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Turkish Journal of Medical Sciences 2023Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting mostly small joints, such as hand and foot joints symmetrically with irreversible joint...
BACKGROUND/AIM
Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting mostly small joints, such as hand and foot joints symmetrically with irreversible joint destruction. In this study, the relationship between CD39 expression and the treatment response of RA patients was examined to investigate its potential as a biomarker that demonstrates treatment response.
MATERIALS AND METHODS
This study included 77 RA patients and 40 healthy controls (HC). The RA patients were divided into 2 groups based on their response to RA treatment, those with a good response to methotrexate (MTX) monotherapy and those with an inadequate response based on the American College of Rheumatology and the European League Against Rheumatism response criteria. Various immunological parameters and Disease Activity Score in 28 Joints (DAS28) were examined between the groups using the Student's t-test.
RESULTS
The monocytic myeloid-derived suppressor cell (M-MDSC) percentage was higher in the RA patient group versus the HC group. The CD39 expression in the T lymphocytes were higher in patients that responded well to the MTX compared to those showing inadequate response. Additionally, s negative correlation was found between the DAS28 and CD39 in the T cells.
CONCLUSION
The results showed that the improvement in treatment response to the therapy in RA patients could be because of the enhancement in the CD39/adenosine (ADO) pathway. Therefore, therapies targeting the CD39/ADO pathway in T cells may improve RA treatments.
Topics: Humans; Arthritis, Rheumatoid; Methotrexate; Female; Male; Apyrase; Middle Aged; Antirheumatic Agents; Adult; Biomarkers; Treatment Outcome; Antigens, CD; Case-Control Studies; Aged; T-Lymphocytes
PubMed: 38813034
DOI: 10.55730/1300-0144.5672 -
Frontiers in Immunology 2024Acute myeloid leukemia (AML) is an aggressive heterogeneous disease characterized by several alterations of the immune system prompting disease progression and treatment...
characterization of acute myeloid leukemia patients undergoing hypomethylating agents and venetoclax regimen reveals a venetoclax-specific effect on non-suppressive regulatory T cells and PD-1TIM3 exhausted CD8 T cells.
Acute myeloid leukemia (AML) is an aggressive heterogeneous disease characterized by several alterations of the immune system prompting disease progression and treatment response. The therapies available for AML can affect lymphocyte function, limiting the efficacy of immunotherapy while hindering leukemia-specific immune reactions. Recently, the treatment based on Venetoclax (VEN), a specific B-cell lymphoma 2 (BCL-2) inhibitor, in combination with hypomethylating agents (HMAs) or low-dose cytarabine, has emerged as a promising clinical strategy in AML. To better understand the immunological effect of VEN treatment, we characterized the phenotype and immune checkpoint (IC) receptors' expression on CD4 and CD8 T cells from AML patients after the first and second cycle of HMA in combination with VEN. HMA and VEN treatment significantly increased the percentage of naïve CD8 T cells and TIM-3 CD4 and CD8 T cells and reduced cytokine-secreting non-suppressive T regulatory cells (Tregs). Of note, a comparison between AML patients treated with HMA only and HMA in combination with VEN revealed the specific contribution of VEN in modulating the immune cell repertoire. Indeed, the reduction of cytokine-secreting non-suppressive Tregs, the increased TIM-3 expression on CD8 T cells, and the reduced co-expression of PD-1 and TIM-3 on both CD4 and CD8 T cells are all VEN-specific. Collectively, our study shed light on immune modulation induced by VEN treatment, providing the rationale for a novel therapeutic combination of VEN and IC inhibitors in AML patients.
Topics: Humans; Leukemia, Myeloid, Acute; Sulfonamides; CD8-Positive T-Lymphocytes; Bridged Bicyclo Compounds, Heterocyclic; Hepatitis A Virus Cellular Receptor 2; Programmed Cell Death 1 Receptor; Middle Aged; Aged; T-Lymphocytes, Regulatory; Female; Male; Antineoplastic Combined Chemotherapy Protocols; Adult; Aged, 80 and over
PubMed: 38812504
DOI: 10.3389/fimmu.2024.1386517 -
Asian Pacific Journal of Cancer... May 2024Deregulation of immune checkpoint is an important point in cancer evolution as well as patients outcome. T-cells is an important arm in immunity against cancer. This...
