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American Journal of Transplantation :... Sep 2023Operational tolerance (OT) after kidney transplantation is defined as stable graft acceptance without the need for immunosuppression therapy. However, it is not clear...
Operational tolerance (OT) after kidney transplantation is defined as stable graft acceptance without the need for immunosuppression therapy. However, it is not clear which cellular and molecular pathways are driving tolerance in these patients. In this first-of-its-kind pilot study, we assessed the immune landscape associated with OT using single-cell analyses. Peripheral mononuclear cells from a kidney transplant recipient with OT (Tol), 2 healthy individuals (HC), and a kidney transplant recipient with normal kidney function on standard-of-care immunosuppression (SOC) were evaluated. The immune landscape of the Tol was drastically different from that of SOC and emerged closer to the profile of HC. TCL1A naive B cells and LSGAL1 regulatory T cells (Tregs) were in higher proportions in Tol. We were unable to identify the Treg subcluster in SOC. The ligand-receptor analysis in HC and Tol identified interactions between B cells, and Tregs that enhance the proliferation and suppressive function of Tregs. SOC reported the highest proportion of activated B cells with more cells in the G2M phase. Our single-cell RNA sequencing study identified the mediators of tolerance; however, it emphasizes the requirement of similar investigations on a larger cohort to reaffirm the role of immune cells in tolerance.
Topics: Humans; Kidney Transplantation; Leukocytes, Mononuclear; Pilot Projects; Graft Rejection; Immune Tolerance; T-Lymphocytes, Regulatory; Sequence Analysis, RNA; Transplantation Tolerance
PubMed: 37201755
DOI: 10.1016/j.ajt.2023.04.035 -
Current Neurology and Neuroscience... Nov 2023Hereditary bleeding disorders may have a wide variety of clinical presentations ranging from mild mucosal and joint bleeding to severe central nervous system (CNS)... (Review)
Review
PURPOSE OF REVIEW
Hereditary bleeding disorders may have a wide variety of clinical presentations ranging from mild mucosal and joint bleeding to severe central nervous system (CNS) bleeding, of which intracranial hemorrhage (ICH) is the most dreaded complication. In this review, we will discuss the pathophysiology of specific hereditary bleeding disorders, namely, hemophilia A, hemophilia B, and von Willebrand disease (vWD); their clinical manifestations with a particular emphasis on neurological complications; a brief overview of management strategies pertaining to neurological complications; and a review of literature guiding treatment strategies.
RECENT FINDINGS
ICH is the most significant cause of morbidity and mortality in patients with hemophilia. Adequate control of bleeding with the administration of specific factors or blood products, identification of risk factors for bleeding, and maintaining optimal coagulant activity are essential for appropriately managing CNS bleeding complications in these patients. The administration of specific recombinant factors is tailored to a patient's pharmacokinetics and steady-state levels. During acute bleeding episodes, initial factor activity should be maintained between 80 and 100%. Availability of monoclonal antibody Emicizumab has revolutionized prophylactic therapies in patients with hemophilia. Management of ICH in patients with vWD involves using plasma-derived factor concentrates, recombinant von Willebrand factor, and supportive antifibrinolytic agents individualized to the type and severity of vWD. Hemophilia and vWD are the most common hereditary bleeding disorders that can predispose patients to life-threatening CNS complications-intracranial bleeds, intraspinal bleeding, and peripheral nerve syndromes. Early care coordination with a hematologist can help develop an effective prophylactic regimen to avoid life-threatening bleeding complications in these patients. Further research is needed to evaluate using emicizumab as an on-demand treatment option for acute bleeding episodes in patients with hemophilia.
Topics: Humans; Hemophilia A; von Willebrand Diseases; Hemorrhage; Intracranial Hemorrhages; Central Nervous System
PubMed: 37864642
DOI: 10.1007/s11910-023-01313-y -
Nature Biomedical Engineering Sep 2023The clinical use of tumour-infiltrating lymphocytes for the treatment of solid tumours is hindered by the need to obtain large and fresh tumour fractions, which is often...
