bluuebunny/crossref_metadata_2025_split huggingface dataset:
NKp30-based chimeric antigen receptors promote T-cell effector functions and anti-tumor efficacy (53.11)
Authors: Wu Ming-Ru , Zhang Tong , Sentman Charles 
Published: January 2023

Abstract
NKp30 is a natural cytotoxicity receptor (NCR) that is expressed on natural killer (NK) cells and recognizes B7-H6, which is expressed on several types of tumors but few normal cells. To target effector T cells against B7-H6-positive tumors, we have developed several chimeric antigen receptors (CAR) based on NKp30, which contain the CD28, Dap10, CD27, and/or CD3ζ signaling domains with the transmembrane domains from CD3ζ, CD28, or CD8α. The NKp30 CAR expressing T cells produced IFN-γ and killed B7-H6 ligand-expressing tumor cells. This response was dependent upon ligand expression on target cells but not on MHC expression. The inclusion of other signaling domains enhanced chimeric NKp30 CAR-mediated activity compared to CD3ζ alone. Adoptive transfer of T cells expressing a chimeric NKp30 receptor containing a CD28 signaling domain inhibited the growth of a B7-H6-expressing murine lymphoma (RMA/B7-H6) in vivo. Moreover, mice that remained tumor-free were resistant to a subsequent challenge with the wild-type RMA tumor cells, suggesting the generation of immunity against other tumor antigens. Overall, this study demonstrates the therapeutic potential of adoptive immunotherapy with NKp30 CAR-expressing T cells against B7-H6+ tumor cells.
Comprehensive, longitudinal T cell functional analyses correlated with clinical outcome of a melanoma immunotherapy trial (53.18)
Authors: Ma Chao , Cheung Ann , Chodon Thinle , Comin-Anduix Begonya , Koya Richard , Ribas Antoni , Heath James 
Published: January 2023

Abstract
Adoptive cell transfer (ACT) of transgenic T lymphocytes expressing tumor antigen specific T cell receptor (TCR) can mediate objective responses. However, little is known about the functional activity of the transferred cells and the dynamics of host immunity. We monitored the transgenic and endogenous immunity of 8 metastatic melanoma patients over 8-10 time points in a MART-1 TCR ACT therapy. Using 3 highly multiplex clinical immune diagnostics methods (Ma, C. et al. Nature Medicine 17, 738-743 (2011)), the abundance of 35 melanoma antigen specific cytotoxic T lymphocyte (CTL) populations, 19 functional proteins from 6 types of phenotypically defined single T cells, and 37 blood tumor and immune markers was quantified, yielding millions of readouts. In all patients there was an initial clinical antitumor response followed by disease progression, which correlated with T cell changes observed. The transgenic MART-1 T cells expanded rapidly after infusion, producing multiple cytotoxic and antitumor cytokines. However, their abundance and polyfunctionality diminished within 2-3 weeks. Around 30 days post infusion, a multi-clonal expansion of melanoma specific CTLs emerged only in patients with regressing metastatic lesions. These cells exhibited antitumor functions initially, but gained inhibitory and non-specific functions and diminished in number when tumor progressed. This study points to the need of maintaining T cell functionality to improve ACT therapy effectiveness.
Adoptive immunotherapy using liver natural killer cells for preventing recurrence of hepatocellular carcinoma in cadaveric donor liver transplantation (53.20)
Authors: Ohira Masahiro , Nishida Seigo , Levi David , Tekin Akin , Selvaggi Gennaro , Ruiz Phillip , Ricordi Camillo , Ohdan Hideki , Tzakis Andreas 
Published: January 2023

Abstract
Tumor recurrence is the limitation of liver transplant (LT) in patients with hepatocellular carcinoma (HCC). However, there is no prevention or treatment for HCC recurrence after LT. Here, we describe a clinical-scale method for an adoptive immunotherapy that uses natural killer (NK) cells derived from donor liver graft perfusate to prevent HCC recurrence after LT. Liver mononuclear cells (LMNC) that were extracted from the deceased donor liver graft perfusate contained a large percentage of NK cells (45.0% ± 4.0%) compared with peripheral blood mononuclear cells (PBMC) (21.8% ± 5.2%) from the same donor. Furthermore, interleukin (IL)-2-stimulated NK cells showed greater upregulation of activation markers and the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is critical for NK cell-mediated anti-tumor cell. Moreover, IL-2 stimulation induced LMNC to exhibit a stronger cytotoxicity against HCC compared with PBMC (p &lt; 0.01). After obtaining approval from the FDA and IRB of our institute, we successfully applied this approach to 10 liver cirrhotic patients (9M / 1F) with HCC (Clinicaltrial.gov #NCT01147380). The average number of administered NK cells was 175 × 106 cells/body. After infusion, cytotoxicity, TRAIL, NKp44, and CD226 expression on NK cells significantly increased in patients’ PBMC (p &lt; 0.05). There are no study related adverse events. In conclusion, the administration of IL-2-stimulated cadaveric donor liver NK cells is well tolerated.
Viral infection induces immune responses to many self-proteins, some of which are known tumor associated antigens (53.23)
Authors: Iheagwara Uzoma , Minden Jonathan , Ross Ted , Beatty Pamela , Finn Olivera 
Published: January 2023

