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Frontiers in Immunology 2024Traumatic and thermal injuries result in a state of systemic immune suppression, yet the mechanisms that underlie its development are poorly understood. Released from...
Severe thermal and major traumatic injury results in elevated plasma concentrations of total heme that are associated with poor clinical outcomes and systemic immune suppression.
BACKGROUND
Traumatic and thermal injuries result in a state of systemic immune suppression, yet the mechanisms that underlie its development are poorly understood. Released from injured muscle and lysed red blood cells, heme is a damage associated molecular pattern with potent immune modulatory properties. Here, we measured plasma concentrations of total heme in over 200 traumatic and thermally-injured patients in order to examine its relationship with clinical outcomes and post-injury immune suppression.
METHODS
Blood samples were collected from 98 burns (≥15% total body surface area) and 147 traumatically-injured (injury severity score ≥8) patients across the ultra-early (≤1 hour) and acute (4-72 hours) post-injury settings. Pro-inflammatory cytokine production by lipopolysaccharide (LPS) challenged whole blood leukocytes was studied, and plasma concentrations of total heme, and its scavengers haptoglobin, hemopexin and albumin measured, alongside the expression of heme-oxygenase-1 (HO-1) in peripheral blood mononuclear cells (PBMCs). LPS-induced tumour necrosis factor-alpha (TNF-α) production by THP-1 cells and monocytes following heme treatment was also examined.
RESULTS
Burns and traumatic injury resulted in significantly elevated plasma concentrations of heme, which coincided with reduced levels of hemopexin and albumin, and correlated positively with circulating levels of pro and anti-inflammatory cytokines. PBMCs isolated from trauma patients 4-12 and 48-72 hours post-injury exhibited increased HO-1 gene expression. Non-survivors of burn injury and patients who developed sepsis, presented on day 1 with significantly elevated heme levels, with a difference of 6.5 µM in heme concentrations corresponding to a relative 52% increase in the odds of post-burn mortality. On day 1 post-burn, heme levels were negatively associated with LPS-induced TNF-α and interleukin-6 production by whole blood leukocytes. THP-1 cells and monocytes pre-treated with heme exhibited significantly reduced TNF-α production following LPS stimulation. This impairment was associated with decreased gene transcription, reduced activation of extracellular signal-regulated kinase 1/2 and an impaired glycolytic response.
CONCLUSIONS
Major injury results in elevated plasma concentrations of total heme that may contribute to the development of endotoxin tolerance and increase the risk of poor clinical outcomes. Restoration of the heme scavenging system could be a therapeutic approach by which to improve immune function post-injury.
Topics: Humans; Heme; Burns; Male; Adult; Female; Middle Aged; Cytokines; Wounds and Injuries; Young Adult; Aged; THP-1 Cells; Leukocytes, Mononuclear; Biomarkers; Lipopolysaccharides; Heme Oxygenase-1
PubMed: 38947312
DOI: 10.3389/fimmu.2024.1416820 -
The Yale Journal of Biology and Medicine Jun 2024: Chronic rhinosinusitis (CRS) is an inflammatory condition classified into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal...
: Chronic rhinosinusitis (CRS) is an inflammatory condition classified into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP). Th cells manage inflammatory cells in CRS. Suppressor of Cytokine Signaling (SOCS) proteins regulate Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in Th cells by polarizing toward Th1, Th2, and Th17 cells. This study evaluated the levels of SOCS1,3,5 in CRS patients to find associations with Th cells. : In this cross-sectional study, 20 CRSwNP patients, 12 CRSsNP patients, and 12 controls participated. The infiltration of CD4 T cells was determined using immunohistochemistry. The expression of specific transcription factors and SOCS proteins was assessed using real-time PCR. Cytokine levels were evaluated using ELISA. SOCS protein levels were investigated using western blot analysis. : The expression of SOCS3 increased in the CRSwNP group compared to CRSsNP and control groups ( <0.001). SOCS3 protein levels increased in the CRSwNP group compared to CRSsNP ( <0.05) and control ( <0.001) groups. Although there was a significant difference in SOCS5 expression between CRSsNP and control groups, SOCS5 protein levels were significantly different between CRSsNP and control ( <0.001) and CRSwNP ( <0.05) groups. : Targeted therapies may be suggested for CRS by modulating SOCS3 and SOCS5 proteins that are responsible for polarization of Th cells toward Th2 or Th1 cells, respectively. JAK-STAT pathway targeting, which encompasses numerous cells, can be limited to SOCS proteins to more effectively orchestrate Th cell differentiation.
