bluuebunny/crossref_metadata_2025_split huggingface dataset:
Redirection of TH17 cells with a chimeric antigen receptor containing the ICOS costimulatory domain enhances function, antitumor activity and persistence of TH17 cells (P4350)
Authors: Guedan Sonia , Carpenito Carmine , Chen Xi , Madar Aviv , McGettigan Shannon , Frigault Matthew , Scholler John , Scholler Nathalie , Bonneau Richard , June Carl 
Published: January 2023

Abstract
Adoptive transfer of TH17 cells polarized and expanded in vitro is an attractive therapy for the treatment of cancer. CD278, the inducible costimulator (ICOS) has been shown to be critical for the sustained expansion of human TH17 cells after their primary activation. We hypothesized that the incorporation of the ICOS intracellular domain in a CAR can promote the Th17 phenotype after antigen priming and enhance the antitumor activity of engineered T cell therapies. Th17 polarized cells were engineered to express a CAR comprised of a single-chain variable fragment that binds mesothelin fused to the T cell receptor- ζ signal transduction domain in tandem with the CD28, CD137 (4-1BB) or CD278 (ICOS) intracellular domains. Upon antigen recognition, Th17 cells redirected with the CAR:ICOS maintained a core molecular signature of Th17 cells, secreted higher amounts of IL17A, IL17F and CCL20 and expressed higher levels of CD161, NKG2D, IL1R-1 when compared with CD28 and 4-1BB CARs. When transferred into NSG mice with large tumors, Th17/Tc17 cells redirected with the CAR: ICOS mediated enhanced anti tumor responses and showed increased persistence. Our studies indicate that redirection of Th17 cells with a CAR encoding the ICOS intracellular domain is critical for obtaining potent Th17 cells with enhanced function and persistence. The design of novel ICOS-based CARs has the potential to augment antitumor effects in clinical trials.
Effect of combined treatment of selective serotonin reuptake inhibitors plus immunomodulator on circulating cytokines levels in patients with major depressive disorder along 52 weeks of follow up (P4521)
Authors: Pavon Lenin , Hernandez Maria Eugenia , Perez-Tapia Sonia Mayra , Mendieta Danelia , Bojalil Rafael , Estrada-Garcia Iris , Estrada-Parra Sergio 
Published: January 2023

Abstract
Major Depressive Disorder (MDD) is a psychiatric illness that commonly displays a deficit of serotonergic neurotransmission in the central nervous system. MDD patients also show alterations in alterations in cortisol and cytokines levels. Those patients are treated with selective serotonin reuptake inhibitors (SSRIs). The aim of this study was to assess the efficacy of the combined treatment with SSRIs plus an immunomodulator -dialyzable leukocyte extract (DLE) - in restoring the balance of both the serotoninergic system and the endocrinoimmune parameters. A total of 34 patients diagnosed with MDD received anti-depressant treatment with SSRIs plus DLE. As control 31 patients received only SSRIs. Proinflammatory cytokines (Th1) IL-1β, IL-2, IFN-γ, anti-inflammatory cytokines (Th2) IL-13, IL-10, and 24-h urine cortisol were determined at weeks (W) 0, 5, 20, 36 and 52 of treatment. The maximum reduction in cortisol levels in SSRIs group was only 30% (W52). By contrast, the treatment with SSRIs plus DLE decreased 53% the cortisol levels from W20. Reduced cortisol in patients treated with SSRI plus DLE correlated with reductions in the concentration of Th2-cytokine and increases in Th1-cytokines at the end of the study. These results suggest that the immune-stimulating action of DLE, in association with the effects of SSRIs, allowed the immune system to balance the ratio of Th1/Th2 cytokines associated and decreased levels of cortisol.
Development of pattern recognition receptor ligands as malaria vaccine adjuvants (P4532)
Authors: Chang Sandra , Chang Martin , Posner Jourdan 
Published: January 2023