Abstract
It has been previously described that viral infection and inflammatory events induced abnormal expression and specific antibodies to tumor associated antigens (TAA). We hypothesize therefore that normal cellular molecules that undergo changes following viral infections generate an immune memory response that participates in tumor immunosurveillance. We are testing this hypothesis by infecting C57BL/6 mice with influenza virus and examining the post infection antibody repertoire for newly generated antibodies that might recognize TAA in Lewis Lung Carcinoma (3LL). We also aim to identify specific molecules most significantly associated with tumor protection. Pre- and post-infection sera were used to immunoprecipitate proteins from the whole cell 3LL tumor lysate. The immunoprecipitated proteins were be subjected to Difference In-Gel Electrophoresis (DiGE) to detect proteins uniquely precipitated by post-infection sera. The selected spots were removed from the gels and analyzed by mass spectrometry. We identified the protein content of 32 new spots precipitated by post-infection serum. Many of these proteins are involved in cytoskeletal and metabolic processes. To start examining their expression on normal, infected or transformed cells, as well as their immunogenicity, we selected the first group of molecules based on previous reports implicating them in anti-tumor immunity. They are: enolase, alpha-actinin-4, 14-3-3 protein sigma, GAPDH, Histone H4, HSP70, and HSP90.
MicroRNA-155 regulates inflammation in alcoholic liver disease via targeting SOCS1 and SHIP1 (54.15)
Authors: Bala Shashi , Petrasek Jan , Csak Timea , Catalano Donna , Kodys Karen , Mundkur Shiv , Szabo Gyongyi 
Published: January 2023

Abstract
Background Fatty liver and inflammation characterize alcoholic liver disease (ALD). Sensitization of liver macrophages (Kupffer cells; KCs) to gut-derived LPS and increased TNFα play a central role in ALD. MicroRNA-155 (miR) is a master regulator of inflammation. In this study we evaluated the role of miR-155 in regulating inflammation after chronic alcohol feeding. Methods C57Bl/6 female mice were fed with 5% alcohol (Liber-DeCarli diet) for 4 weeks and total liver and KCs were isolated. Results MiR-155 positively regulates TNFα and we found increased TNFα mRNA and protein in KCs of alcohol-fed mice. Furthermore increased miR-155 levels correlated with TNFα production in KCs of alcohol-fed mice. To dissect the mechanism by which miR-155 regulates TNFα in ALD, we evaluated the miR-155 target genes SOCS1, SHIP1 and IRAKM that are negative regulators of LPS signaling. We found increased miR-155 and decreased expression of SOCS1, SHIP1 and IRAKM in KCs of alcohol-fed mice. Importantly inhibition of miR-155 by using a specific miR-155 inhibitor, inhibited TNFα production in KCs of alcohol-fed mice, suggesting a role of miR-155 in TNFα regulation. C/EBPβ, another miR-155 target, regulates monocyte maturation and cytokine production. We found increased miR-155 and decreased DNA binding of C/EBPβ in livers of alcohol-fed mice. Conclusion Collectively our results indicate that alcohol induced-miR-155 contributes to inflammation via targeting multiple genes of LPS/TLR4 signaling.
Differential lumbar spinal cord mononuclear cell responses among wild type, CD4 knockout, and CD40 knockout mice in spinal nerve L5 transection-induced neuropathic pain (54.17)
Authors: Cao Ling , Beaulac Holly , Eurich Adriana 
Published: January 2023

