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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 -
Free Radical Biology & Medicine Jun 2024Innovative solutions for rapid protection against broad-spectrum infections are very important in dealing with complex infection environments. We utilized a functionally...
A Streptococcus pneumoniae endolysin mutant protein ΔA146Ply elicits rapid broad-spectrum mucosal protection in mice via upregulation of GPX4 through TLR4/IRG1/NRF2 to alleviate macrophage ferroptosis.
Innovative solutions for rapid protection against broad-spectrum infections are very important in dealing with complex infection environments. We utilized a functionally inactive mutated endolysin protein of Streptococcus pneumoniae (ΔA146Ply) to immunize mice against pneumonic infections by multidrug-resistant bacteria, Candida albicans and influenza virus type A. ΔA146Ply protection relied on both immunized tissue-resident and monocyte-derived alveolar macrophages and inhibited infection induced ferroptosis that upregulated expression of GPX4 (glutathione peroxidase) in alveolar macrophages. Ferroptosis resistance endowed macrophages with enhanced phagocytosis by inhibiting lipid peroxidation during infection. Moreover, we demonstrated ΔA146Ply upregulated GPX4 through the TLR4/IRG1/NRF2 pathway. ΔA146Ply also induced ferroptosis inhibition and phagocytosis improvement in human monocytes. This mode of action is a novel and potentially prophylactic and rapid broad-spectrum anti-infection mechanism. Our study provides new insights into protective interventions that act by regulating ferroptosis to improve multiple pathogen resistance via GPX4 targeting.
PubMed: 38945457
DOI: 10.1016/j.freeradbiomed.2024.06.025 -
European Journal of Pharmaceutics and... Jun 2024Liposomes represent one of the most extensively studied nano-carriers due to their potential in targeted drug delivery. However, the complex in vivo fate, particularly...
Liposomes represent one of the most extensively studied nano-carriers due to their potential in targeted drug delivery. However, the complex in vivo fate, particularly under pathological conditions, presents challenges for clinical translation of liposomal therapeutics. Liver serves as the most important organ for liposome accumulation and metabolism. Unfortunately, the fate of liposomes under pathological liver conditions has been significantly overlooked. This study aimed to investigate the in vivo pharmacokinetic profile and biodistribution profile of liposomes under drug-induced liver injury (DILI) conditions. Two classic DILI animal models, i.e. acetaminophen-induced acute liver injury (AILI) and triptolide-induced subacute liver injury (TILI), were established to observe the effect of pathological liver conditions on the in vivo performance of liposomes. The study revealed significant changes in the in vivo fate of liposomes following DILI, including prolonged blood circulation and enhanced hepatic accumulation of liposomes. Changes in the composition of plasma proteins and mononuclear phagocyte system (MPS)-related cell subpopulations collectively led to the altered in vivo fate of liposomes under liver injury conditions. Despite liver injury, macrophages remained the primary cells responsible for liposomes uptake in liver, with the recruited monocyte-derived macrophages exhibiting enhanced ability to phagocytose liposomes under pathological conditions. These findings indicated that high capture of liposomes by the recruited hepatic macrophages not only offered potential solutions for targeted delivery, but also warned the clinical application of patients under pathological liver conditions.
PubMed: 38945407
DOI: 10.1016/j.ejpb.2024.114389 -
Mucosal Immunology Jun 2024Intestinal stromal cells (SCs), which synthesize the extracellular matrix that gives the mucosa its structure, are newly appreciated to play a role in mucosal...
