Role of interferon-gamma (IFN-γ) and IFN-γ receptor 1/2 (IFNγR1/2) in regulation of immunity, infection, and cancer development: IFN-γ-dependent or independent pathway

Biomedicine & Pharmacotherapy, Год журнала: 2022, Номер 155, С. 113683 - 113683

Опубликована: Сен. 12, 2022

IFN-γ, a soluble cytokine being produced by T lymphocytes, macrophages, mucosal epithelial cells, or natural killer is able to bind the IFN-γ receptor (IFNγR) and in turn activate Janus kinase (JAK)-signal transducer transcription protein (STAT) pathway induce expression of IFN-γ-stimulated genes. critical for innate adaptive immunity aberrant functions have been associated with different human diseases. However, IFN-γ/IFNγR signaling could be double-edged sword cancer development because tissue microenvironments determine its anti- pro-tumorigenic activities. The IFNγR consists two IFNγR1 IFNγR2 chains, subunits which play roles under certain conditions. This review assessed polymorphisms, progression various diseases an IFN-γ-dependent independent manner. also discussed tumor microenvironment, microbial infection, vital molecules upstream that might regulate expression, drug resistance, druggable strategy, provide evidence further application IFNγR.

Язык: Английский

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Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июнь 9, 2023

Abstract Chimeric antigen receptor T (CAR-T) cell therapy may achieve long-lasting remission in patients with B-cell malignancies not responding to conventional therapies. However, potentially severe and hard-to-manage side effects, including cytokine release syndrome (CRS), neurotoxicity macrophage activation syndrome, the lack of pathophysiological experimental models limit applicability development this form therapy. Here we present a comprehensive humanized mouse model, by which show that IFNγ neutralization clinically approved monoclonal antibody, emapalumab, mitigates toxicity related CAR-T We demonstrate emapalumab reduces pro-inflammatory environment thus allowing control CRS preventing brain damage, characterized multifocal hemorrhages. Importantly, our vitro vivo experiments inhibition does affect ability CD19-targeting (CAR.CD19-T) cells eradicate CD19+ lymphoma cells. Thus, study provides evidence anti-IFNγ treatment might reduce immune adverse effect without compromising therapeutic success rationale for an emapalumab-CAR.CD19-T combination humans.

Язык: Английский

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Targeting inflammasomes and pyroptosis in retinal diseases—molecular mechanisms and future perspectives

Progress in Retinal and Eye Research, Год журнала: 2024, Номер 101, С. 101263 - 101263

Опубликована: Апрель 23, 2024

Retinal diseases encompass various conditions associated with sight-threatening immune responses and are leading causes of blindness worldwide. These include age-related macular degeneration, diabetic retinopathy, glaucoma uveitis. Emerging evidence underscores the vital role innate response in retinal diseases, beyond previously emphasized T-cell-driven processes adaptive system. In particular, pyroptosis, a newly discovered programmed cell death process involving inflammasome formation, has been implicated loss membrane integrity release inflammatory cytokines. Several disease-relevant animal models have provided that formation inflammasomes induction pyroptosis cells contribute to inflammation diseases. this review article, we summarize current knowledge about system We also provide insights into translational targeting approaches, including novel drugs countering improve diagnosis treatment

Язык: Английский

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Inflammation in atherosclerosis: a Big Idea that has underperformed so far

Current Opinion in Lipidology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 23, 2025

Purpose of review For many years, inflammation has been a major concept in basic research on atherosclerosis and the development potential diagnostic tools treatments. The purpose this is to assess performance with an emphasis recent clinical trials. In addition, contemporary literature may help identify new therapeutic targets, particularly context treatment early, rather than end-stage, arterial disease. Recent findings Newly reported trials cast doubt efficacy colchicine, sole anti-inflammatory agent currently approved for use patients atherosclerotic cardiovascular disease (ASCVD). New analyses also challenge hypothesis that residual ASCVD event risk after optimal management lipids, blood pressure, smoking arises primarily from inflammatory risk. Current practice initiate interventions so late course be better explanation. Lipid-lowering therapy early atherosclerosis, possibly combined novel add-on agents specifically accelerate resolution maladaptive inflammation, more fruitful conventional approach testing immunosuppressive strategies end-stage Also discussed ongoing revolution noninvasive technologies image wall. These are changing screening, diagnosis, including reversable Summary burden proof Big Idea value remains responsibility its advocates. This requires convincing trial data but still seems largely unmet. Unfortunately, focus as source distracted us need screen treat earlier.