Abstract
We have previously demonstrated that both lumbar spinal cord-infiltrating CD4+ T cells and lumbar spinal cord microglial CD40 contribute to the maintenance of mechanical hypersensitivity in the murine model of neuropathic pain spinal nerve L5 transection (L5Tx). To further delineate the CD4 and CD40-mediated mechanisms involved in the development of L5Tx-induced neuropathic pain behaviors, we examined the lumbar spinal cord mononuclear cells of wild type (WT) BALB/c, BALB/c-CD4 knockout (KO), and BALB/c-CD40 KO mice in time course studies via flow cytometry. In WT mice, L5Tx significantly increased the total numbers of lumbar spinal cord mononuclear cells, microglial cells (CD45loCD11b+), and infiltrating leukocytes (CD45hi) in the ipsilateral side of the spinal cord on both days 3 and 7 post-surgery. Meanwhile, in CD4 KO mice, the only significant elevation in microglial cells was observed on day 7 post-L5Tx, and there were no increases in mononuclear cells and infiltrating leukocytes numbers post-L5Tx. On the other hand, in CD40 KO mice, L5Tx did not induce any of the changes observed in WT mice. Altogether, these data indicate that both CD4 and CD40 play a role in L5Tx-induced leukocyte infiltration into the lumbar spinal cord but have differential contributions to spinal cord microglial activation following peripheral nerve injury.
Inflammation Promoting Activity Of HMGB-1 In Type-II Diabetes And As a Marker Of Tissue Injury . (54.3)
Authors: Kannan Krishnaswamy , Ortmann Robert 
Published: January 2023

Abstract
HMGB-1 is a well characterized DNA-binding protein and a potent proinflammatory molecule when released extracellularly during tissue injury. Accelerated atherosclerosis is a major cause of morbidity in diabetes and a causative factor of coronary artery disease, stroke and vascular disease. HMGB-1 is elevated in ischemia-reperfusion injury of the heart and also highly expressed in endothelial cells, vascular smooth muscles, and macrophages present in atherosclerotic lesions. Since HMGB1 is a ligand for advanced glycation end products (RAGE) and is capable of interacting with toll-like receptors, it is likely that a vicious cycle of pro-inflammatory activity occur in patients with diabetes. In this study, the role of HMGB-1 in type II patients (T2D) was examined to better understand its role in chronic inflammation. Plasma samples from T2D patients (n=13) and age matched healthy normal controls (n=20) were analyzed for HMGB-1 and proinflammatory cytokines IL-6 and TNF-α. Our results showed that patients with T2D had significantly elevated levels of TNF-α and IL-6 as compared to healthy controls. Elevated levels of pro-inflammatory cytokines also correlate well with HMGB-1 levels found in patient sera. Collectively, our data suggests a pro-inflammatory activity in patients with T2D. Endogenous danger signals such as HMGB-1 may promote autocrine loop of inflammation and contribute to the persistence of inflammation in type II diabetes and autoimmune diseases.
Adenosine receptor involvement in both the initiation and resolution of inflammation in the central nervous system during experimental autoimmune encephalomyelitis (54.6)
Authors: Mills Jeffrey , Kim DoGeun , Chen Jiang-Fan , Bynoe Margaret 
Published: January 2023

Abstract
Extracellular adenosine is a key regulator of inflammatory immune responses. Utilizing the experimental autoimmune encephalomyelitis (EAE) animal model of multiple sclerosis, we have shown that both the lack of CD73 (catalyzes extracellular adenosine) and antagonist blockade of the A2A adenosine receptor (AR) can protect mice from EAE development. To fully define the importance of A2AAR signaling during EAE progression, we induced disease in A2AAR-/- mice. Surprisingly, A2AAR-/- mice were not only susceptible to EAE, but developed more severe disease associated with an increased number of brain and spinal cord lymphocytes and activated microglial cells. Severe EAE was also found in radiation bone marrow chimeric mice given stem cells from A2AAR-/- donor mice. However, irradiated A2AAR-/- mice given wild type donor cells were protected from disease progression. Our data strongly suggests that A2AAR expression on lymphocytes is important in controlling the magnitude of the inflammatory response during EAE, as A2AAR-/- lymphocytes had a higher proliferative potential and produced more IFNγ following MOG stimulation compared to those from wild type mice. However, A2AAR signaling on non-hematopoietic cells also has an important role in promoting disease progression as A2AAR blockade prevented EAE development in T cell deficient mice given A2AAR-/- donor cells. Overall, our results indicate that A2AAR signaling is involved in both the progression and resolution of EAE.
Dectin-1 controls maturation of fungal phagosomes (55.1)
Authors: Mansour Michael , Tam Jenny , Khan Nida , Puranam Srav , Vyas Jatin 
Published: January 2023