Intestinal stromal cells (SCs), which synthesize the extracellular matrix that gives the mucosa its structure, are newly appreciated to play a role in mucosal inflammation. Here we show that human intestinal vimentinCD90SMA SCs synthesize retinoic acid (RA) at levels equivalent to intestinal epithelial cells, a function in the human intestine previously attributed exclusively to epithelial cells. Crohn's disease SCs (Crohn's SCs), however, synthesized markedly less RA than SCs from healthy intestine (Normal SCs). We also show that microbe-stimulated Crohn's SCs, which are more inflammatory than stimulated Normal SCs, induced less RA-regulated differentiation of mucosal DCS (circulating pre-DCs and monocyte-derived DCs), leading to the generation of more potent inflammatory IFN-γ/IL-17 T cells than Normal SCs. Explaining these results, Crohn's SCs expressed more DHRS3, a retinaldehyde reductase that inhibits retinol conversion to retinal, and thus synthesized less RA than Normal SCs. These findings uncover a microbe-SC-DC crosstalk in which luminal microbes induce Crohn's disease SCs to initiate and perpetuate inflammation through impaired synthesis of RA.
PubMed: 38945396
DOI: 10.1016/j.mucimm.2024.06.009 -
Advances in Gerontology = Uspekhi... 2024Metabolic syndrome is a group of disorders that are closely related to both the risk of developing type 2 diabetes mellitus and cardiovascular diseases, and generally... (Review)
Review
[Markers of inflammation with decreased functionality in the cognitive and psychological domains of individual vitality in middle-aged and elderly patients with metabolic syndrome.].
Metabolic syndrome is a group of disorders that are closely related to both the risk of developing type 2 diabetes mellitus and cardiovascular diseases, and generally leading to the phenomenon of premature aging of the body. Excessive accumulation of adipose tissue contributes to the development of chronic immune inflammation and oxidative stress, which are both precursors to various disorders, such as insulin resistance, arterial hypertension and dyslipidemia, but also trigger inflammatory processes in patients. An increasing number of studies support the importance of chronic immune inflammation in the pathogenesis of metabolic syndrome, as pro-inflammatory markers such as TNF-α, IL-1β, IL-6, monocyte chemotactic protein-1 and growth of vascular endothelium. Among a wide range of cytokines, monocyte chemotactic protein-1 is considered one of the most important chemokines, which activates monocytes and other immune cells actively involved in inflammation. Another important point of chronic immune inflammation is its impact on the mental health of patients with metabolic syndrome. Increased levels of anxiety and depression are associated with levels of pro-inflammatory cytokines produced by adipose tissue, which ultimately has an adverse effect on the cognitive status of patients.
Topics: Humans; Metabolic Syndrome; Inflammation; Biomarkers; Aged; Cytokines; Middle Aged; Aging; Oxidative Stress
PubMed: 38944784
DOI: No ID Found -
International Immunopharmacology Jun 2024The most common and serious complication among hospitalized and critically ill patients is sepsis-associated acute kidney damage (S-AKI), which raises the risk of...
The most common and serious complication among hospitalized and critically ill patients is sepsis-associated acute kidney damage (S-AKI), which raises the risk of comorbidities and is linked to a high mortality rate. Cholinergic anti-inflammatory pathway (CAP), an anti-inflammatory pathway mediated by the vagus nerve, acetylcholine, and α7 nicotinic acetylcholine receptors (α7nAChRs), offers new perspectives for the treatment of S-AKI. In this study, we investigated the role of CAP and α7nAChR in kidney injury by employing an LPS-induced septic kidney injury mouse model and GTS-21 intervention. C57BL/6 mice were injected with LPS, with or without GTS-21, in different subgroups. Kidney function was assessed by plasma creatinine, histology, and markers of kidney injury 24 h after intervention. The results demonstrated that GTS-21 could inhibit the systemic inflammatory response and directly protect the tubular cell injury from LPS. To explore the novel gene involved in this response, RNA sequencing of the renal proximal tubular epithelial cell (HK-2), pretreated with LPS and GTS-21, was conducted. The results indicate that GTS-21 administration reduces LPS-induced cytokines and chemokines secretion by HK-2, including CCL20, a potent chemokine attracting monocytes/macrophages. Furthermore, a macrophage transmigration assay revealed that GTS-21 inhibits macrophage transmigration by downregulating the expression of CCL20 in HK-2 cells. In conclusion, GTS-21, as an α7nAChR agonist, emerges as a noteworthy and versatile treatment for S-AKI. Its dual function of directly protecting renal tubular cells and regulating inflammatory responses represents a major advancement in the treatment of sepsis-induced AKI. This finding might pave the way for novel approaches to improving patient outcomes and reducing death rates in sepsis-related complications.