BACKGROUND
Deregulation of immune checkpoint is an important point in cancer evolution as well as patients outcome. T-cells is an important arm in immunity against cancer. This study aimed to assess CTLA4/LAG3 expression on different T-cell subsets and its effect on disease outcome.
METHODS
This study included 81 newly diagnosed Egyptian adult AML patients. For each one of the patients CTLA4/ LAG3 expression on T-cell subsets was identified by flowcytometry before start of induction chemotherapy.
RESULTS
Total CD3 count in AML patients was lower than control. LAG3 expression were significantly higher in total CD3, T-cell subsets (CD4, CD8) as compared to healthy control. Moreover, co-expression of LAG3/CTLA4 on T-cell subsets were significantly higher in AML as compared to healthy control . NPM-/ FLT3+ was significantly associated with high LAG3 expression in T-cells subsets as compared to other molecular subtypes. Shorter OS, DFS were significantly associated with higher expression of LAG3 on T-cells subsets as compared to patients harbor low expression. COX regression analysis revealed that high expression of CD3/LAG3, CD4/LAG3, CD8/LAG4, CD3/CTLA4/LAG3 were considered a poor prognostic risk factor.
CONCLUSION
High LAG3/CTLA4 expression could predict AML Patients' outcome Conclusion: Our findings indicated that high expression of LAG3/CTL4 on T cells subsets identify a subgroup of AML patients with poor prognosis.
Topics: Humans; Leukemia, Myeloid, Acute; Male; Female; Lymphocyte Activation Gene 3 Protein; Prognosis; CTLA-4 Antigen; Adult; Antigens, CD; Middle Aged; Case-Control Studies; Biomarkers, Tumor; T-Lymphocyte Subsets; Follow-Up Studies; Young Adult; Survival Rate; Adolescent
PubMed: 38809650
DOI: 10.31557/APJCP.2024.25.5.1777 -
ImmunoHorizons May 2024The mammalian Siglec receptor sialoadhesin (Siglec1, CD169) confers innate immunity against the encapsulated pathogen group B Streptococcus (GBS). Newborn lung...
The mammalian Siglec receptor sialoadhesin (Siglec1, CD169) confers innate immunity against the encapsulated pathogen group B Streptococcus (GBS). Newborn lung macrophages have lower expression levels of sialoadhesin at birth compared with the postnatal period, increasing their susceptibility to GBS infection. In this study, we investigate the mechanisms regulating sialoadhesin expression in the newborn mouse lung. In both neonatal and adult mice, GBS lung infection reduced Siglec1 expression, potentially delaying acquisition of immunity in neonates. Suppression of Siglec1 expression required interactions between sialic acid on the GBS capsule and the inhibitory host receptor Siglec-E. The Siglec1 gene contains multiple STAT binding motifs, which could regulate expression of sialoadhesin downstream of innate immune signals. Although GBS infection reduced STAT1 expression in the lungs of wild-type newborn mice, we observed increased numbers of STAT1+ cells in Siglece-/- lungs. To test if innate immune activation could increase sialoadhesin at birth, we first demonstrated that treatment of neonatal lung macrophages ex vivo with inflammatory activators increased sialoadhesin expression. However, overcoming the low sialoadhesin expression at birth using in vivo prenatal exposures or treatments with inflammatory stimuli were not successful. The suppression of sialoadhesin expression by GBS-Siglec-E engagement may therefore contribute to disease pathogenesis in newborns and represent a challenging but potentially appealing therapeutic opportunity to augment immunity at birth.
Topics: Animals; Mice; Streptococcus agalactiae; Animals, Newborn; N-Acetylneuraminic Acid; Sialic Acid Binding Ig-like Lectin 1; Streptococcal Infections; STAT1 Transcription Factor; Mice, Knockout; Immunity, Innate; Mice, Inbred C57BL; Lung; Macrophages, Alveolar; Female; Macrophages; Lectins; Sialic Acid Binding Immunoglobulin-like Lectins; Antigens, CD; Antigens, Differentiation, B-Lymphocyte
PubMed: 38809232
DOI: 10.4049/immunohorizons.2300076 -
Clinical and Translational Science Jun 2024Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. The approved step-up dose regimen of...
Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. The approved step-up dose regimen of 1/2/60/30 mg IV is designed to mitigate cytokine release syndrome (CRS) and maximize efficacy in early cycles. A population pharmacokinetic (popPK) model was developed from 439 patients with relapsed/refractory B-Cell Non-Hodgkin lymphoma receiving Mosun IV monotherapy, including fixed dosing (0.05-2.8 mg IV every 3 weeks (q3w)) and Cycle 1 step-up dosing groups (0.4/1/2.8-1/2/60/30 mg IV q3w). Prior to Mosun treatment, ~50% of patients had residual levels of anti-CD20 drugs (e.g., rituximab or obinutuzumab) from prior treatment. CD20 receptor binding dynamics and rituximab/obinutuzumab PK were incorporated into the model to calculate the Mosun CD20 receptor occupancy percentage (RO%) over time. A two-compartment model with time-dependent clearance (CL) best described the data. The typical patient had an initial CL of 1.08 L/day, transitioning to a steady-state CL of 0.584 L/day. Statistically relevant covariates on PK parameters included body weight, albumin, sex, tumor burden, and baseline anti-CD20 drug concentration; no covariate was found to have a clinically relevant impact on exposure at the approved dose. Mosun CD20 RO% was highly variable, attributed to the large variability in residual baseline anti-CD20 drug concentration (median = 10 μg/mL). The 60 mg loading doses increased Mosun CD20 RO% in Cycle 1, providing efficacious exposures in the presence of the competing anti-CD20 drugs. PopPK model simulations, investigating Mosun dose delays, informed treatment resumption protocols to ensure CRS mitigation.
Topics: Humans; Antigens, CD20; Middle Aged; Male; Aged; Lymphoma, B-Cell; Female; Adult; Antibodies, Bispecific; Antibodies, Monoclonal, Humanized; Aged, 80 and over; Models, Biological; Antineoplastic Agents, Immunological; Young Adult; Dose-Response Relationship, Drug; Drug Administration Schedule; Rituximab
PubMed: 38808543
DOI: 10.1111/cts.13825 -
Frontiers in Immunology 2024The pulmonary endothelium is the primary target of lung ischemia-reperfusion injury leading to primary graft dysfunction after lung transplantation. We hypothesized that...
INTRODUCTION
The pulmonary endothelium is the primary target of lung ischemia-reperfusion injury leading to primary graft dysfunction after lung transplantation. We hypothesized that treating damaged rat lungs by a transient heat stress during ex-vivo lung perfusion (EVLP) to elicit a pulmonary heat shock response could protect the endothelium from severe reperfusion injury.
METHODS
Rat lungs damaged by 1h warm ischemia were reperfused on an EVLP platform for up to 6h at a constant temperature (T°) of 37°C (EVLP group), or following a transient heat stress (HS) at 41.5°C from 1 to 1.5h of EVLP (EVLP group). A group of lungs exposed to 1h EVLP only (pre-heating conditions) was added as control (Baseline group). In a first protocol, we measured lung heat sock protein expression (HSP70, HSP27 and Hsc70) at selected time-points (n=5/group at each time). In a second protocol, we determined (n=5/group) lung weight gain (edema), pulmonary compliance, oxygenation capacity, pulmonary artery pressure (PAP) and vascular resistance (PVR), the expression of PECAM-1 (CD31) and phosphorylation status of Src-kinase and VE-cadherin in lung tissue, as well as the release in perfusate of cytokines (TNFα, IL-1β) and endothelial biomarkers (sPECAM, von Willebrand Factor -vWF-, sE-selectin and sICAM-1). Histological and immunofluorescent studies assessed perivascular edema and formation of 3-nitrotyrosine (a marker of peroxinitrite) in CD31 lung endothelium.
