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Poultry Science Jun 2024This study was conducted to investigate the protective effects of chlorogenic acid (CGA) on inflammatory responses and intestinal health of lipopolysaccharide...
This study was conducted to investigate the protective effects of chlorogenic acid (CGA) on inflammatory responses and intestinal health of lipopolysaccharide (LPS)-challenged broilers. One hundred and forty-four 1-day-old male broiler chicks were divided into 3 groups with 6 replicates of 8 birds each. The groups were as follows: 1) Control group: birds fed a basal diet; 2) LPS group: LPS-challenged birds fed a basal diet; 3) CGA group: LPS-challenged birds fed a CGA-supplemented diet. The LPS was intraperitoneally administered at a dose of 1 mg/kg of body weight. CGA increased the weight gain and feed intake of LPS-challenged birds by 37.05% and 24.29%, respectively (P < 0.05). CGA also alleviated LPS-induced inflammation, as evidenced by lower levels of pro-inflammatory cytokines in the serum and jejunum (tumor necrosis factor-α, interferon-γ, interleukin-1β, and interleukin-6), and the decreased myeloperoxidase activity in the jejunum (P < 0.05). These effects were accompanied by a decrease in the mRNA abundance of toll-like receptor 4 and myeloid differentiation factor 88 and an inhibition of nuclear factor kappa-B translocation in the jejunum (P < 0.05). CGA reduced circulating diamine oxidase activity and levels of D-lactate and endotoxin, and positively regulated the expression of jejunal claudin-3 and zonula occludens-1 in LPS-challenged broilers (P < 0.05). Compared to the LPS group, CGA reduced the apoptotic rate of epithelial cells and cytochrome c concentration in the jejunum, and normalized the expression of genes responsible for proliferation and apoptosis in jejunal epithelial cells, including cysteine aspartate-specific protease-9, B cell lymphoma-2, and proliferating cell nuclear antigen (P < 0.05). Furthermore, CGA normalized the altered phosphorylation of protein kinase B and glycogen synthase kinase-3β, as well as the translocation of nuclear β-catenin in the jejunum of LPS-challenged broilers (P < 0.05). These results suggested that CGA supplementation improved growth performance, alleviated inflammation, and helped maintain intestinal integrity and barrier function in LPS-challenged broilers, possibly through the regulation of the toll-like receptor 4/nuclear factor kappa-B and protein kinase B/Wnt/β-catenin pathways.
PubMed: 38917604
DOI: 10.1016/j.psj.2024.103949 -
BioRxiv : the Preprint Server For... Jun 2024Memory CD8 T cells (T ) can be activated into innate-like killers by cytokines like IL-12, IL-15, and/or IL-18; but mechanisms regulating this phenomenon (termed...
Memory CD8 T cells (T ) can be activated into innate-like killers by cytokines like IL-12, IL-15, and/or IL-18; but mechanisms regulating this phenomenon (termed bystander activation) are not fully resolved. We found strain-intrinsic deficiencies in bystander activation using specific pathogen-free mice, whereby basal IL-4 signals antagonize IL-18 sensing. We show that therapeutic and helminth-induced IL-4 impairs protective bystander-mediated responses against pathogens. However, this IL-4/IL-18 axis does not completely abolish bystander activation but rather tunes the expression of direct versus indirect mediators of cytotoxicity (granzymes and interferon-γ, respectively). We show that antigen-experience overrides strain-specific deficiencies in bystander activation, leading to uniform IL-18 receptor expression and enhanced capacity for bystander activation/cytotoxicity. Our data highlight that bystander activation is not a binary process but tuned/deregulated by other cytokines that are elevated by contemporaneous infections. Further, our findings underscore the importance of antigen-experienced T to dissect the contributions of bystander T in health and disease.
PubMed: 38915668
DOI: 10.1101/2024.06.10.598293 -
BioRxiv : the Preprint Server For... Jun 2024Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular morbidity and mortality, yet the etiology is poorly understood. We previously...