PubMed: 38943973
DOI: 10.1016/j.intimp.2024.112555 -
Cell Reports Jun 2024The intestinal environment facilitates HIV-1 infection via mechanisms involving the gut-homing vitamin A-derived retinoic acid (RA), which transcriptionally reprograms...
The intestinal environment facilitates HIV-1 infection via mechanisms involving the gut-homing vitamin A-derived retinoic acid (RA), which transcriptionally reprograms CD4 T cells for increased HIV-1 replication/outgrowth. Consistently, colon-infiltrating CD4 T cells carry replication-competent viral reservoirs in people with HIV-1 (PWH) receiving antiretroviral therapy (ART). Intriguingly, integrative infection in colon macrophages, a pool replenished by monocytes, represents a rare event in ART-treated PWH, thus questioning the effect of RA on macrophages. Here, we demonstrate that RA enhances R5 but not X4 HIV-1 replication in monocyte-derived macrophages (MDMs). RNA sequencing, gene set variation analysis, and HIV interactor NCBI database interrogation reveal RA-mediated transcriptional reprogramming associated with metabolic/inflammatory processes and HIV-1 resistance/dependency factors. Functional validations uncover post-entry mechanisms of RA action including SAMHD1-modulated reverse transcription and CDK9/RNA polymerase II (RNAPII)-dependent transcription under the control of mammalian target of rapamycin (mTOR). These results support a model in which macrophages residing in the intestine of ART-untreated PWH contribute to viral replication/dissemination in an mTOR-sensitive manner.
PubMed: 38943643
DOI: 10.1016/j.celrep.2024.114414 -
Molekuliarnaia Biologiia 2024Melatonin (N-acetyl-5-methoxytryptamine, MEL) is a hormone synthesized by the pineal gland. Due to its oncostatic effect, it can be considered as an antitumor agent and...
Melatonin (N-acetyl-5-methoxytryptamine, MEL) is a hormone synthesized by the pineal gland. Due to its oncostatic effect, it can be considered as an antitumor agent and used for combination therapy. ABT-737, a Bcl-2 inhibitor, promotes cell death after treatment with agents that induce pro-apoptotic signals. In the present study, the combined effect of MEL and ABT-737 on changes in proliferative and mitotic activity, mitochondrial membrane potential, intracellular production of reactive oxygen species (ROS), and cytosolic Ca^(2+) was studied. Moreover, changes in the expression of anti- and pro-apoptotic proteins (Bcl-2 and Bax), autophagy markers (LC3A/B (I, II)), endoplasmic reticulum stress markers (chaperones BIP and PDI, CHOP) were studied under these conditions. The effect of MEL together with ABT-737 led to an increase in the level of cytosolic Ca^(2+), intracellular production of ROS and a decrease in the membrane potential of mitochondria. The content of Bcl-2 increased, while the level of Bax decreased. Activation of CHOP stimulated autophagy and led to a decrease in the synthesis of chaperones BIP and PDI. It is assumed that melatonin can enhance the effect of other chemotherapeutic agents and can be used in the treatment of tumors.
Topics: Humans; Sulfonamides; Melatonin; Nitrophenols; Piperazines; Biphenyl Compounds; Reactive Oxygen Species; Membrane Potential, Mitochondrial; Apoptosis; Proto-Oncogene Proteins c-bcl-2; THP-1 Cells; bcl-2-Associated X Protein; Drug Synergism; Autophagy; Endoplasmic Reticulum Stress; Endoplasmic Reticulum Chaperone BiP; Cell Proliferation; Microtubule-Associated Proteins; Calcium; Neoplasm Proteins; Transcription Factor CHOP
PubMed: 38943585
DOI: No ID Found -
Thrombosis Journal Jun 2024Hypercoagulability emerges as a central pathological feature and clinical complication in nephrotic syndrome. Increased platelet activation and aggregability are closely...