The clinical use of tumour-infiltrating lymphocytes for the treatment of solid tumours is hindered by the need to obtain large and fresh tumour fractions, which is often not feasible in patients with unresectable tumours or recurrent metastases. Here we show that circulating tumour-reactive lymphocytes (cTRLs) can be isolated from peripheral blood at high yield and purity via microfluidic immunomagnetic cell sorting, allowing for comprehensive downstream analyses of these rare cells. We observed that CD103 is strongly expressed by the isolated cTRLs, and that in mice with subcutaneous tumours, tumour-infiltrating lymphocytes isolated from the tumours and rapidly expanded CD8CD103 cTRLs isolated from blood are comparably potent and respond similarly to immune checkpoint blockade. We also show that CD8CD103 cTRLs isolated from the peripheral blood of patients and co-cultured with tumour cells dissociated from their resected tumours resulted in the enrichment of interferon-γ-secreting cell populations with T-cell-receptor clonotypes substantially overlapping those of the patients' tumour-infiltrating lymphocytes. Therapeutically potent cTRLs isolated from peripheral blood may advance the clinical development of adoptive cell therapies.
Topics: Animals; Mice; Microfluidics; CD8-Positive T-Lymphocytes; Neoplasms; Lymphocytes, Tumor-Infiltrating; Interferon-gamma
PubMed: 37037966
DOI: 10.1038/s41551-023-01023-3 -
Advanced Science (Weinheim,... Dec 2023Systemic Lupus Erythematosus (SLE) etiopathogenesis highlights the contributions of overproduction of CD4 T cells and loss of immune tolerance. However, the involvement...
Systemic Lupus Erythematosus (SLE) etiopathogenesis highlights the contributions of overproduction of CD4 T cells and loss of immune tolerance. However, the involvement of CD8 T cells in SLE pathology and disease progression remains unclear. Here, the comprehensive immune cell dysregulation in total 263 clinical peripheral blood samples composed of active SLE (aSLE), remission SLE (rSLE) and healthy controls (HCs) is investigated via mass cytometry, flow cytometry and single-cell RNA sequencing. This is observed that CD8 CD27 CXCR3 T cells are increased in rSLE compare to aSLE. Meanwhile, the effector function of CD8 CD27 CXCR3 T cells are overactive in aSLE compare to HCs and rSLE, and are positively associated with clinical SLE activity. In addition, the response of peripheral blood mononuclear cells (PBMCs) is monitored to interleukin-2 stimulation in aSLE and rSLE to construct dynamic network biomarker (DNB) model. It is demonstrated that DNB score-related parameters can faithfully predict the remission of aSLE and the flares of rSLE. The abundance and functional dysregulation of CD8 CD27 CXCR3 T cells can be potential biomarkers for SLE prognosis and concomitant diagnosis. The DNB score with accurate prediction to SLE disease progression can provide clinical treatment suggestions especially for drug dosage determination.
Topics: Humans; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Leukocytes, Mononuclear; Lupus Erythematosus, Systemic; Biomarkers; Disease Progression; Receptors, CXCR3
PubMed: 37875396
DOI: 10.1002/advs.202300123 -
Cytokine Nov 2023Mycobacterium tuberculosis(MTB) most often infects the lungs and results in pulmonary tuberculosis(TB). MTB-specific memory T cells are able to respond quickly against...
BACKGROUND
Mycobacterium tuberculosis(MTB) most often infects the lungs and results in pulmonary tuberculosis(TB). MTB-specific memory T cells are able to respond quickly against antigens and help reduce the burden of pulmonary bacteria. The characteristics, function and chemotaxis axis of memory T cells in the lung remain unclear. The current study aimed to clarify the classification, function and recruitment of local antigen-specific memory T cells in the lung and the periphery blood of patients with pulmonary TB.
METHODS
A total of 85 patients with active pulmonary TB were included in the study. Bronchoalveolar lavage fluid (BALF) and Peripheral blood were collected for further detection. The cell-surface markers and intracellular staining of memory T cell subtypes were measured by flow cytometry. The level of CXCL9, CXCL10 and CXCL11 in Bronchoalveolar lavage fluid cells and peripheral blood mononuclear cells (PBMC) were measured by Real-time PCR.
