematopoietic stem cell transplantation (HSCT) and improved clinical care throughout and following HSCT have led to not only long-term survival but also to an increasing incidence and prevalence of graft-versus-host disease (GVHD). Chronic GVHD (cGVHD) affects almost 50% of adult patients post-HSCT, with increasing incidence in pediatric patients as well. Oral cGVHD specifically has a reported prevalence ranging from 45% to 83% in patients who develop cGVHD and is more extensive in adult patients than in children. Oral cGVHD affects patients through clinically significant oral symptoms that may lead to significantly decreased caloric intake, oral infections, and increased health service utilization, and may thus affect overall health and survival. The most commonly used therapy for mucosal involvement of oral cGVHD is topical high-dose and ultra-high potency corticosteroids, and calcineurin inhibitors. This review of oral complications of cGVHD presents the clinical significance of oral cGVHD to HSCT survivors, our current understanding of the pathobiology of oral cGVHD and gaps in this evidence, and the global targeted interdisciplinary clinical research efforts, including the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. Current challenges regarding the management of oral cGVHD and strategies to advance our scientific understanding of this clinically significant chronic oral disease are presented.

| S-EPMC6699578 | biostudies-literature

Project description:Chronic graft-versus-host disease (cGVHD) is a heterogenous syndrome whose symptoms and treatment are often associated with decreases in functional status and quality of life among survivors of transplantation. We explored definitions of cGVHD-related disability and factors associated with disability in cGVHD. We analyzed 371 patients with cGVHD requiring a new systemic therapy with enrollment and 18-month assessments through the Chronic GVHD Consortium, evaluating disability as a composite endpoint including any 1 of 5 impairments previously defined by Fatobene et al [1] (score 2 or 3 keratoconjunctivitis sicca, score 2 or 3 scleroderma, any diagnosis of bronchiolitis obliterans, score 2 or 3 joint/fasciae involvement, or score 3 esophageal stricture requiring dilation). We also evaluated disability, defined as an ≥8-point decline in a human activity profile (HAP) score or a ≥20% decline in Karnofsky Performance Status (KPS) from enrollment to 18 months. At enrollment, 47% of patients had at least 1 of the 5 Flowers disability features, with 50% of this group acquiring additional impairments at 18 months. Of the 197 patients (53%) with no Flowers disability at enrollment, 50% progressed with disability features at 18 months. We found that any progressive Flowers impairment was associated with a decline in HAP/KPS as well as with increased National Institutes of Health severity scores at 18 months. Enrollment mouth scores and patient-reported eye and skin scores were significantly associated with progressive impairment at 18 months. Progressive disability at 18 months did not predict subsequent nonrelapse mortality. Additional studies to define chronic GVHD related-disability and risk factors are needed to develop this important patient-centered outcome.

| S-EPMC7180104 | biostudies-literature

Biomarker Panel for Chronic Graft-Versus-Host Disease.

Project description:PurposeTo identify diagnostic and prognostic markers of chronic graft-versus-host disease (cGVHD), the major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT).Patients and methodsUsing a quantitative proteomics approach, we compared pooled plasma samples obtained at matched time points after HCT (median, 103 days) from 35 patients with cGVHD and 18 without cGVHD (data are available via ProteomeXchange with identifier PXD002762). Of 105 proteins showing at least a 1.25-fold difference in expression, 22 were selected on the basis of involvement in relevant pathways and enzyme-linked immunosorbent assay availability. Chemokine (C-X-C motif) ligand 9 (CXCL9) and suppression of tumorigenicity 2 (ST2) also were measured on the basis of previously determined associations with GVHD. Concentrations of the four lead biomarkers were measured at or after diagnosis in plasma from two independent verification cohorts (n = 391) to determine their association with cGVHD. Their prognostic ability when measured at approximately day +100 after HCT was evaluated in plasma of a second verification cohort (n = 172).ResultsOf 24 proteins measured in the first verification cohort, nine proteins were associated with cGVHD, and only four (ST2, CXCL9, matrix metalloproteinase 3, and osteopontin) were necessary to compose a four-biomarker panel with an area under the receiver operating characteristic curve (AUC) of 0.89 and significant correlation with cGVHD diagnosis, cGVHD severity, and nonrelapse mortality. In a second verification cohort, this panel distinguished patients with cGVHD (AUC, 0.75), and finally, the panel measured at day +100 could predict cGVHD occurring within the next 3 months with an AUC of 0.67 and 0.79 without and with known clinical risk factors, respectively.ConclusionWe conclude that the biomarker panel measured at diagnosis or day +100 after HCT may allow patient stratification according to risk of cGVHD.

| S-EPMC5012688 | biostudies-literature

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