Topics: Humans; Sinusitis; Suppressor of Cytokine Signaling Proteins; Chronic Disease; Male; Suppressor of Cytokine Signaling 3 Protein; Rhinitis; Female; Adult; Middle Aged; T-Lymphocytes, Helper-Inducer; Cross-Sectional Studies; Nasal Polyps; Cytokines; Suppressor of Cytokine Signaling 1 Protein; Signal Transduction; Rhinosinusitis
PubMed: 38947108
DOI: 10.59249/HZFN2950 -
Gynecological Endocrinology : the... Dec 2024Telomeres maintain chromosome stability, while telomerase counteracts their progressive shortening. Telomere length varies between cell types, with leukocyte telomere...
BACKGROUND
Telomeres maintain chromosome stability, while telomerase counteracts their progressive shortening. Telomere length varies between cell types, with leukocyte telomere length (LTL) decreasing with age. Reduced telomerase activity has been linked to reproductive issues in females, such as low pregnancy rates and premature ovarian failure, with recent studies indicating correlations between telomere length in granulosa cells and IVF outcomes.
OBJECTIVES
The study aims to explore the relationship between telomere length, telomerase activity, and euploid blastocyst rate in infertile women undergoing IVF/ICSI PGT-A cycles.
METHODS
This prospective study involves 108 patients undergoing controlled ovarian stimulation and PGT-A. Telomere length and telomerase activity were measured in peripheral mononuclear cells and granulosa cells (GC), respectively.
RESULTS
The telomere repeat copy number to single gene copy number ratio (T/S) results respectively 0.6 ± 0.8 in leukocytes and 0.7 ± 0.9 in GC. An inverse relationship was found between LTL and the patient's age ( < .01). A higher aneuploid rate was noticed in patients with short LTL, with no differences in ovarian reserve markers ( = .15), number of oocytes retrieved ( = .33), and number of MII ( = 0.42). No significant association was noticed between telomere length in GC and patients' age ( = 0.95), in ovarian reserve markers ( = 0.32), number of oocytes retrieved ( = .58), number of MII ( = .74) and aneuploidy rate ( = .65).
CONCLUSION
LTL shows a significant inverse correlation with patient age and higher aneuploidy rates. Telomere length in GCs does not correlate with patient age or reproductive outcomes, indicating differential telomere dynamics between leukocytes and granulosa cells.
Topics: Humans; Female; Adult; Telomerase; Telomere; Prospective Studies; Pregnancy; Aneuploidy; Fertilization in Vitro; Granulosa Cells; Infertility, Female; Ovulation Induction; Blastocyst; Telomere Homeostasis; Sperm Injections, Intracytoplasmic
PubMed: 38946430
DOI: 10.1080/09513590.2024.2373742 -
Internal Medicine (Tokyo, Japan) 2024Objective Chimeric antigen receptor (CAR) T cell therapy is an emerging and effective therapy for relapsed or refractory diffuse large B cell lymphoma (R/R DLBCL). The...
Activated CD4 T Cell Proportion in the Peripheral Blood Correlates with the Duration of Cytokine Release Syndrome and Predicts Clinical Outcome after Chimeric Antigen Receptor T Cell Therapy.
Objective Chimeric antigen receptor (CAR) T cell therapy is an emerging and effective therapy for relapsed or refractory diffuse large B cell lymphoma (R/R DLBCL). The characteristic toxicities of CAR T cell therapy include cytokine release syndrome (CRS) and prolonged cytopenia. We investigated the factors associated with these complications after CAR T cell therapy by analyzing lymphocyte subsets following CAR T cell infusion. Methods We retrospectively analyzed peripheral blood samples on days 7, 14, and 28 after tisagenlecleucel (tisa-cel) infusion by flow cytometry at our institution between June 2020 and September 2022. Patients Thirty-five patients with R/R DLBCL who received tisa-cel therapy were included. Results A flow cytometry-based analysis of blood samples from these patients revealed that the proportion of CD4CD25CD127 T cells (hereafter referred to as "activated CD4 T cells" ) among the total CD4 T cells on day 7 after tisa-cel infusion correlated with the duration of CRS (r=0.79, p<0.01). In addition, a prognostic analysis of the overall survival (OS) using time-dependent receiver operating characteristic curves indicated a significantly more favorable OS and progression-free survival of patients with a proportion of activated CD4 T cells among the total CD4 T cells <0.73 (p=0.01, and p<0.01, respectively). Conclusion These results suggest that the proportion of activated CD4 T cells on day 7 after tisa-cel infusion correlates with the CRS duration and predicts clinical outcomes after CAR T cell therapy. Further studies with a larger number of patients are required to validate these observations.