RESULTS
The ratio of effective Memory T cells (TEM) were the highest in BALF of patients with pulmonary TB. In patients, CXCR3 and its ligands was increased in memory T cells of BALF compared with PBMC. IFN-γTNF-α effective Memory T cells and central memory T cells from BALF were increased after antigen stimulation. CXCR3 was higher in IFN-γ+ compared with IFN-γ in CD4 TCM and TEM from BALF of patients. Compared with PBMC, the PD-1 levels of terminal effector memory RA+(TEMRA) and TEM cells in CD4 memory T cells of BALF were significantly increased. In addition, PD-1 was increased in IFN-γ compared with IFN-γ in CD4TEM from BALF of patients. There was no difference in Treg ratio between PBMC and BALF of TB patients.
CONCLUSIONS
The CXCL9/CXCL11-CXCR3 axis may participate in the chemotaxis of memory T cells from the peripheral to lung. CD4TEM and TEMRA in BALF may have exhausted, especially the cytokine producing TEM. Our study clarified the characteristics of antigen-specific memory T cells in local lung and may have impact on strategies of therapy and vaccine.
Topics: Humans; Mycobacterium tuberculosis; Memory T Cells; Leukocytes, Mononuclear; Programmed Cell Death 1 Receptor; Tuberculosis, Pulmonary; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; CD4-Positive T-Lymphocytes
PubMed: 37782984
DOI: 10.1016/j.cyto.2023.156374 -
The Journal of Allergy and Clinical... Dec 2023Impaired virus clearance in a subgroup of atopic dermatitis (AD) patients can lead to severe herpes simplex virus (HSV) infections called eczema herpeticum (EH). We...
BACKGROUND
Impaired virus clearance in a subgroup of atopic dermatitis (AD) patients can lead to severe herpes simplex virus (HSV) infections called eczema herpeticum (EH). We recently identified a type 2 skewed viral immune response in EH patients. Clinical data suggest a reduced incidence of EH in AD patients treated with dupilumab, although immunologic investigations of this phenomenon are still lacking.
OBJECTIVE
We examined the impact of dupilumab on the HSV type 1 (HSV-1) specific immune response in AD, focusing on patients with (ADEH) and without (ADEH) a history of EH.
METHODS
Sera and peripheral blood mononuclear cells were collected from ADEH and ADEH patients, a subgroup of whom was receiving dupilumab treatment, and healthy controls. Serum samples were tested for IgE against HSV-1 glycoprotein D (n = 85). Peripheral blood mononuclear cells were stimulated with HSV peptides, and activated CD4 and CD8 cells were characterized by flow cytometry after magnetic enrichment via CD154 or CD137 (n = 60). Cytokine production of HSV-1-reactive T-cell lines (n = 33) and MHC-I tetramer (HSV-1-UL25) CD8 T cells was investigated by bead assay and intracellular cytokine staining (n = 21).
RESULTS
We confirmed that HSV-1-specific IgE is elevated in ADEH patients. During dupilumab treatment, the IgE levels were significantly decreased, reaching levels of healthy controls. HSV-1-specific T1 frequencies were elevated in ADEH patients treated with dupilumab compared to dupilumab-negative patients. There were no changes in the frequencies of HSV-1-specific T cells while receiving dupilumab therapy. AD patients receiving dupilumab exhibited elevated IFN-γ and reduced IL-4 production in HSV-1-UL25-epitope-specific T cells compared to dupilumab-negative patients.
CONCLUSION
Dupilumab may improve the HSV-1-specific immune response in AD as a result of an increased type I immune response and a reduction of HSV-1-specific IgE.
Topics: Humans; Herpesvirus 1, Human; Dermatitis, Atopic; Leukocytes, Mononuclear; CD8-Positive T-Lymphocytes; Kaposi Varicelliform Eruption; Cytokines; Immunity; Immunoglobulin E
PubMed: 37660986
DOI: 10.1016/j.jaci.2023.08.024 -
Autoimmunity Dec 2023High-throughput sequencing was used to screen expressing differences of miRNA, lncRNA, and mRNA in CD19+ B peripheral blood samples of newly diagnosed immune...