Abstract
A critical obstacle to malaria vaccine development is the lack of appropriate adjuvants to elicit potent and protective immunity. Recent insights into the role of pattern recognition receptors (PRRs) in dendritic cell (DC) activation and identification of follicular helper T (Tfh) cells, as specialized providers of B cell help, enable a novel approach to adjuvant selection. We hypothesize that specific combinations of PRR agonists will be effective adjuvants by promoting the differentiation of Tfh cells. We evaluated PRR ligands that activate through distinct intracellular signaling pathways: a Toll-like receptor (TLR) agonist signaling through the MyD88-dependent pathway (R848), TLR agonists signaling through the TRIF-dependent pathway (p(I:C) and GLA); an agonist of Nod1 (C12-iE-DAP) that signals through RIP2; and an agonist for Mincle (synthetic trehalose-dibehenate) that signals through FcRγ Src-family kinase. R848 was a strong inducer of DC activation in vitro, particularly when combined with p(I:C), inducing significantly higher cytokine RNA (IL-12, TNFα) and protein (IL-12, TNFα, IL-6, IFN-γ), producing higher DC expression of CD86, and activating both pDCs and cDCs. IL-6, a potent Tfh stimulator, was maximal in DC cultures stimulated with R848 combinations. Ongoing studies will evaluate the ability of specific PRR combinations to polarize naïve CD4+ T cells to differentiate into Tfh cells in vitro and in vivo and provide help for P. falciparum blood-stage vaccines.
Flow cytometric analysis of bone marrow and spleen cells in adjuvant-treated animals (P4502)
Authors: Yang Ya-Wun , Chang Chih-Feng 
Published: January 2023

Abstract
Despite the poorly understood mechanisms, vaccine adjuvants have been extensively used to enhance the immunogenicity of specific antigens in vaccination. To examine the effect of adjuvants on the differentiation of the hematopoietic system, C57BL/6J mice were immunized with ovalbumin (OVA) with alum, followed by flow cytometric analysis of cells in the bone marrow and spleens after vaccination. Our data showed that treatment of animals with alum upregulated the expression of AA4.1 in the Dump(CD3/CD8/Gr-1/F4/80)(-)CD24(+) population, and a concomitant increase of both B220(-)CD11b(+) and CD24(+)CD43(+) cells in the spleen, indicating the differentiation effect on the hematopoietic cell development. Our results also showed that Dump(-)B220(-)CD24(+) population in the bone marrow were significantly elevated, suggesting the potential induction of myeloid differentiation from proB populations in the adjuvant-treated animals. Similar results were obtained in the complete-Freund's adjuvant (CFA)-treated mice. Treatment of animals with CFA was found to elevate the lineage2 (CD3/CD19/NK1.1/B220/Ter119)(-)CD11b(+) population at the expense of lineage2(+) cells, suggesting the potential differentiation of hematopoietic stem cells towards the myeloid lineage from the lymphoid progenitors. These results raised the potential effect of vaccine adjuvants on modulation of hematopoietic hierarchy, explaining their actions of mechanism on stimulation of the specific immunological responses.
BPV VLPs presenting HIV-1 epitopes from membrane-proximal external region of gp41 induced HIV-specific mucosal and systemic cross-clade neutralizing antibodies (P4507)
Authors: Zhai Yougang , Zhong Zhenyu , Zariffard Mohammadreza , Spear Gregory , Qiao Liang 
Published: January 2023