Topics: Humans; Male; Female; Cytokine Release Syndrome; Immunotherapy, Adoptive; Middle Aged; Lymphoma, Large B-Cell, Diffuse; Aged; Retrospective Studies; CD4-Positive T-Lymphocytes; Adult; Treatment Outcome; Receptors, Chimeric Antigen; Prognosis; Receptors, Antigen, T-Cell
PubMed: 38945932
DOI: 10.2169/internalmedicine.2556-23 -
Journal For Immunotherapy of Cancer Jun 2024How distinct methods of host preconditioning impact the efficacy of adoptively transferred antitumor T helper cells is unknown.
BACKGROUND
How distinct methods of host preconditioning impact the efficacy of adoptively transferred antitumor T helper cells is unknown.
METHODS
CD4 T cells with a transgenic T-cell receptor that recognize tyrosinase-related peptide (TRP)-1 melanoma antigen were polarized to the T helper 17 (Th17) phenotype and then transferred into melanoma-bearing mice preconditioned with either total body irradiation or chemotherapy.
RESULTS
We found that preconditioning mice with a non-myeloablative dose of total body irradiation (TBI of 5 Gy) was more effective than using an equivalently dosed non-myeloablative chemotherapy (cyclophosphamide (CTX) of 200 mg/kg) at augmenting therapeutic activity of antitumor TRP-1 Th17 cells. Antitumor Th17 cells engrafted better following preconditioning with TBI and regressed large established melanoma in all animals. Conversely, only half of mice survived long-term when preconditioned with CTX and infused with anti-melanoma Th17 cells. Interleukin (IL)-17 and interferon-γ, produced by the infused Th17 cells, were detected in animals given either TBI or CTX preconditioning. Interestingly, inflammatory cytokines (granulocyte colony stimulating factor, IL-6, monocyte chemoattractant protein-1, IL-5, and keratinocyte chemoattractant) were significantly elevated in the serum of mice preconditioned with TBI versus CTX after Th17 therapy. The addition of fludarabine (FLU, 200 mg/kg) to CTX (200 mg/kg) improved the antitumor response to the same degree mediated by TBI, whereas FLU alone with Th17 therapy was ineffective.
CONCLUSIONS
Our results indicate, for the first time, that the antitumor response, persistence, and cytokine profiles resulting from Th17 therapy are impacted by the specific regimen of host preconditioning. This work is important for understanding mechanisms that promote long-lived responses by adoptive cellular therapy, particularly as CD4 based T-cell therapies are now emerging in the clinic.
Topics: Animals; Th17 Cells; Mice; Mice, Inbred C57BL; Immunotherapy, Adoptive; Whole-Body Irradiation; Melanoma, Experimental; Cyclophosphamide; Adoptive Transfer; Female; Melanoma
PubMed: 38945552
DOI: 10.1136/jitc-2023-008715 -
Nature Communications Jun 2024Children in malaria-endemic regions can experience repeated Plasmodium infections over short periods of time. Effects of re-infection on multiple co-existing CD4 T cell...
Children in malaria-endemic regions can experience repeated Plasmodium infections over short periods of time. Effects of re-infection on multiple co-existing CD4 T cell subsets remain unresolved. Here, we examine antigen-experienced CD4 T cells during re-infection in mice, using scRNA-seq/TCR-seq and spatial transcriptomics. TCR transgenic T cells initiate rapid Th1/Tr1 recall responses prior to proliferating, while GC Tfh counterparts are refractory, with T/Tfh-like cells exhibiting modest non-proliferative responses. Th1-recall is a partial facsimile of primary Th1-responses, with no upregulated effector-associated genes being unique to recall. Polyclonal, TCR-diverse, CD4 T cells exhibit similar recall dynamics, with individual clones giving rise to multiple effectors including highly proliferative Th1/Tr1 cells, as well as GC Tfh and Tfh-like cells lacking proliferative capacity. Thus, we show substantial diversity in recall responses mounted by multiple co-existing CD4 T cell subsets in the spleen, and present graphical user interfaces for studying gene expression dynamics and clonal relationships during re-infection.