OBJECTIVE
High-throughput sequencing was used to screen expressing differences of miRNA, lncRNA, and mRNA in CD19+ B peripheral blood samples of newly diagnosed immune thrombocytopenia (ITP) patients and healthy controls. The study aimed to explore the regulatory role of ceRNA network in the pathogenesis of dysfunctional CD19 + B lymphocytes of ITP patients.
METHODS
CD19+ B lymphocytes were isolated from peripheral blood samples of ITP patients and their healthy counterparts. High-throughput sequencing was used to screen for the expression of miRNA, lncRNA, and mRNA of ITP patients and healthy controls, which were analysed by the ceRNA network. Moreover, qPCR was used to verify the differential expression of miRNA, lncRNA, and mRNA in ITP patients and healthy controls. The correlation between differentially expressed miRNA, lncRNA, mRNA, and B lymphocyte subsets was also analysed.
RESULTS
The CD19+ B lymphocytes of 4 newly diagnosed ITP patients and 4 healthy controls were sequenced and analysed. There were 65 differentially expressed lncRNA and 149 mRNA forming a ceRNA network showed that 12 lncRNA and 136 differentially expressed mRNA were closely associated. Similarly, miR-144-3p, miR-374c-3p, and miR-451a were highly expressed in ITP patients, as confirmed by qPCR, which was consistent with the high-throughput sequence results. LOC102724852 and CCL20 were highly expressed in ITP patients, while LOC105378901, LOC112268311, ALAS2, and TBC1D3F were not as compared to healthy controls, which was consistent with the high-throughput sequence results. In addition, the expression of miR-374c-3p, LOC112268311, LOC105378901, and CXCL3 were correlated with the percentage of B lymphocyte subsets.
CONCLUSIONS
The ceRNA network of miRNA, lncRNA, and mRNA in peripheral CD19 + B lymphocytes plays an essential role in the pathogenesis of ITP.
Topics: Humans; Purpura, Thrombocytopenic, Idiopathic; RNA, Long Noncoding; Thrombocytopenia; MicroRNAs; B-Lymphocytes; RNA, Messenger; Antigens, CD19; Gene Regulatory Networks; 5-Aminolevulinate Synthetase
PubMed: 38053370
DOI: 10.1080/08916934.2023.2281225 -
Alzheimer's & Dementia : the Journal of... Dec 2023Fast and minimally invasive approaches for early diagnosis of Alzheimer's disease (AD) are highly anticipated. Evidence of adaptive immune cells responding to cerebral...
INTRODUCTION
Fast and minimally invasive approaches for early diagnosis of Alzheimer's disease (AD) are highly anticipated. Evidence of adaptive immune cells responding to cerebral β-amyloidosis has raised the question of whether immune markers could be used as proxies for β-amyloid accumulation in the brain.
METHODS
Here, we apply multidimensional mass-cytometry combined with unbiased machine-learning techniques to immunophenotype peripheral blood mononuclear cells from a total of 251 participants in cross-sectional and longitudinal studies.
RESULTS
We show that increases in antigen-experienced adaptive immune cells in the blood, particularly CD45RA-reactivated T effector memory (TEMRA) cells, are associated with early accumulation of brain β-amyloid and with changes in plasma AD biomarkers in still cognitively healthy subjects.
DISCUSSION
Our results suggest that preclinical AD pathology is linked to systemic alterations of the adaptive immune system. These immunophenotype changes may help identify and develop novel diagnostic tools for early AD assessment and better understand clinical outcomes.
Topics: Humans; tau Proteins; Cross-Sectional Studies; Leukocytes, Mononuclear; T-Lymphocytes; Amyloid beta-Peptides; Alzheimer Disease; Brain; Biomarkers
PubMed: 37314431
DOI: 10.1002/alz.13136 -
Frontiers in Immunology 2023The search for biomarkers to identify ideal candidates for immune checkpoint inhibitor (ICI) therapy is fundamental. In this study, we analyze peripheral blood...