Abstract
Two conserved epitopes, located in the membrane-proximal external region (MPER) of gp41 of the human immunodeficiency virus type 1 (HIV-1) envelope spike, are promising targets for vaccine design in efforts to elicit 2F5 and 4E10-like anti-HIV-1 broadly neutralizing antibodies. Since most HIV-1 infections initiate at mucosal surfaces, the induction of mucosal neutralizing antibodies is necessary and of utmost importance to counteract HIV-1 infection. Here, we utilized a mucosal vaccine vector, bovine papillomavirus (BPV) virus-like particles (VLPs), as a platform to present HIV-1 neutralizing epitopes by inserting the extended 2F5 (ELLELDKWASLWN) or 4E10 epitope (NWFDITNWLWYIK) or the MPER domain into surface loops of BPV L1 respectively. In order to enhance the presentation of the neutralizing epitopes, the modified 4E10 and 2F5 epitope were presented by inserting two alanines (AA) in N-terminal, C-terminal or both terminals of the epitopes. The chimeric VLPs presenting MPER domain resembled the HIV-1 natural epitopes better than the chimeric VLPs presenting unmodified single ones. Moreover, N-terminal modified 2F5 epitope further enhanced the epitope presentation when inserted in D-E loop. Oral immunization of mice with the chimeric VLPs displaying 2F5 or MPER elicited epitope-specific serum IgGs and mucosal secretory IgAs. The antibodies induced by chimeric VLPs presenting MPER domain are capable of neutralizing clade B and clade C HIV-1 viruses, although modest.
Associating long-lived liver CD49b+CD8b+ T cells with long-lasting immunity against malaria (P4481)
Authors: Jang Ihn , Chen Lin , Peng Xiaohong , Choi Kimberly , Gibson Claire , Wang Ruobing 
Published: January 2023

Abstract
The sterile and long-lasting immunity against malaria can be induced by vaccination with genetically attenuated parasites (GAP). We have demonstrated that GAP-specific CD8+ T cells are key in protective immunity against pre-erythrocytic stages in mice. Here, we further characterized the CD8+ T cell phenotype and function associated with the longevity of the sterile protection induced by PyFabb/f- GAP. We demonstrated that vaccination of mice with Fabb/f- GAP resulted in a significant increase of effector/memory CD8+ T cells characterized as CD8bhi or CD8blo T cells expressing integrin CD49b primarily detected in the liver, a primary infection site. More importantly, CD49b+CD8blo T cell subset persisted for a long period and strongly associated with GAP-induced prolonged protection in Balb/c mice. In contrast, Fabb/f- GAP induced a short-lived CD49b+CD8bhi T cells but failed to induce a sustainable CD49b+CD8blo T cells leading to a short-term protection in C57Bl/6 mice. In understanding the biological effects of these CD8 T cell subsets, ex vivo functions and transcriptional analysis are underway. The predictive contributions of short-lived and long-lived CD8 T cells induced by GAP vaccination in protective efficacy against malaria would be highlighted by our findings.
Activated mesenchymal stem cells amplify antibiotic activity against chronic Staphylococcus aureus infection (P5056)
Authors: Johnson Valerie , Webb Tracy , Dow Steven 
Published: January 2023

Abstract
Background/Rationale: Antimicrobial resistance is one of the greatest challenges facing the medical community today and new interventions are needed. Recent studies have shown that mesenchymal stem cells (MSC) exhibit antimicrobial activity when activated by Toll-like receptor (TLR) ligands in vitro. We hypothesized that activated MSC could enhance the activity of conventional antibiotics in common wound infections. Methods: MSC derived from adipose tissue of mice were expanded in vitro and activated with TLR ligands to assess the effects on antimicrobial activity and production of antimicrobial peptides (AMP). The effects of MSC treatment in vivo were assessed using a mouse model of chronic S. aureus biofilm infection. Mice were treated with a series of 4 MSC i.v. injections, with or without antibiotic treatment, and bacterial load assessed over 14 days via IVIS imaging and bacterial culture of the wound site. Results: Activation of MSC with TLR ligands significantly increased production of the AMP CXCL10 and inhibited bacterial growth in vitro. The most potent TLR agonist in vitro was the TLR3 agonist polyI:C. In the chronic S. aureus infection model, activation of MSC with polyI:C resulted in decreased bacterial counts. Conclusions: Treatment with activated MSC induced AMP production and enhanced antibiotic therapy in vivo. These results suggest that stem cell therapy using activated MSC may be an effective means to enhance antibiotic therapy for chronic infections.
Co-transplantation of mesenchymal stem cell and fibroblast reduces inflammation and corrects defective dermal remodeling (P5062)
Authors: Yates Cecelia , Rodrigues Melanie , Wells Alan 
Published: January 2023