BACKGROUND
Hypercoagulability emerges as a central pathological feature and clinical complication in nephrotic syndrome. Increased platelet activation and aggregability are closely related to hypercoagulability in nephrotic syndrome. Monocyte-platelet aggregates (MPAs) have been proposed to represent a robust biomarker of platelet activation. The aim of this study was to investigate levels of the circulating MPAs and MPAs with the different monocyte subsets to evaluate the association of MPAs with hypercoagulability in nephrotic syndrome.
METHODS
Thirty-two patients with nephrotic syndrome were enrolled. In addition, thirty-two healthy age and sex matched adult volunteers served as healthy controls. MPAs were identified by CD14 monocytes positive for CD41a platelets. The classical (CD14 + + CD16-, CM), the intermediate (CD14 + + CD16+, IM) and the non-classical (CD14 + CD16++, NCM) monocytes, as well as subset specific MPAs, were measured by flow cytometry.
RESULTS
Patients with nephrotic syndrome showed a higher percentage of circulating MPAs as compared with healthy controls (p < 0.001). The percentages of MPAs with CM, IM, and NCM were higher than those of healthy controls (p = 0.012, p < 0.001 and p < 0.001, respectively). Circulating MPAs showed correlations with hypoalbuminemia (r=-0.85; p < 0.001), hypercholesterolemia (r = 0.54; p < 0.001), fibrinogen (r = 0.70; p < 0.001) and D-dimer (r = 0.37; p = 0.003), but not with hypertriglyceridemia in nephrotic syndrome. The AUC for the prediction of hypercoagulability in nephrotic syndrome using MPAs was 0.79 (95% CI 0.68-0.90, p < 0.001). The sensitivity of MPAs in predicting hypercoagulability was 0.71, and the specificity was 0.78.
CONCLUSION
Increased MPAs were correlated with hypercoagulability in nephrotic syndrome. MPAs may serve as a potential biomarker for thrombophilic or hypercoagulable state and provide novel insight into the mechanisms of anticoagulation in nephrotic syndrome.
PubMed: 38943162
DOI: 10.1186/s12959-024-00626-3 -
Scientific Reports Jun 2024The tobacco alkaloid nicotine is known for its activation of neuronal nicotinic acetylcholine receptors. Nicotine is consumed in different ways such as through...
The tobacco alkaloid nicotine is known for its activation of neuronal nicotinic acetylcholine receptors. Nicotine is consumed in different ways such as through conventional smoking, e-cigarettes, snuff or nicotine pouches. The use of snuff has been associated with several adverse health effects, such as inflammatory reactions of the oral mucosa and oral cavity cancer. We performed a metabolomic analysis of nicotine-exposed THP-1 human monocytes. Cells were exposed to 5 mM of the alkaloid for up to 4 h, and cell extracts and medium subjected to untargeted liquid chromatography high-resolution mass spectrometry. Raw data processing revealed 17 nicotine biotransformation products. Among these, cotinine and nornicotine were identified as the two major cellular biotransformation products. The application of multi- and univariate statistical analyses resulted in the annotation, up to a certain level of identification, of 12 compounds in the cell extracts and 13 compounds in the medium that were altered by nicotine exposure. Of these, four were verified as methylthioadenosine, cytosine, uric acid, and L-glutamate. Methylthioadenosine levels were affected in both cells and the medium, while cytosine, uric acid, and L-glutamate levels were affected in the medium only. The effects of smoking on the pathways involving these metabolites have been previously demonstrated in humans. Most of the other discriminating compounds, which were merely tentatively or not fully identified, were amino acids or amino acid derivatives. In conclusion, our preliminary data suggest that some of the potentially adverse effects related to smoking may also be expected when nicotine is consumed via snuff or nicotine pouches.
Topics: Humans; Nicotine; Metabolomics; Monocytes; Mass Spectrometry; THP-1 Cells; Cotinine; Chromatography, Liquid; Metabolome; Glutamic Acid
PubMed: 38942832
DOI: 10.1038/s41598-024-65733-7