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Lung parenchyma-derived IL-6 promotes IL-17A-dependent acute lung injury after allogeneic stem cell transplantation.

ABSTRACT: Idiopathic pneumonia syndrome (IPS) is a relatively common, frequently fatal clinical entity, characterized by noninfectious acute lung inflammation following allogeneic stem cell transplantation (SCT), the mechanisms of which are unclear. In this study, we demonstrate that immune suppression with cyclosporin after SCT limits T-helper cell (Th) 1 differentiation and interferon-γ secretion by donor T cells, which is critical for inhibiting interleukin (IL)-6 generation from lung parenchyma during an alloimmune response. Thereafter, local IL-6 secretion induces donor alloantigen-specific Th17 cells to preferentially expand within the lung, and blockade of IL-17A or transplantation of grafts lacking the IL-17 receptor prevents disease. Studies using IL-6(-/-) recipients or IL-6 blockade demonstrate that IL-6 is the critical driver of donor Th17 differentiation within the lung. Importantly, IL-6 is also dysregulated in patients undergoing clinical SCT and is present at very high levels in the plasma of patients with IPS compared with SCT recipients without complications. Furthermore, at the time of diagnosis, plasma IL-6 levels were higher in a subset of IPS patients who were nonresponsive to steroids and anti-tumor necrosis factor therapy. In sum, pulmonary-derived IL-6 promotes IPS via the induction of Th17 differentiation, and strategies that target these cytokines represent logical therapeutic approaches for IPS.

SUBMITTER: Varelias A

PROVIDER: S-EPMC5457133 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Modulation of Renal Parenchyma in Response to Allogeneic Adipose-Derived Mesenchymal Stem Cells Transplantation in Acute Kidney Injury.

Project description:Background and objectivesIn regenerative medicine, mesenchymal stem cells derived from adipose tissues (Ad-MSCs) are a very attractive target to treat many diseases. In relation to nephrology, the aim of the current study is to investigate the effects of Ad-MSCs for the amelioration of acute kidney injury and to explore the mechanism of renal parenchymal changes in response to allogeneic transplantation of Ad-MSCs.Methods and resultsThe nephrotoxicity was induced by cisplatin (CP) in balb/c mice according to RIFLE Class and AKIN Stage 3. PCR, qRT-PCR and fluorescent labeled cells infusion, histopathology, immunohistochemistry, functional analyses were used for genes and proteins expressions data acquisition respectively. We demonstrated that single intravenous infusion of 2.5×107/kg mAd-MSCs in mice pre-injected with CP recruited to the kidney, restored the renal structure, and function, which resulted in progressive survival of mice. The renal tissue morphology was recovered in terms of diminished necrosis or epithelial cells damage, protein casts formation, infiltration of inflammatory cells, tubular dilatation, and restoration of brush border protein; Megalin and decreased Kim-1 expressions in mAd-MSCs transplanted mice. Significant reduction in serum creatinine with slashed urea and urinary protein levels were observed. Anti-BrdU staining displayed enhanced tubular cells proliferation. Predominantly, downgrade expressions of TNF-α and TGF-β1 were observed post seven days in mAd-MSCs transplanted mice.ConclusionsAd-MSCs exerts pro-proliferative, anti-inflammatory, and anti-fibrotic effects. Ad-MSCs transplantation without any chemical or genetic manipulation can provide the evidence of therapeutic strategy for the origin of regeneration and overall an improved survival of the system in functionally deprived failed kidneys.

| S-EPMC6457705 | biostudies-literature

Gut microbiota injury in allogeneic haematopoietic stem cell transplantation.