BACKGROUND
Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular morbidity and mortality, yet the etiology is poorly understood. We previously found that serum/glucocorticoid-regulated kinase 1 (SGK1) and epoxyeicosatrienoic acids (EETs) regulate epithelial sodium channel (ENaC)-dependent sodium entry into monocyte-derived antigen-presenting cells (APCs) and activation of NADPH oxidase, leading to the formation of isolevuglandins (IsoLGs) in SSBP. Whereas aldosterone via the mineralocorticoid receptor (MR) activates SGK1 leading to hypertension, our past findings indicate that levels of plasma aldosterone do not correlate with SSBP, and there is little to no MR expression in APCs. Thus, we hypothesized that cortisol acting via the glucocorticoid receptor (GR), not the MR in APCs mediates SGK1 actions to induce SSBP.
METHODS
We performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) analysis on peripheral blood mononuclear cells of humans rigorously phenotyped for SSBP using an inpatient salt loading/depletion protocol to determine expression of MR, GR, and SGK1 in immune cells. In additional experiments, we performed bulk transcriptomic analysis on isolated human monocytes following treatment with high salt from a separate cohort. We then measured urine and plasma cortisol, cortisone, renin, and aldosterone. Subsequently, we measured the association of these hormones with changes in systolic, diastolic, mean arterial pressure and pulse pressure as well as immune cell activation via IsoLG formation.
RESULTS
We found that myeloid APCs predominantly express the GR and SGK1 with no expression of the MR. Expression of the GR in APCs increased after salt loading and decreased with salt depletion in salt-sensitive but not salt-resistant people and was associated with increased expression of . Moreover, we found that plasma and urine cortisol/cortisone but not aldosterone/renin correlated with SSBP and APCs activation via IsoLGs. We also found that cortisol negatively correlates with EETs.
CONCLUSION
Our findings suggest that renal cortisol signaling via the GR but not the MR in APCs contributes to SSBP via cortisol. Urine and plasma cortisol may provide an important currently unavailable feasible diagnostic tool for SSBP. Moreover, cortisol-GR-SGK1-ENaC signaling pathway may provide treatment options for SSBP.
NOVELTY AND RELEVANCE
Although salt sensitivity is a major risk factor for cardiovascular morbidity and mortality, the mechanisms underlying the salt sensitivity of blood pressure (SSBP) are poorly understood.High salt modifies glucocorticoid-receptor expression in antigen-presenting cells (APCs), suggesting a critical role of glucocorticoids in SSBP. Elevated glucocorticoid receptor (GR) expression compared to mineralocorticoid receptor (MR) expression in APCs provides evidence for a GR-dependent pathway to SSBP. Isolevuglandins (IsoLGs) increased in APCs after hydrocortisone treatment compared to aldosterone treatment, indicating that cortisol was the predominant driver of IsoLG production in these cells. Our studies suggest a mechanism for expression through GR activation by cortisol that differs from the currently accepted mechanism for SSBP pathogenesis. Although aldosterone has been used to study SSBP, there has been no consideration of cortisol as a major driver of the condition.Understanding alternative inflammatory pathways that affect SSBP may provide insights into the mechanism of SSBP and suggest a range of therapeutic targets.Our studies may provide a practical approach to understanding and treating salt-sensitive hypertension. Our findings firmly support a GR-dependent signaling pathway for activating SSBP via expression. A cortisol-driven mechanism could provide a practical approach for targeted treatments for salt-sensitive hypertension. Moreover, it could pave the way for a diagnostic approach.
PubMed: 38915603
DOI: 10.1101/2024.06.10.598374 -
BioRxiv : the Preprint Server For... Jun 2024Placentation presents immune conflict between mother and fetus, yet in normal pregnancy maternal immunity against infection is maintained without expense to fetal...