Язык: Английский

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Emapalumab for the treatment of refractory cytokine release syndrome in pediatric patients

Blood Advances, Год журнала: 2023, Номер 7(18), С. 5603 - 5607

Опубликована: Сен. 18, 2023

Язык: Английский

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Resolvin E1 improves efferocytosis and rescues severe aplastic anemia in mice

Cell Death and Disease, Год журнала: 2024, Номер 15(5)

Опубликована: Май 9, 2024

Severe aplastic anemia (SAA) is a rare, fatal disease characterized by severe cytopenias and loss of hematopoietic stem cells (HSCs). Immune-mediated destruction inflammation are known drivers SAA, however, the underlying mechanisms driving persistent unknown. Current treatments for SAA rely on immunosuppressive therapies or HSC transplantation, these not always effective. Using an established mouse model we observed significant increase in apoptotic within bone marrow (BM) impaired efferocytosis mice, relative to radiation controls. Single-cell transcriptomic analysis revealed heterogeneity among BM monocytes unique populations emerged during increased inflammatory signatures significantly expression Sirpa Cd47. CD47, "don't eat me" signal, was both live cells, concurrent with markedly signal regulatory protein alpha (SIRPα) monocytes. Functionally, SIRPα blockade improved cell clearance reduced accumulation CD47-positive cells. Lipidomic reduction precursors specialized pro-resolving lipid mediators (SPMs) prostaglandins indicative resolution. Specifically, 18-HEPE, precursor E-series resolvins, SAA-induced mice Treatment Resolvin E1 (RvE1) efferocytic function, cellularity, platelet output, survival. Our data suggest that resolution contributes progression demonstrate SPMs, such as RvE1, offer new and/or complementary do immune suppression.

Язык: Английский

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TCRαβ/CD19 depleted HSCT from an HLA-haploidentical relative to treat children with different nonmalignant disorders

Blood Advances, Год журнала: 2021, Номер 6(1), С. 281 - 292

Опубликована: Окт. 1, 2021

Several nonmalignant disorders (NMDs), either inherited or acquired, can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). Between January 2012 and April 2020, 70 consecutive children affected primary immunodeficiencies, inherited/acquired bone marrow failure syndromes, red blood disorders, metabolic diseases, lacking a fully matched donor requiring urgent underwent TCRαβ/CD19-depleted haploidentical HSCT from an HLA-partially relative as part of prospective study. The median age at transplant was 3.5 years (range 0.3-16.1); the time diagnosis to 10.5 months (2.7 for SCID patients). Primary engraftment obtained in 51 patients, while 19 2 patients experienced secondary graft (GF), overall incidence this complication being 30.4%. Most GFs were observed with disease risk (eg, aplastic anemia, thalassemia). All but 5 experiencing GF successfully retransplanted. Six died infectious complications (4 had active/recent infections HSCT), cumulative transplant-related mortality (TRM) 8.5%. Cumulative grade 1-2 acute GVHD 14.4% (no patient developed 3-4 GVHD). Only one mild chronic GVHD. With follow-up years, 5-year probability disease-free survival 91.4% 86.8%, respectively. In conclusion, is confirmed effective treatment NMDs. Prompt availability, low GVHD, TRM make strategy attractive option NMDs patients. study registered ClinicalTrial.gov NCT01810120.

Язык: Английский

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Targeting interleukin-6 as a treatment approach for peritoneal carcinomatosis

Journal of Translational Medicine, Год журнала: 2024, Номер 22(1)

Опубликована: Апрель 30, 2024

Abstract Peritoneal carcinomatosis (PC) is a complex manifestation of abdominal cancers, with poor prognosis and limited treatment options. Recent work identifying high concentrations the cytokine interleukin-6 (IL-6) its soluble receptor (sIL-6-Rα) in peritoneal cavity patients PC has highlighted this pathway as an emerging potential therapeutic target. This review article provides comprehensive overview current understanding role IL-6 development progression PC. We discuss mechansims by which may contribute to tumor dissemination, mesothelial adhesion invasion, stromal invasion proliferation, immune response modulation. Finally, we prospects for targeting PC, focusing on common sites origin, including ovarian, gastric, pancreatic, colorectal appendiceal cancer, mesothelioma.

Язык: Английский

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Role of Hematopoietic Cell Transplantation in Pediatric and Adult Hemophagocytic Lymphohistiocytosis—Remaining Unknowns and Challenges

Hematology/Oncology Clinics of North America, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

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Association of zinc level with DNA methylation and its consequences: A systematic review

Heliyon, Год журнала: 2022, Номер 8(10), С. e10815 - e10815

Опубликована: Сен. 28, 2022

DNA methylation is an effective epigenetic process that frequently linked to changes in gene expression. Zinc a vital micronutrient plays crucial role methylation. Therefore, abnormal zinc levels may cause aberrant and other diseases.To investigate the influence of on gene-specific global humans rodents, their tissues cells.Systematic literature searches were conducted using Medline, Scopus, Google Scholar, Web Science databases. Studies met inclusion criteria published English language included. Data including first author, sample size, subjects, targeted genes, tissue types or cells analysed, level, molecular techniques, outcomes, consequences extracted.From total 2360 articles screened by title abstract, 15 criteria. Qualitative analysis indicates there are associations between deficiency hypomethylation hypermethylation rodents. did not LINE-1 humans. Depending cell type, could have positive negative effect As predicted, general, expression was elevated corresponding protein also upregulated. However, some studies showed led reduced no alteration mRNA levels.Our study shows links greater significance be achieved if more than one independent investigator analyses same set genes type. gene-cell animal-specific investigations recommended reduce variability allow comparisons across studies.

Язык: Английский

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