Abstract
Dectin-1 recognizes the fungal wall carbohydrate, β-1,3-D-glucan. Defects in Dectin-1 have been isolated in patients suffering from recurrent Candidal infections demonstrating the essential role of carbohydrate recognition in eliciting protective immunity. In the following work, we sought to characterize the intracellular steps following β-1,3-D-glucan phagocytosis by macrophages. In previous studies, we described a fungal-like particle (FLP) consisting of a polystyrene bead platform covalently conjugated to β-1,3-D-glucan thus mimicking the geometry and surface of fungal pathogens. Using a RAW cell line expressing GFP-Dectin-1, we show that there is translocation of Dectin-1 from the surface to the FLP-containing phagosome which is eliminated by 2h. In order to explore the contribution of Dectin-1-specific intracellular signaling towards the off-rate, a TYR to PHE substitution was introduced within the ITAM-like motif of the cytoplasmic domain of Dectin-1 (ΔY3). GFP-Dectin-1-ΔY3 showed prolonged retention to the phagosome when compared to WT Dectin-1. We next explored subsequent phagolysosomal maturation milestones. Interestingly, phagosomes with intense Dectin-1-ΔY3 did not acidify or recruit LAMP-1 suggesting phagolysosomal maturation blockade. Using Candida albicans, similar deficits in phagosomal maturation were seen with Dectin-1-ΔY3-positive Candida containing phagosomes. These data suggest novel role for Dectin-1 as a controller of fungal phagosome maturation.
Elevated resistin levels in severe pulmonary tuberculosis weaken mycobacterium-mediated inflammasome activation (55.10)
Authors: Chao Wen-Cheng , Yen Chia-Liang , Shieh Chi-Chang 
Published: January 2023

Abstract
Resistin, a protein produced by immune cells in human, causes insulin resistance and impairs the reactive oxygen species (ROS) production in granulocytes. Recent studies suggested that IL-1β production in pulmonary tuberculosis (TB) correlates with inflammasome activation which may be regulated by ROS. We first investigated the serum levels of resistin in pulmonary TB patients with different clinical severity. We found that serum resistin levels were significantly higher in severe TB cases and diabetes-only (DM) group when compared with mild TB cases and healthy controls. Moreover, elevation of serum resistin correlated with impairment of ROS production of granulocytes in DMTB cases. In human macrophages, we further demonstrated that resistin inhibits ROS production and ROS regulated the mycobacterium-mediated inflammasome activation. Finally, using macrophages derived from WT and Ncf1-/- mice, we verified that ROS regulate the mycobacterium mediated inflammasome activation. We concluded that resistin, which suppresses the mycobacterium-mediated inflammasome activation through inhibition of ROS production, is a useful biomarker in severe pulmonary tuberculosis.
Role of inflammasome-dependent cytokine production and neutrophil recruitment during acute lung injury that protects from Burkholderia species infection (55.17)
Authors: Re Fabio , Sahoo Manoranjan , Barrio Laura , Ratsimandesy Rojo , Miller Mark , Ceballos-Olvera Ivonne 
Published: January 2023

Abstract
Burkholderia pseudomallei is a Gram-negative bacterium that infects macrophages and other cell types and causes melioidosis. We have recently shown that the Nod-like receptors (NLR) NLRP3 and NLRC4 differentially regulate pyroptosis and production of IL-1β and IL-18 in response to B. pseudomallei infection. Pyroptosis and IL-18 production were equally important for resistance to B. pseudomallei. Surprisingly, IL-1β was found to be deleterious in melioidosis. The detrimental role of IL-1β during melioidosis was due, in part, to excessive recruitment of neutrophils to the lung. We showed that neutrophils do not express NLRC4, fail to undergo pyroptosis, and, therefore, may be permissive to B. pseudomallei intracellular replication leading to increased bacterial burden and morbidity/mortality. Results will be presented to extended the analysis of the role of the inflammasome components NLRP3, NLRC4, ASC, and Caspase-1 and of IL-1β, IL-18, and pyroptosis during lung infection with other Burkholderia species like B. thailandensis and B. cepacia. Preliminary studies indicate that mice that underwent an acute lung injury (ALI) protocol showed an increased resistance to Burkholderia infection. We will show results that characterize the role of IFNγ and neutrophils recruitment in the protective effect of ALI.
Pseudomonas aeruginosa infection after burn injury polarizes innate immune cells towards an alternatively activated phenotype (55.19)
Authors: Neely Crystal , Kartchner Laurel , Mendoza April , Cairns Bruce , Maile Robert 
Published: January 2023