Placentation presents immune conflict between mother and fetus, yet in normal pregnancy maternal immunity against infection is maintained without expense to fetal tolerance. This is believed to result from adaptations at the maternal-fetal interface (MFI) which affect T cell programming, but the identities (i.e., memory subsets and antigenic specificities) of T cells and the signals that mediate T cell fates and functions at the MFI remain poorly understood. We found intact recruitment programs as well as pro-inflammatory cytokine networks that can act on maternal T cells in an antigen-independent manner. These inflammatory signals elicit T cell expression of co-stimulatory receptors necessary for tissue retention, which can be engaged by local macrophages. Although pro-inflammatory molecules elicit T cell effector functions, we show that additional cytokine (TGF-β1) and metabolite (kynurenine) networks may converge to tune T cell function to those of sentinels. Together, we demonstrate an additional facet of fetal tolerance, wherein T cells are broadly recruited and restrained in an antigen-independent, cytokine/metabolite-dependent manner. These mechanisms provide insight into antigen-nonspecific T cell regulation, especially in tissue microenvironments where they are enriched.
PubMed: 38915597
DOI: 10.1101/2024.06.10.598377 -
BioRxiv : the Preprint Server For... Jun 2024Chimeric antigen receptor (CAR) T cell therapy has shown remarkable efficacy in cancer treatment. Still, most patients receiving CAR T cells relapse within 5 years of...
UNLABELLED
Chimeric antigen receptor (CAR) T cell therapy has shown remarkable efficacy in cancer treatment. Still, most patients receiving CAR T cells relapse within 5 years of treatment. CAR-mediated trogocytosis (CMT) is a potential tumor escape mechanism in which cell surface proteins transfer from tumor cells to CAR T cells. CMT results in the emergence of antigen-negative tumor cells, which can evade future CAR detection, and antigen-positive CAR T cells, which is hypothesized to lead to CAR T cell fratricide and dysfunction. Using a system to selectively degrade trogocytosed antigen in CAR T cells, we show that the presence of trogocytosed antigen in CAR T cells directly causes CAR T cell fratricide and exhaustion. By performing a small molecule screening using a custom high throughput CMT-screening assay, we identified the cysteine protease cathepsin B (CTSB) as a key driver of CMT. We show that overexpression of cystatin A (CSTA), an endogenous human inhibitor of CTSB, reduces trogocytosis resulting in prolonged antitumor activity and increased CAR T cell expansion/persistence. Overall, we show that targeting CMT is an effective approach to enhance CAR T cell function, which may improve their clinical efficacy.
ONE SENTENCE SUMMARY
CAR-mediated trogocytosis directly causes CAR T cell exhaustion and fratricide but can be prevented by inhibiting the cysteine protease cathepsin B through overexpression of human cystatins.
PubMed: 38915559
DOI: 10.1101/2024.06.11.598379 -
Acute kidney injury after CAR-T cell therapy: exploring clinical patterns, management, and outcomes.Clinical Kidney Journal Jun 2024Acute kidney injury (AKI) has been reported after CAR-T cells, but available data are limited. We sought to describe the incidence of AKI in a cohort of patients...
BACKGROUND
Acute kidney injury (AKI) has been reported after CAR-T cells, but available data are limited. We sought to describe the incidence of AKI in a cohort of patients hospitalized in the intensive care unit (ICU) following CAR-T cell reinjection, identify the primary factors linked to the onset of AKI, and ascertain the key determinants associated with kidney outcomes and mortality.
METHODS
We retrospectively analyzed 119 patients hospitalized in ICU after CAR-T cell therapy between 2017 and 2023. Factors associated with AKI, mortality, and kidney sequelae were identified using multivariate analyses.
RESULTS
Of the 119 patients, 41 patients fulfilled diagnostic criteria of AKI (34%). By multivariate analysis, grade ≥3 cytokine release syndrome (CRS) [OR = 1.20 CI95% (1.01-1.43)] and elevated lactate dehydrogenase (LDH) levels at admission [OR = 1.44 CI95% (1.04-1.99)] were significantly associated with the occurrence of AKI during ICU stay. AKI KDIGO ≥2 was an independent risk factor for hospital mortality [OR = 1.50 (1.22-1.85), < 0.001]. Nine out of 12 (75%) and 6/9 (67%) patients who had experienced AKI and survived had chronic kidney disease (CKD) at 6 months and 1 year, respectively. We did not identify any specific factor associated with kidney recovery.