Abstract
Mesenchymal stem cell have been reported to enhance wound healing following transplantation however the mechanism for this response is unknown. The mechanism responsible for enhance wound healing includes the possible restorative paracrine effects of MSC synthesized soluble factors on dermal cell type. This study examines the influence MSC have on matrix remodeling during repair an in vivo system. We recently developed a chronic wound scar model based on the absence of signaling through the CXCR3 system; these mice develop sterile chronic inflammation and hypertrophic scars contributed in part by the defective fibroblast. Using these fibroblasts encapsulated with MSC, we sought to determine whether the fibroblast could overcome endogenous deficiencies and generate a physiological dermal tissue. Xenotransplantation of labeled CXCR3-/- mouse fibroblast and hMSC into wounds of both a CXCR3-/- scarring model revealed altered healing patterns. Results showed an enhanced healing response, correction of matrix regeneration, and reduced inflammation during the first 30 days. Flow cytometric analysis of the wound bed at days 1,3,5 revealed a reduction in CD4+ and CD8+ T-cells. Changes in matrix and soluble signals were also examined histologically. These data suggest there is a connection between the initial inflammatory response and matrix changes that regulates scarring. The current study provides insight into cellular therapies as viable method for antifibrotic treatment.
Resolvin E1 modulates Mac-1 signaling and promotes neutrophil apoptosis and the resolution of acute inflammation (P5064)
Authors: Filep Janos , Gjorstrup Per , El Kebir Driss 
Published: January 2023

Abstract
Resolvin E1 (RvE1), derived from the omega-3 polyunsaturated fatty acid eicosapentaenoic acid inhibits Mac-1 (CD11b/CD18)-mediated neutrophil trafficking. Mac-1also generates ligand-specific outside-in signals to modulate neutrophil apoptosis, a critical control point in the resolution of inflammation. We studied the impact of RvE1 on Mac-1signaling and neutrophil apoptosis. Culture of human neutrophils with RvE1 (0.1-10 nM) mitigated ERK and Akt-mediated survival signals from the Mac-1 ligand myeloperoxidase, leading to Mcl-1 degradation and mitochondrial dysfunction. RvE1 facilitated phagocytosis of C3b-opsonized E. coli and triggered phagocytosis-induced apoptosis. RvE1 through the leukotriene B4 receptor BLT1 evoked ROS generation by NADPH oxidase, leading to activation of caspase-8 and 3. In mice, treatment with RvE1 at the peak of inflammation enhanced the resolution of E. coli pneumonia, E. coli peritonitis-associated and carrageenan plus myeloperoxidase-evoked neutrophil-mediated lung injury through facilitating neutrophil apoptosis and removal of apoptotic neutrophils by macrophages. These actions of RvE1 were prevented by the pan-caspase inhibitor zVAD-fmk. Our results identify a novel resolution circuit, in which RvE1 through BLT1 shifts the balance between Mac-1-generated competing pro- and anti-apoptotic signals toward apoptotic pathways, and consequently enhances resolution of acute lung inflammation.
Serum amyloid A induces M2 macrophage-specific genes expression and promotes efferocytosis of apoptotic neutrophils (P5072)
Authors: Sun Lei , Zhou Huibin , Zhu Ziyan , Yan Qian , Ye Richard 
Published: January 2023