Project description:Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered to be the strongest curative immunotherapy for various malignancies (primarily, but not limited to, haematologic malignancies). However, application of allo-HSCT is limited owing to its life-threatening major complications, such as graft-versus-host disease (GVHD), relapse and infections. Recent advances in large-scale DNA sequencing technology have facilitated rapid identification of the microorganisms that make up the microbiota and evaluation of their interactions with host immunity in various diseases, including cancer. This has resulted in renewed interest regarding the role of the intestinal flora in patients with haematopoietic malignancies who have received an allo-HSCT and in whether the microbiota affects clinical outcomes, including GVHD, relapse, infections and transplant-related mortality. In this Review, we discuss the potential role of intestinal microbiota in these major complications after allo-HSCT, summarize clinical trials evaluating the microbiota in patients who have received allo-HSCT and discuss how further studies of the microbiota could inform the development of strategies that improve outcomes of allo-HSCT.

| S-EPMC7485905 | biostudies-literature

IL-2 promotes early Treg reconstitution after allogeneic hematopoietic cell transplantation.

Project description:Graft-versus-host disease (GvHD) remains a major cause of transplant-related mortality. Interleukin-2 (IL-2) plus sirolimus (SIR) synergistically reduces acute GvHD in rodents and promotes regulatory T cells. This phase II trial tested the hypothesis that IL-2 would facilitate STAT5 phosphorylation in donor T cells, expand regulatory T cells, and ameliorate GvHD. Between 16th April 2014 and 19th December 2015, 20 patients received IL-2 (200,000 IU/m2 thrice weekly, days 0 to +90) with SIR (5-14 ng/mL) and tacrolimus (TAC) (3-7 ng/mL) after HLA-matched related or unrelated allogeneic hematopoietic cell transplantation (HCT). The study was designed to capture an increase in regulatory T cells from 16.0% to more than 23.2% at day +30. IL-2/SIR/TAC significantly increased regulatory T cells at day +30 compared to our published data with SIR/TAC (23.8% vs. 16.0%, P=0.0016; 0.052 k/uL vs. 0.037 k/uL, P=0.0163), achieving the primary study end point. However, adding IL-2 to SIR/TAC led to a fall in regulatory T cells by day +90 and did not reduce acute or chronic GvHD. Patients who discontinued IL-2 before day +100 showed a suggested trend toward less grade II-IV acute GvHD (16.7% vs. 50%, P=0.1475). We surmise that the reported accumulation of IL-2 receptors in circulation over time may neutralize IL-2, lead to progressive loss of regulatory T cells, and offset its clinical efficacy. The amount of phospho-STAT3+ CD4+ T cells correlated with donor T-cell activation and acute GvHD incidence despite early T-cell STAT5 phosphorylation by IL-2. Optimizing IL-2 dosing and overcoming cytokine sequestration by soluble IL-2 receptor may sustain lasting regulatory T cells after transplantation. However, an approach to target STAT3 is needed to enhance GvHD prevention. (clinicaltrials.gov identifier: 01927120).

| S-EPMC5477614 | biostudies-literature

Faecal Microbiota Transplantation After Allogeneic Stem Cell Transplantation

Project description:The aim of this study is to assess the Fecal Microbiota Transplantation (FMT) efficacy in the prevention of allogeneic hematopoietic stem cell transplantation (allo-HSCT) complications and particularly Graft versus Host Disease (GvHD). The hypothesis of this study is that allogeneic FMT may improve outcomes of these patients.

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Impact of lung function impairment after allogeneic hematopoietic stem cell transplantation.

Project description:Late-onset noninfectious pulmonary complications (LONIPC) are a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). However, the clinical impact of lung function deterioration itself in long-term adult survivors of HSCT remains to be fully investigated. This retrospective, longitudinal study aimed to investigate pulmonary function following HSCT in terms of its change and the clinical significance of its decline. We examined 167 patients who survived for at least 2 years without relapse. The median follow-up period was 10.3 years. A linear mixed-effects model showed that the slope of pulmonary function tests values, including percent vital capacity (%VC), percent forced expiratory volume in one second (%FEV1), and FEV1/forced VC ratio (FEV1%), decreased over time. The cumulative incidence of newly obstructive and restrictive lung function impairment (LFI) at 10 years was 15.7% and 19.5%, respectively. Restrictive LFI was a significant, independent risk factor for overall survival (hazard ratio 7.11, P = 0.007) and non-relapse mortality (hazard ratio 12.19, P = 0.003). Our data demonstrated that lung function declined over time after HSCT and that the decline itself had a significant impact on survival regardless of LONIPC.

| S-EPMC9389505 | biostudies-literature

First-Onset Herpesviral Infection and Lung Injury in Allogeneic Hematopoietic Cell Transplantation.