CONCLUSION
AKI may occur in ICU patients receiving CAR-T cell therapy, especially those who experience CRS and exhibit elevated LDH levels. Early recognition of AKI is of utmost importance as it substantially compromises survival in these patients. Future studies should aim to elucidate the underlying pathophysiological mechanisms of AKI in this context and pinpoint predictive factors for long-term risks of CKD.
PubMed: 38915438
DOI: 10.1093/ckj/sfae123 -
Frontiers in Immunology 2024Immune system recognizes invading microbes at both pathogen and antigen levels. Toll-like receptors (TLRs) play a key role in the first-line defense against pathogens.... (Review)
Review
Immune system recognizes invading microbes at both pathogen and antigen levels. Toll-like receptors (TLRs) play a key role in the first-line defense against pathogens. Major functions of TLRs include cytokine and chemokine production. TLRs share common downstream signaling pathways with other receptors. The crosstalk revolving around TLRs is rather significant and complex, underscoring the intricate nature of immune system. The profiles of produced cytokines and chemokines via TLRs can be affected by other receptors. Integrins are critical heterodimeric adhesion molecules expressed on many different cells. There are studies describing synergetic or inhibitory interplay between TLRs and integrins. Thus, we reviewed the crosstalk between TLRs and integrins. Understanding the nature of the crosstalk could allow us to modulate TLR functions via integrins.
Topics: Humans; Toll-Like Receptors; Integrins; Animals; Signal Transduction; Receptor Cross-Talk; Cytokines; Immunity, Innate
PubMed: 38915411
DOI: 10.3389/fimmu.2024.1403764 -
Frontiers in Immunology 2024Cytomegalovirus (CMV) reactivation is a significant concern following allogeneic stem cell transplantation. While previous research has highlighted the anti-CMV...
BACKGROUND
Cytomegalovirus (CMV) reactivation is a significant concern following allogeneic stem cell transplantation. While previous research has highlighted the anti-CMV reactivation effect of γδ T cells in immunocompromised transplant patients, their characterization in recipients at high risk of CMV reactivation remains limited.
METHODS
This study focused on D+/R+ recipients (where both donor and recipient are CMV seropositive) at high risk of CMV reactivation. We analyzed 28 patients who experienced CMV recurrence within 100 days post-allogeneic hematopoietic stem cell transplantation, along with 36 matched recipients who did not experience CMV recurrence. Clinical data from both groups were compared, and risk factors for CMV reactivation were identified. Additionally, CMV viral load was measured, and flow cytometric analysis was conducted to assess changes in peripheral blood γδ T cell proportions, subpopulation distribution, and differentiation status. We also analyzed the CDR3 repertoire of the TCR δ chain in different γδ T cell subsets. Functional analysis was performed by measuring the lysis of CMV-infected cells upon stimulation.
RESULTS
CMV reactivation post-transplantation was associated with acute graft-versus-host disease (aGvHD) and reactivation of non-CMV herpesviruses. Notably, CMV reactivation led to sustained expansion of γδ T cells, primarily within the Vδ2 γδ T cell subpopulation, with a trend toward differentiation from Naive to effector memory cells. Analysis of the δ chain CDR3 repertoire revealed a delay in the reconstitution of clonal diversity in Vδ2 γδ T cells following CMV reactivation, while Vδ2 T cells remained unaffected. Upon stimulation with CMV-infected MRC5 cells, the Vδ2 γδ T cell subpopulation emerged as the primary effector cell group producing IFN-γ and capable of lysing CMV-infected cells. Moreover, our findings suggest that NKG2D is not necessary involved in Vδ2 γδ T cell-mediated anti-CMV cytotoxicity.
CONCLUSION
This study provides novel insights into the role of γδ T cells in the immune response to CMV reactivation in transplantation recipients at high risk of CMV infection. Specifically, the Vδ2 γδ T cell subpopulation appears to be closely associated with CMV reactivation, underscoring their potential role in controlling infection and reflecting CMV reactivation in HSCT patients.