Topics: Animals; Malaria; CD4-Positive T-Lymphocytes; Mice; Reinfection; Th1 Cells; Mice, Inbred C57BL; Spleen; Receptors, Antigen, T-Cell; Mice, Transgenic; Female; Immunologic Memory
PubMed: 38944658
DOI: 10.1038/s41467-024-49879-6 -
Cancer Imaging : the Official... Jun 2024This study was based on MRI features and number of tumor-infiltrating CD8 + T cells in post-operative pathology, in predicting meningioma recurrence risk.
OBJECTIVE
This study was based on MRI features and number of tumor-infiltrating CD8 + T cells in post-operative pathology, in predicting meningioma recurrence risk.
METHODS
Clinical, pathological, and imaging data of 102 patients with surgically and pathologically confirmed meningiomas were retrospectively analyzed. Patients were divided into recurrence and non-recurrence groups based on follow-up. Tumor-infiltrating CD8 + T cells in tissue samples were quantitatively assessed with immunohistochemical staining. Apparent diffusion coefficient (ADC) histogram parameters from preoperative MRI were quantified in MaZda. Considering the high correlation between ADC histogram parameters, we only chose ADC histogram parameter that had the best predictive efficacy for COX regression analysis further. A visual nomogram was then constructed and the recurrence probability at 1- and 2-years was determined. Finally, subgroup analysis was performed with the nomogram.
RESULTS
The risk factors for meningioma recurrence were ADCp1 (hazard ratio [HR] = 0.961, 95% confidence interval [95% CI]: 0.937 ~ 0.986, p = 0.002) and CD8 + T cells (HR = 0.026, 95%CI: 0.001 ~ 0.609, p = 0.023). The resultant nomogram had AUC values of 0.779 and 0.784 for 1- and 2-years predicted recurrence rates, respectively. The survival analysis revealed that patients with low CD8 + T cells counts or ADCp1 had higher recurrence rates than those with high CD8 + T cells counts or ADCp1. Subgroup analysis revealed that the AUC of nomogram for predicting 1-year and 2-year recurrence of WHO grade 1 and WHO grade 2 meningiomas was 0.872 (0.652) and 0.828 (0.751), respectively.
CONCLUSIONS
Preoperative ADC histogram parameters and tumor-infiltrating CD8 + T cells may be potential biomarkers in predicting meningioma recurrence risk.
CLINICAL RELEVANCE STATEMENT
The findings will improve prognostic accuracy for patients with meningioma and potentially allow for targeted treatment of individuals who have the recurrent form.
Topics: Humans; Meningioma; Nomograms; Male; Female; Neoplasm Recurrence, Local; Middle Aged; CD8-Positive T-Lymphocytes; Retrospective Studies; Meningeal Neoplasms; Lymphocytes, Tumor-Infiltrating; Aged; Adult; Magnetic Resonance Imaging; Risk Factors; Prognosis
PubMed: 38943200
DOI: 10.1186/s40644-024-00731-6 -
Journal of Nanobiotechnology Jun 2024Lipid nanoparticles (LNPs) have proven themselves as transformative actors in chimeric antigen receptor (CAR) T cell therapy, surpassing traditional methods and... (Review)
Review
Lipid nanoparticles (LNPs) have proven themselves as transformative actors in chimeric antigen receptor (CAR) T cell therapy, surpassing traditional methods and addressing challenges like immunogenicity, reduced toxicity, and improved safety. Promising preclinical results signal a shift toward safer and more effective CAR T cell treatments. Ongoing research aims to validate these findings in clinical trials, marking a new era guided by LNPs utility in CAR therapy. Herein, we explore the preference for LNPs over traditional methods, highlighting the versatility of LNPs and their effective delivery of nucleic acids. Additionally, we address key challenges in clinical considerations, heralding a new era in CAR T cell therapy.