BACKGROUND
The search for biomarkers to identify ideal candidates for immune checkpoint inhibitor (ICI) therapy is fundamental. In this study, we analyze peripheral blood CD3+HLADR+ cells (activated T-cells) as a novel biomarker for ICI therapy and how its association to certain gut microbiome species can indicate individual treatment outcomes.
METHODS
Flow cytometry analysis of peripheral mononuclear blood cells (PBMCs) was performed on n=70 patients undergoing ICI therapy for solid malignancies to quantify HLA-DR on circulating CD3+ cells. 16s-rRNA sequencing of stool samples was performed on n=37 patients to assess relative abundance of gut microbiota.
RESULTS
Patients with a higher frequency of CD3+HLADR+ cells before treatment initiation showed a significantly reduced tumor response and overall survival (OS), a worst response and experienced less toxicities to ICI therapy. As such, patients with a frequency of CD3+HLADR+ cells above an ideal cut-off value of 18.55% had a median OS of only 132 days compared to 569 days for patients below. Patients with increasing CD3+HLADR+ cell counts during therapy had a significantly improved OS. An immune signature score comprising CD3+HLADR+ cells and the neutrophil-lymphocyte ratio (NLR) was highly significant for predicting OS before and during therapy. When allied to the relative abundance of microbiota from the Burkholderiales order and the species Bacteroides vulgatus, two immune-microbial scores revealed a promising predictive and prognostic power.
CONCLUSION
We identify the frequencies and dynamics of CD3+HLADR+ cells as an easily accessible prognostic marker to predict outcome to ICIs, and how these could be associated with immune modulating microbiome species. Two unprecedented immune-microbial scores comprising CD3+HLADR+, NLR and relative abundance of gut bacteria from the Burkhorderiales order or Bacteroides vulgatus species could accurately predict OS to immune checkpoint blockade.
Topics: Humans; Gastrointestinal Microbiome; Immune Checkpoint Inhibitors; Microbiota; Blood Cells
PubMed: 37705980
DOI: 10.3389/fimmu.2023.1206953 -
Immunology Letters Sep 2023West Syndrome (WS) is an epileptic encephalopathy that typically occurs in infants and is characterized by hypsarrhythmia, infantile spasms, and neurodevelopmental...
BACKGROUND
West Syndrome (WS) is an epileptic encephalopathy that typically occurs in infants and is characterized by hypsarrhythmia, infantile spasms, and neurodevelopmental impairment. Demonstration of autoantibodies and cytokines in some WS patients and favorable response to immunotherapy have implicated inflammation as a putative trigger of epileptiform activity in WS. Our aim was to provide additional support for altered inflammatory responses in WS through peripheral blood immunophenotype analysis.
METHODS
Eight WS cases treated with synacthen and 11 age- and sex-matched healthy volunteers were included. Peripheral blood mononuclear cells (PBMC) were isolated and immunophenotyping was performed in pre-treatment baseline (8 patients) and 3 months post-treatment (6 patients) samples. The analysis included PBMC expressing NFκB transcription and NLRP3 inflammasome factors.
RESULTS
In pre-treatment baseline samples, switched memory B cells (CD19IgDCD27) were significantly reduced, whereas plasma cells (CD19CD38CD138) and cytotoxic T cells (CD3CD8) were significantly increased. Regulatory T and B cell ratios were not significantly altered. Synacthen treatment only marginally reduced helper T cell ratios and did not significantly change other T, B, NK and NKT cell and monocyte ratios.
CONCLUSIONS
Our findings lend further support for the involvement of inflammation-related mechanisms in WS. New-onset WS patients are inclined to display increased plasma cells in the peripheral blood. Synacthen treatment does not show a beneficial effect on most effector acquired and innate immunity subsets.
Topics: Infant; Humans; Spasms, Infantile; B-Lymphocytes; Plasma Cells; Natural Killer T-Cells; Inflammation
PubMed: 37459957
DOI: 10.1016/j.imlet.2023.07.007