RESULTS
HS induced an early (3h) and persisting expression of HSP70 and HSP27, without influencing Hsc70. Lungs from the EVLP group developed massive edema, low compliance and oxygenation, elevated PAP and PVR, substantial release of TNFα, IL-1β, s-PECAM, vWF, E-selectin and s-ICAM, as well as significant Src-kinase activation, VE-cadherin phosphorylation, endothelial 3-NT formation and reduced CD31 expression. In marked contrast, all these alterations were either abrogated or significantly attenuated by HS treatment.
CONCLUSION
The therapeutic application of a transient heat stress during EVLP of damaged rat lungs reduces endothelial permeability, attenuates pulmonary vasoconstriction, prevents src-kinase activation and VE-cadherin phosphorylation, while reducing endothelial peroxinitrite generation and the release of cytokines and endothelial biomarkers. Collectively, these data demonstrate that therapeutic heat stress may represent a promising strategy to protect the lung endothelium from severe reperfusion injury.
Topics: Animals; Lung; Rats; Heat-Shock Response; Male; Perfusion; Reperfusion Injury; Lung Transplantation; Endothelium, Vascular; Platelet Endothelial Cell Adhesion Molecule-1
PubMed: 38807604
DOI: 10.3389/fimmu.2024.1390026 -
Frontiers in Immunology 2024Leukocyte immunoglobulin (Ig)-like receptors (LILRs) on human chromosome 19q13.4 encode 11 immunoglobulin superfamily receptors, exhibiting genetic diversity within and...
Leukocyte immunoglobulin (Ig)-like receptors (LILRs) on human chromosome 19q13.4 encode 11 immunoglobulin superfamily receptors, exhibiting genetic diversity within and between human populations. Among the genes, the genomic region surrounding and has yet to be fully characterized due to their significant sequence homology, which makes it difficult to differentiate between them. To examine the and genomic region, a tool named JoGo-LILR CN Caller, which can call copy number from short-read whole genome sequencing (srWGS) data, was applied to an extensive international srWGS dataset comprising 2,504 samples. During this process, a previously unreported loss of both and was detected in three samples. Using long-read sequencing of these samples, we have discovered a novel large deletion (33,692 bp) in the and genomic regions in the Japanese population. This deletion spanned three genes, , , and , resulting in exons 12-13 being located immediately downstream of exons 1-12 with the loss of , suggesting the potential expression of a hybrid gene between and (). Transcription and subsequent translation of the hybrid gene were also verified. The hybrid junction was located within the intracellular domain, resulting in an LILRB5 extracellular domain fused to a partial LILRB3 intracellular domain with three immunoreceptor tyrosine-based inhibitory motifs (ITIMs), suggesting that LILRB5-3 acquired a novel signaling function. Further application of the JoGo-LILR tool to srWGS samples suggested the presence of the hybrid gene in the CEU population. Our findings provide insight into the genetic and functional diversity of the LILR family.
Topics: Humans; Receptors, Immunologic; Signal Transduction; Whole Genome Sequencing; DNA Copy Number Variations; Antigens, CD
PubMed: 38807600
DOI: 10.3389/fimmu.2024.1398935 -
Frontiers in Immunology 2024CD4CD25Foxp3 regulatory T cells (Tregs), a vital component of the immune system, are responsible for maintaining immune homeostasis and preventing excessive immune... (Review)
Review
CD4CD25Foxp3 regulatory T cells (Tregs), a vital component of the immune system, are responsible for maintaining immune homeostasis and preventing excessive immune responses. This review explores the signaling pathways of the cytokines that regulate Treg cells, including transforming growth factor beta (TGF-β), interleukin (IL)-2, IL-10, and IL-35, which foster the differentiation and enhance the immunosuppressive capabilities of Tregs. It also examines how, conversely, signals mediated by IL-6 and tumor necrosis factor -alpha (TNF-α) can undermine Treg suppressive functions or even drive their reprogramming into effector T cells. The B7 family comprises indispensable co-stimulators for T cell activation. Among its members, this review focuses on the capacity of CTLA-4 and PD-1 to regulate the differentiation, function, and survival of Tregs. As Tregs play an essential role in maintaining immune homeostasis, their dysfunction contributes to the pathogenesis of autoimmune diseases. This review delves into the potential of employing Treg-based immunotherapy for the treatment of autoimmune diseases, transplant rejection, and cancer. By shedding light on these topics, this article aims to enhance our understanding of the regulation of Tregs by cytokines and their therapeutic potential for various pathological conditions.