Abstract
Macrophages play an important role in the quality, duration and magnitude of most inflammatory reactions in a polarized manner. However, the determinants that modulate their plasticity remain unclear. Serum amyloid A is an acute-phase protein which induces both anti-inflammatory and pro-inflammatory cytokines during inflammation. In this study, we explored the potential involvement of SAA in modulating macrophage polarization. SAA not only induced the expression of anti-inflammatory M2-specific genes such as IL-10, Arginase-1, Ym-1, Fizz-1, Mrc-1, IL-1Rn, CCL17, but also promoted efferocytosis of apoptotic neutrophils, a process that is critical for the resolution of inflammation. Through experiments with formyl peptide receptor 2 antogonist WRW4 and Fpr2 deficient macrophages, we showed that the induction of M2-specific genes and efferocytosis by SAA were mediated specifically by Fpr2. Additionally, SAA stimulation resulted in the increase expression and activation of the transcription factor interferon regulatory factor 4. Selective inhibitors of ERK activity abrogated SAA induction upon M2 macrophages and efferocytosis by decreasing the expression and activation of IRF4. Knocking down the expression of IRF4 abrogated the effect of SAA on M2 macrophage. Our results demonstrate that SAA can induce M2 macrophage-specific genes and promote efferocytosis via Fpr2-ERK-IRF4 signaling, and suggests an alternative mechanism by which SAA is involved in anti-inflammatory responses.
Transcription factor Fli-1 is involved in regulation of inflammatory mediator production and ECM remodeling in primary dermal fibroblasts (P5088)
Authors: Sztokman Nicole , Zhang Xian 
Published: January 2023

Abstract
Numerous inflammatory and fibrotic disorders arise from process malfunctions in fibroblast regulation of extracellular matrix remodeling and cytokine expression in which the Friend leukemia integration factor 1, an E26 transformation-specific family transcription factor, participates. We have previously shown that Fli-1 regulates inflammatory monocyte chemoattractant protein 1 expression in endothelial cells and Fli-1 is highly expressed in fibroblasts. In this report, we investigated the involvement of Fli-1 in extracellular matrix remodeling and regulation of inflammatory mediators in dermal fibroblasts. We isolated primary dermal fibroblasts from wild type and Fli-1 heterozygous C57/BL6 mice. Expression of Fli-1 in fibroblasts from Fli-1 heterozygous mice was reduced by half compared to expression in wild-type mice. We measured the concentration of MCP-1 in supernatants from dermal fibroblasts after simulation with lipopolysaccharide and found MCP-1 concentrations in Fli-1 heterozygous mice to be significantly increased compared with wild type controls. The concentrations of other inflammatory mediators including matrix metalloproteinase I in the supernatants are currently being studied. Our results suggest that Fli-1 is involved in regulating the expression of inflammatory mediators in dermal fibroblasts.
Inadequate CD18 shedding and increased depletion of soluble CD18 contributes to inflammatory activity in spondyloarthritis (P5090)
Authors: Kragstrup Tue , Jalilian Babak , Hvid Malene , Kjærgaard Anders , Østgård René , Schiøttz-Christensen Berit , Jurik Anne , Vorup-Jensen Thomas , Deleuran Bent 
Published: January 2023

Abstract
Spondyloarthritis (SpA) is characterized by inflammation in the axial skeleton and entheses. Integrin adhesion molecules containing the CD18 chain are pivotal regulators of leukocyte extravasation from the blood into zones of inflammation. Recently, we showed that CD18 is shed from leukocytes forming a soluble form of CD18 (sCD18) in the blood. Here we show that plasma sCD18 is a marker of inflammatory activity in SpA. The plasma levels of sCD18 were decreased in SpA patients compared with healthy controls and showed inverse correlations with disease activity scores including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score. Remarkably, this situation could be simulated in vitro. Thus, the degree of CD18 shedding from SpA patient-derived PBMC correlated inversely with the BASDAI score. According to flow cytometric analyses, CD18 was primarily shed from intermediate (CD14++ CD16+) monocytes. In agreement with earlier reports identifying CD18 as a substrate for MMP-9, the concentration of this enzyme in the culture supernatants correlated with the sCD18 concentration. Also, sCD18 complexes adhered to TNFα-stimulated endothelial cells expressing high levels of ICAM-1 but not to unstimulated cells. Taken together, our data links alterations in plasma sCD18 and inflammatory activity in SpA. The low plasma level of sCD18 in SpA seems to be a combination of inadequate CD18 shedding and increased depletion of sCD18 potentially affecting leukocyte migration.
Ephedrine hydrochloride inhibits PGN-induced inflammatory responses by promoting IL-10 production and decreasing proinflammatory cytokine secretion via PI3K/Akt/GSK3β pathway (P5048)
Authors: Yu Yizhi , Zheng Yuejuan , Cao Xuetao 
Published: January 2023