Abstract
Severe burn injury causes profound immunosuppression resulting in prevalent bacterial infections. We hypothesized that bacterial infection after burn injury polarizes macrophage (Mo) and neutrophil (No) responses into an alternatively activated (M2/N2) phenotype. To test this, we used a murine model of burn injury and bacterial challenge. Female C57BL/6 mice underwent either a 20% TBSA full thickness contact burn or control sham procedure. Twenty-four hours later mice were either given a subcutaneous injection of Pseudomonas aeruginosa or control saline and sacrificed two days later to determine bacterial burden in skin, liver and lung. Serum cytokine levels were measured by cytometric bead array. Splenocytes were cultured in the presence of Brefeldin-A for intracellular cytokine analysis, and Mo and No were identified by surface staining. Burn mice had bacterial dissemination indicated by positive cultures from all tissue samples. No bacteria were recovered from sham mice. Burn injury, but not infection, induced a significant increase in serum IFN-γ and TNF-α. IL-6 was also significantly increased after burn injury alone but was significantly higher in infected burn mice. IL-10 was elevated in infected burn mice only. Flow cytometry confirmed expression of IL-10 protein within Mo and No. These data suggest that after burn injury, bacterial infection polarizes serum cytokine and innate cell phenotype into an alternatively activated phenotype allowing systemic infection.
Fibrosis and expression of mast cells peptidase: chymase and tryptase in oral paracoccidioidomycosis lesions (55.25)
Authors: Rodrigues Denise , Araujo Marcelo , Alves Polyanna , Pereira Sanivia , Lima Lilian , Silva Marcelo , Rodrigues Virmondes 
Published: January 2023

Abstract
Mast cells belong to the innate immune system, which provides the first line of defense against tissue damage. Tryptases and chymases are mast cells peptidases that promote inflammation, matrix destruction, and tissue remodeling by several mechanisms. They also modulate immune responses by hydrolyzing chemokines and cytokines. Oral lesions in Paracoccidioidomycosis(PCM), microscopically shows granulomatous inflammatory reaction with giant cells, macrophages, lymphocytes, plasma cells and mast cells. Mast cells were seen in PCM, but their participation and interaction with other cells remains to be determined. This study evaluated in situ expression of mast cell peptidase and fibrosis on oral lesions of PCM patients. Fifteen oral biopsies from patients with clinical and histopathological diagnosis of oral PCM and thirteen biospies from normal oral mucous (control group) were analyzed. Fibrosis was significantly higher in disorganized granuloma when compared to controls. Indirect immunohistochemistry was used to evaluate the expression of peptidase chymase and tryptase. The number of immunostained cells for chymase and tryptase was significantly higher in control group, when compared to the Pmycosis patients (p&lt;0.025). The down modulation of chymase and tryptase expression and the increase fibrosis in PCM oral lesion may be a consequence of inflammatory process induced by the presence of fungus and also are potentially involved in the regulation of immune response.
Ageing and expression of TLR pathway associated genes in macrophages to Porphyromonas gingivalis challenge. (55.26)
Authors: Shaik-Dasthagirisaheb Yazdani , Shen Steve , Genco Caroline , Gibson III Frank 
Published: January 2023

Abstract
Background: Periodontal disease is a chronic inflammatory disease that leads to progressive loss of soft and hard tissues supporting the teeth. Porphyromonas gingivalis (Pg) is a bacterium closely associated with periodontal disease. Toll-like receptors (TLR) and their intracellular signaling pathways play roles in host response to Pg. The focus of the current study was to define the expression profile of TLR pathway associated genes in macrophages (MØ) cultured with Pg, and to define changes in expression of these genes as a consequence of ageing. Methods: Bone marrow MØ from 2 months and1 year old wild type (WT), TLR2 knockout (KO), TLR4KO, MyD88KO and LPS2 mice were cultured with Pg. RNA was harvested from unchallenged and Pg challenged cells and expression of TLR pathway associated genes was measured by qPCR microarrays. Results: Pg challenge of WT MØ induced expression of a large set of TLR pathway associated genes. MØ gene expression data revealed 19, 48, 45 and 56 genes differentially regulated in TLR2KO, TLR4KO, MyD88KO and LPS2 mice respectively as compared with WT in response to Pg. We identified 19 genes that are commonly regulated in all four mutant genotypes. Age had little effect on the differential regulation of these genes by mutant MØ as compared with WT. Conclusions: Regulation of TLR pathway associated genes by MØ was highly responsive to Pg challenge. Pg challenge and mouse genotype had the strongest effects on gene expression in this model.