Topics: Humans; T-Lymphocytes, Regulatory; Signal Transduction; Animals; Cytokines; CTLA-4 Antigen; Neoplasms; Autoimmune Diseases; Programmed Cell Death 1 Receptor; Immunotherapy
PubMed: 38807592
DOI: 10.3389/fimmu.2024.1387975 -
Scientific Reports May 2024Natural killer (NK) cells are closely associated with malignant tumor progression and metastasis. However, studies on their relevance in colorectal cancer (CRC) are...
Natural killer (NK) cells are closely associated with malignant tumor progression and metastasis. However, studies on their relevance in colorectal cancer (CRC) are limited. We aimed to comprehensively analyze the absolute counts, phenotypes, and function of circulating NK cells in patients with CRC using multiparametric flow cytometry. The distribution of NK cell subsets in the peripheral circulation of patients with CRC was significantly altered relative to the control group. This is shown by the decreased frequency and absolute count of CD56CD16 NK cells with antitumor effects, contrary to the increased frequency of CD56 NK and CD56CD16 NK cells with poor or ineffective antitumor effects. NK cells in patients with CRC were functionally impaired, with decreased intracellular interferon (IFN)-γ secretion and a significantly lower percentage of cell surface granzyme B and perforin expression. In addition, IFN-γ expression decreased significantly with the tumor stage progression. Based on a comprehensive analysis of the absolute counts, phenotypes, and functional markers of NK cells, we found an altered subset distribution and impaired function of circulating NK cells in patients with CRC.
Topics: Humans; Killer Cells, Natural; Colorectal Neoplasms; Male; Female; Middle Aged; Interferon-gamma; Aged; Granzymes; Perforin; CD56 Antigen; Flow Cytometry; Adult
PubMed: 38806640
DOI: 10.1038/s41598-024-63103-x -
Nature Communications May 2024The mechanisms by which the number of memory CD8 T cells is stably maintained remains incompletely understood. It has been postulated that maintaining them requires help...
The mechanisms by which the number of memory CD8 T cells is stably maintained remains incompletely understood. It has been postulated that maintaining them requires help from CD4 T cells, because adoptively transferred memory CD8 T cells persist poorly in MHC class II (MHCII)-deficient mice. Here we show that chronic interferon-γ signals, not CD4 T cell-deficiency, are responsible for their attrition in MHCII-deficient environments. Excess IFN-γ is produced primarily by endogenous colonic CD8 T cells in MHCII-deficient mice. IFN-γ neutralization restores the number of memory CD8 T cells in MHCII-deficient mice, whereas repeated IFN-γ administration or transduction of a gain-of-function STAT1 mutant reduces their number in wild-type mice. CD127 memory cells proliferate actively in response to IFN-γ signals, but are more susceptible to attrition than CD127 terminally differentiated effector memory cells. Furthermore, single-cell RNA-sequencing of memory CD8 T cells reveals proliferating cells that resemble short-lived, terminal effector cells and documents global downregulation of gene signatures of long-lived memory cells in MHCII-deficient environments. We propose that chronic IFN-γ signals deplete memory CD8 T cells by compromising their long-term survival and by diverting self-renewing CD127 cells toward terminal differentiation.
Topics: Animals; CD8-Positive T-Lymphocytes; Interferon-gamma; CD4-Positive T-Lymphocytes; Mice; Immunologic Memory; STAT1 Transcription Factor; Mice, Inbred C57BL; Histocompatibility Antigens Class II; Signal Transduction; Mice, Knockout; Memory T Cells; Interleukin-7 Receptor alpha Subunit; Cell Proliferation; Adoptive Transfer
PubMed: 38806459
DOI: 10.1038/s41467-024-48704-4