Project description:Rationale: "Noninfectious" pulmonary complications are significant causes of morbidity and mortality after allogeneic hematopoietic cell transplant. Early-onset viral reactivations or infections are common after transplant. Whether the first-onset viral infection causes noninfectious pulmonary complications is unknown. Objectives: To determine whether the first-onset viral infection within 100 days after transplant predisposes to development of noninfectious pulmonary complications. Methods: We performed a retrospective review of 738 allogeneic hematopoietic cell transplant patients enrolled from 2005 to 2011. We also established a novel bone marrow transplantation mouse model to test whether herpesviral reactivation after transplant causes organ injury. Measurements and Main Results: First-onset viral infections with human herpesvirus 6 or Epstein-Barr virus within 100 days after transplant increase the risk of developing idiopathic pneumonia syndrome (adjusted hazard ratio [aHR], 5.52; 95% confidence interval [CI], 1.61-18.96; P = 0.007; and aHR, 9.21; 95% CI, 2.63-32.18; P = 0.001, respectively). First infection with human cytomegalovirus increases risk of bronchiolitis obliterans syndrome (aHR, 2.88; 95% CI, 1.50-5.55; P = 0.002) and grade II-IV acute graft-versus-host disease (aHR, 1.59; 95% CI, 1.06-2.39; P = 0.02). Murine roseolovirus, a homolog of human herpesvirus 6, can also be reactivated in the lung and other organs after bone marrow transplantation. Reactivation of murine roseolovirus induced an idiopathic pneumonia syndrome-like phenotype and aggravated acute graft-versus-host disease. Conclusions: First-onset herpesviral infection within 100 days after allogeneic hematopoietic cell transplant increases risk of pulmonary complications. Experimentally reactivating murine roseolovirus causes organ injury similar to phenotypes seen in human transplant recipients.

| S-EPMC6603051 | biostudies-literature

Proteome Profiling in Lung Injury Following Hematopoietic Stem Cell Transplantation

Project description:The goal of this study was to apply protein expression profiling tools in cases with lung injury following HSCT or cellular therapy infusion to identify the proteins and biological processes that differentiate IPS from infectious lung injury in HSCT recipients. We performed comprehensive label-based quantitative protein profiling of BALF in patients undergoing HSCT

2018-10-24 | PXD002437 | Pride

Transplantation of neural stem cells clonally derived from embryonic stem cells promotes recovery after murine spinal cord injury.

Project description:The pathology of spinal cord injury (SCI) makes it appropriate for cell-based therapies. Treatments using neural stem cells (NSCs) in animal models of SCI have shown positive outcomes, although uncertainty remains regarding the optimal cell source. Pluripotent cell sources such as embryonic stem cells (ESCs) provide a limitless supply of therapeutic cells. NSCs derived using embryoid bodies (EB) from ESCs have shown tumorigenic potential. Clonal neurosphere generation is an alternative method to generate safer and more clinically relevant NSCs without the use of an EB stage for use in cell-based therapies. We generated clonally derived definitive NSCs (dNSCs) from ESC. These cells were transplanted into a mouse thoracic SCI model. Embryonic stem cell-derived definitive neural stem cell (ES-dNSC)-transplanted mice were compared with controls using behavioral measures and histopathological analysis of tissue. In addition, the role of remyelination in injury recovery was investigated using transmission electron microscopy. The SCI group that received ES-dNSC transplantation showed significant improvements in locomotor function compared with controls in open field and gait analysis. The cell treatment group had a significant enhancement of spared neural tissue. Immunohistological assessments showed that dNSCs differentiated primarily to oligodendrocytes. These cells were shown to express myelin basic protein, associate with axons, and support nodal architecture as well as display proper compact, multilayer myelination in electron microscopic analysis. This study provides strong evidence that dNSCs clonally derived from pluripotent cells using the default pathway of neuralization improve motor function after SCI and enhance sparing of neural tissue, while remaining safe and clinically relevant.