Abstract
The approaches to control the inflammatory responses and reduce the mortality rate of sepsis are still not very effective in clinics and new potential drugs are needed to be confirmed to be useful in the induction of anti-inflammatory response. Ephedrine hydrochloride (EH) is a compound widely used for cardiovascular diseases, especially to treat hypotension caused by anesthesia or overdose of antihypertensive drugs. In this study, we reported that EH also plays an important role in the control of inflammatory response. It increases interleukin 10 (IL-10) and decreases proinflammatory cytokine (IL-6, TNF-α, IL-12, and IL-1β) expression in response to gram-positive cell wall component peptidoglycan (PGN) in primary peritoneal macrophages and Raw264.7 cells. The anti-inflammatory role of EH was also observed in experimental peritonitis mouse model induced by intraperitoneally PGN injection. Phosphatidylinositol 3-kinase (PI3K)/Akt pathway was found to be responsible for EH-enhanced IL-10 production and EH-decreased IL-6 expression. Therefore, our results illustrated that EH can help to maintain immune equilibrium and diminish host damage by balancing the production of proinflammatory cytokines and anti-inflammatory cytokine after PGN challenge. EH may be a new potential anti-inflammatory drug in treatment of severe invasive gram-positive bacterial infection.
Identification of a G-Protein coupled receptor for esterified 15(S)hydroxyeicosatetraenoic acid on human primary bronchial epithelial cells (P6255)
Authors: Vonakis Becky , Hise Kathleen , Liu Yun , Plunkett Beverly , Fang Xi , Haddad El-Bdaoui , Cox Paul 
Published: January 2023

Abstract
In asthmatic epithelium, the TH2 cytokine milieu results in production of phospholipid-esterified 15-HETE and elevated mucus secretion. A high-throughput 15-HETE binding assay was developed using 15-HETE esterified to biotin and Streptavidin-AlexaFluor488 to form the ligand (15HETE-Bt:SA-AlF). 15HETE-Bt:SA-AlF binding to Beas-2B cells and PBEC grown under air-liquid interface were assessed from 2- 60 min. Specificity of binding was monitored with unlabeled fatty acids [0.05-10 μM], biotin-hydrazide and SA-ALF. CyclicAMP (cAMP) was quantified using a competitive immunoassay kit. Intracellular calcium [Ca2+]i was measured (Fluo-3 / Fura-red) by flow cytometry. Beas-2B (n=8) and PBEC (n=3 donors) demonstrated time-dependent binding of 15HETE-Bt:SA-AlF, reaching equilibrium at 30 min., 4 deg.C. Binding of 15HETE-Bt:SA-AlF was dose-dependently displaced on Beas2B with 15-HETE&gt;12-HETE, 5-HETE &gt; 5,15diHETE,&gt;15-KETE &gt;&gt; LTB4 (p&lt; .05, 15-HETE vs. other fatty acids) whereas biotin-hydrazide:SA-ALF or SA-ALF were ineffective. In Beas2B cells, 15-HETE-Bt [0.1 - 10 μM] induced pM [cAMP] (n =4) whereas cholera toxin pretreatment (1 μg/ml, 5 hr.) inhibited 55-100% of cAMP production (n=2). A transient increase in [Ca2+]i was detected with 3-10 μM 15-HETE-Bt or 15-HETE in Beas2B (n=2). Bronchial epithelial cells exhibit specific, reversible binding of esterified 15-HETE suggesting a unique Gs- GPCR for esterified 15-HETE that may regulate airway inflammation in asthma.