Topics: Nanoparticles; Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Animals; Lipids; T-Lymphocytes; Neoplasms; Liposomes
PubMed: 38943167
DOI: 10.1186/s12951-024-02630-1 -
BMC Infectious Diseases Jun 2024Human T-cell lymphotropic virus type 1 (HTLV-1), also denominated Human T-cell leukemia virus-1, induces immune activation and secretion of proinflammatory cytokines,...
BACKGROUND
Human T-cell lymphotropic virus type 1 (HTLV-1), also denominated Human T-cell leukemia virus-1, induces immune activation and secretion of proinflammatory cytokines, especially in individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Regulatory T lymphocytes (Tregs) may control of inflammation through the production of regulatory cytokines, including IL10 and TGF-β. In this study we determined the frequencies of CD4 + and CD8 + Tregs in a HAM/TSP population, compared to asymptomatic carriers and uninfected individuals, as well as investigated the profiles of regulatory and inflammatory cytokines.
METHODS
Asymptomatic HTLV-1 carriers and HAM/TSP patients were matched by sex and age. The frequencies of IL10- and/or TGF-β-producing Tregs were quantified by flow cytometry. Real-time reverse transcription polymerase chain reaction (RT-PCR) was used to quantify HTLV-1 proviral load and the mRNA expression of cytokines and cellular receptors in peripheral blood mononuclear cells.
RESULTS
Total frequencies of CD4 + Tregs, as well as the IL10-producing CD4 + and CD8 + Treg subsets, were statistically higher in patients with HAM/TSP compared to asymptomatic HTLV-1-infected individuals. In addition, a positive correlation was found between the frequency of CD4 + IL10 + Tregs and proviral load in the HAM/TSP patients evaluated. A positive correlation was also observed between gene expression of proinflammatory versus regulatory cytokines only in HAM / TSP group.
CONCLUSIONS
A higher frequencies of IL10-producing Tregs were identified in patients with HAM/TSP. Imbalanced production of IL10 in relation to TGF-β may contribute to the increased inflammatory response characteristically seen in HAM/TSP patients.
Topics: Humans; T-Lymphocytes, Regulatory; Male; Female; Paraparesis, Tropical Spastic; Interleukin-10; Middle Aged; Human T-lymphotropic virus 1; Transforming Growth Factor beta; Adult; Viral Load; Aged; HTLV-I Infections; Carrier State
PubMed: 38943078
DOI: 10.1186/s12879-024-09494-8 -
BMC Immunology Jun 2024Variations in the innate and adaptive immune response systems are linked to variations in the severity of COVID-19. Natural killer cell (NK) function is regulated by...
BACKGROUND
Variations in the innate and adaptive immune response systems are linked to variations in the severity of COVID-19. Natural killer cell (NK) function is regulated by sophisticated receptor system including Killer-cell immunoglobulin-like receptor (KIR) family. We aimed to investigate the impact of possessing certain KIR genes and genotypes on COVID19 severity in Iranians. KIR genotyping was performed on 394 age/sex matched Iranians with no underlying conditions who developed mild and severe COVID- 19. The presence and/or absence of 11 KIR genes were determined using the PCR with sequence specific primers (PCR-SSP).
RESULTS
Patients with mild symptoms had higher frequency ofKIR2DS1 (p = 0.004) and KIR2DS2 (p = 0.017) genes compared to those with severe disease. While KIR3DL3 and deleted variant of KIR2DS4 occurred more frequently in patients who developed a severe form of the disease. In this study, a significant increase of and B haplotype was observed in the Mild group compared to the Severe group (respectively, p = 0.002 and p = 0.02). Also, the prevalence of haplotype A was significantly higher in the Severe group than in the Mild group (p = 0.02).
CONCLUSIONS
These results suggest that the KIR2DS1, KIR2DS, and B haplotype maybe have a protective effect against COVID-19 severity. The results also suggest the inhibitory gene KIR2DL3 and haplotype A are risk factors for the severity of COVID-19.
Topics: Humans; COVID-19; Receptors, KIR; Iran; Male; Female; Genetic Predisposition to Disease; SARS-CoV-2; Middle Aged; Adult; Severity of Illness Index; Haplotypes; Genotype; Gene Frequency; Killer Cells, Natural; Aged
PubMed: 38943065
DOI: 10.1186/s12865-024-00631-1