| S-EPMC4273190 | biostudies-literature

Blockade of Interplay between IL-17A and Endoplasmic Reticulum Stress Attenuates LPS-Induced Lung Injury.

Project description:IL-17 is a cytokine mainly from IL-17-producing T cells, which are one of subsets of CD4+ T cells and play a role in adaptive immune system. Recent studies have demonstrated that IL-17A can act rapidly as an innate immune responder during infection before the onset of its classic adaptive immune response. This role of IL-17A in innate immune response is implicated in lipopolysaccharide (LPS)-induced lung inflammation. Very recently, we have reported that endoplasmic reticulum (ER) stress is involved in LPS-induced lung inflammation in vivo and in vitro. This study aimed to elucidate the role of IL-17A in LPS-induced lung injury, focusing on the link with ER stress. We treated a murine model of LPS-induced lung injury with IL-17A neutralizing antibody and 4-phenylbutyrate (4-PBA), a representative ER stress inhibitor. In addition, we evaluated the effects of IL-17A on ER stress in LPS-stimulated bronchial epithelial cells. Our results showed that inhibition of IL-17A decreased LPS-induced pulmonary neutrophilia, vascular leakage, nuclear translocation of nuclear factor-?B (NF-?B), infiltration of dendritic cells, increased expression of Toll-like receptor 4 (TLR4), activation of NLRP3 inflammasome, and increased ER stress in the lung. 4-PBA or TAK-242, a TLR4 inhibitor attenuated expression of IL-17A thereby improving LPS-induced lung inflammation. Intriguingly, we observed that stimulation with LPS increased expression of IL-17A in airway epithelial cells and co-stimulation with IL-17A further increased ER stress and NF-?B activation. This study indicates that the interrelationship between IL-17A and ER stress plays an important role in LPS-induced injury showing a positive feedback in airway epithelial cells and suggests that targeting their interaction can be a potential therapeutic approach to overcome one of severe refractory pulmonary disorders.

| S-EPMC4615737 | biostudies-literature

Allogeneic hematopoietic stem cell transplantation for treating severe lung involvement in Gaucher disease.

Project description:ObjectiveTo provide strategies for monitoring and treating severe lung involvement in Gaucher disease.Study designWe reviewed the chart of a 5-year-old boy who developed rapidly progressive, severe infiltrative lung involvement of Gaucher disease (GD) and improved after allogeneic hematopoietic stem cell transplant (HSCT), along with other case studies reported before December 2019. He was diagnosed with GD (homozygous mutation at c.1448 T > C, p.L483P), and started receiving enzyme replacement therapy (ERT) at 17 months old. He developed respiratory distress symptoms after 45 months of ERT; chest imaging reported diffuse interstitial infiltration of the bilateral lungs and consolidations at the right lungs. Allogeneic HSCT using cells from a matched unrelated donor was performed four months upon progressive respiratory symptoms.ResultsHis respiratory symptoms subsided in one month; chest imaging improvement, pulmonary function test improvement, and normalized activity of β-glucocerebrosidase were reported in three months.ConclusionThis is the first report of a patient who received early and regular ERT but developed severe infiltrative lung involvement and recovered after allogeneic HSCT. Based on study results, we suggest regular chest imaging, even for asymptomatic patients. For patients with severe lung involvement, rapid deterioration, and unresponsive to higher ERT dosages, allogeneic HSCT should be considered.

| S-EPMC7576510 | biostudies-literature

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