Topics: Humans; Cytomegalovirus Infections; Male; Cytomegalovirus; Virus Activation; Female; Adult; Middle Aged; Hematopoietic Stem Cell Transplantation; Receptors, Antigen, T-Cell, gamma-delta; Transplantation, Homologous; Graft vs Host Disease; Young Adult; Memory T Cells; Aged
PubMed: 38915409
DOI: 10.3389/fimmu.2024.1397483 -
Frontiers in Immunology 2024Chimeric antigen receptor (CAR) T-cell therapy (CAR T therapy) is a treatment option for patients with relapsed or refractory multiple myeloma that has led to...
INTRODUCTION
Chimeric antigen receptor (CAR) T-cell therapy (CAR T therapy) is a treatment option for patients with relapsed or refractory multiple myeloma that has led to unprecedented treatment outcomes. Among CAR T therapies available, ciltacabtagene autoleucel (cilta-cel) is a good candidate for outpatient administration due to its generally predictable safety profile. There are multiple advantages of outpatient administration of cilta-cel, including reduced healthcare burden, expanded access, and patient autonomy. This mixed methods qualitative study aimed to identify key factors for outpatient administration of CAR T and best practice recommendations by combining a targeted literature review with expert interviews and panels.
METHODS
The targeted review (Phase 1) aimed to identify factors for outpatient CAR T administration in the US and determine key topics for the exploratory interviews (Phase 2) and expert panels (Phase 3), which aimed to inform on best practices and challenges of outpatient CAR T administration (focusing on cilta-cel). Participants in clinical and administrative positions based in treatment centers that had experience with real-world outpatient administration of cilta-cel were recruited.
RESULTS
Seventeen studies were identified in Phase 1. Key factors for outpatient administration included the development of protocols for CAR T complications, education for caregivers, outpatient specialists, hospital staff, and emergency services staff for identification and referral after possible adverse events, the creation of multidisciplinary teams for effective communication and management, straightforward patient intake processes encompassing financial eligibility review and provision of patient education materials, and close patient monitoring throughout the treatment journey. In Phase 2, 5 participants from 2 centers were interviewed. In Phase 3, 14 participants across 6 treatment centers were interviewed. Two 90-minute virtual panel discussions took place. All participants agreed that cilta-cel can be safely and effectively administered in an outpatient setting. Key recommendations included the creation of educational resources for patients and caregivers, the development of standard operating procedures, dedicated outpatient infrastructure and establishment of interdisciplinary teams, outpatient monitoring for toxicity management, and monitoring of the reimbursement landscape.
DISCUSSION
This study offers a comprehensive understanding of the feasibility of outpatient cilta-cel administration in participating CAR T centers and provides actionable recommendations while acknowledging existing challenges.
Topics: Humans; Multiple Myeloma; Immunotherapy, Adoptive; Outpatients; Biological Products; Ambulatory Care; Receptors, Chimeric Antigen; Male
PubMed: 38915401
DOI: 10.3389/fimmu.2024.1405452 -
Journal of Hematology & Oncology Jun 2024Significant advances have been made in chimeric antigen receptor T (CAR-T)-cell therapy for the treatment of recurrent or refractory B-cell hematologic malignancies.... (Review)
Review
Significant advances have been made in chimeric antigen receptor T (CAR-T)-cell therapy for the treatment of recurrent or refractory B-cell hematologic malignancies. However, CAR-T-cell therapy has not yet achieved comparable success in the management of aggressive T-cell malignancies. This article reviews the challenges of CAR-T-cell therapy in treating T-cell malignancies and summarizes the progress of preclinical and clinical studies in this area. We present an analysis of clinical trials of CAR-T-cell therapies for the treatment of T-cell malignancies grouped by target antigen classification. Moreover, this review focuses on the major challenges encountered by CAR-T-cell therapies, including the nonspecific killing due to T-cell target antigen sharing and contamination with cell products during preparation. This review discusses strategies to overcome these challenges, presenting novel therapeutic approaches that could enhance the efficacy and applicability of CAR-T-cell therapy in the treatment of T-cell malignancies. These ideas and strategies provide important information for future studies to promote the further development and application of CAR-T-cell therapy in this field.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; T-Lymphocytes; Hematologic Neoplasms; Animals; Receptors, Antigen, T-Cell
PubMed: 38915099
DOI: 10.1186/s13045-024-01568-z