bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intrahepatic Vα14iNKT cells Promote Liver Pathology during Adenovirus infection by Regulating Hepatic CCL5 and Intrahepatic γδT cell Activation: Implications for Vaccine Development (89.2)
Authors: Ajuebor Maureen , Chen Qingling 
Published: January 2023

Abstract
Replication-defective recombinant Adenoviruses are potential innovative viral vaccine vectors for treating many inherited and acquired human diseases. Broad clinical application of Adenoviruses in vaccine development is being hindered by the induction of vigorous innate and adaptive immune responses against the vector resulting in loss of Adenovirus transgene and deleterious effects in the liver. Vα14iNKT cells are thymic-derived innate T cells at the interface between the two arms of the immune response. The pathophysiological role of Vα14iNKT cells during replication-defective Adenovirus infection is not known, and is therefore a focus of our study. Our results revealed that Vα14iNKT cells were activated in response to Adenovirus infection to produce hepatic CCL5. In vivo studies utilizing CCL5 deficient mice showed that CCL5 deficiency caused reduced liver pathology and Adenovirus transgene loss. Similar results were also seen after blocking the biological effects of CCL5 receptors. Additionally, our data also revealed a novel and previously unrecognized pro-inflammatory role for activated intrahepatic Vα14iNKT cells in promoting liver pathology by positively regulating intrahepatic γδT cell activation. In summary, we have identified a novel and important pro-inflammatory role for activated intrahepatic Vα14iNKT cells in positively regulating both hepatic CCL5 and activated intrahepatic γδT cells to induce liver pathology without loss of Adenovirus transgene.
A protein superantigen, Staphylococcal Enterotoxin B (SEB), directly activates invariant Natural Killer T cells and leads to Acute Lung Injury and Acute Respiratory Distress Syndrome (ARDS) (89.37)
Authors: Rieder Sadiye , Nagarkatti Prakash , Nagarkatti Mitzi 
Published: January 2023

Abstract
Invariant Natural Killer T (iNK T) express T and NK cell markers and secrete a variety of pro- and anti-inflammatory cytokines. Glycolipids such as alpha-galactosylceramide (α-GalCer) are potent activators of iNK T cells when presented by the antigen presenting molecule, CD1d. In this study, we investigated a novel protein antigen, SEB, for the activation of iNK T cells, using ARDS model in mice. In general, SEB activates T cells that posses T cell receptors (TCR) with Vβ8, -7 or -2 chains, and since iNK T cells also have this particular TCR, we hypothesized that SEB can directly activate iNK T cells. We demonstrate that after intranasal administration of SEB, vascular leak and infiltration of lymphocytes were significantly reduced in the lungs of Jα18-/- and CD1d-/- mice as compared to WT mice. The pore size in the endothelial cells of the capillaries of the lung was greater than 500nm for WT mice, while it was between 100 and 500nm for Jα18-/- and Cd1d-/- mice. We also show that cytokine storm induced by SEB was significantly reduced in the serum and bronchialveolar fluid of Jα18-/- and CD1d-/- mice. In vitro cultures that contained SEB-pulsed bone marrow derived dendritic cells (BMDCs) and FACS purified iNK T cells produced significant amounts of IFN-γ and IL-4, comparable to the α-GalCer-pulsed BMDC and iNK T cell cultures. We show for the first time that iNK T cells are activated by a protein antigen, and they are innate responders in Acute Respiratory Distress Syndrome.
The connection between Serum Amyloid P/Pentraxin-2 and IL-10 in the treatment of kidney fibrosis (89.43)
Authors: Castano Ana , Lupher Jr Mark , Duffield Jeremy 
Published: January 2023

Abstract
In models of kidney fibrosis, systemic administration of Serum amyloid P or Pentraxin-2 (PTX-2) significantly inhibits fibrosis through a monocyte/macrophage-dependent mechanism, and as such represents a potential novel therapy for the treatment of chronic inflammation with fibrosis. In transgenic Coll-GFP reporter mice, PTX-2 inhibited myofibroblast synthesis of collagen, but myofibroblast numbers were unaffected. PTX-2 is deposited on injured tissue and debris in the kidney, and is detected in endosomes/phagosomes of macrophages (Mϕs). It does not bind to, or inhibit collagen production by, fibroblasts in vitro, but it binds with high affinity to activating Fcγ receptors on monocytes/ Mϕs. Purified Mϕs from fibrotic kidney are less activated and produce 20 fold more IL10 in mice treated with PTX-2. To test the direct role of IL10 in the inhibition of fibrosis mediated by PTX-2, we systemically administered IL10 producing adenovirus (Ad-IL10 and control virus (Ad-mock) in models of kidney fibrosis. Ad-IL10 resulted in high levels of systemic IL10 and markedly attenuated fibrosis accumulation in the kidney. Systemic IL10 inhibited both monocyte/ Mϕ activation and myofibroblast proliferation and activation in vivo. We propose that the major mechanism of action of PTX-2 is to switch M2 or wound healing Mϕs into regulatory Mϕs. Local generation of IL10 blocks Mϕs driven fibrosis and directly inhibits myofibroblasts.
Characterization of the therapeutic increases in natural killer (NK) activity of xenotropic murine leukemia virus-related virus (XMRV)-positive chronic fatigue syndrome (CFS) patients effected by poly (I): poly (C12U) (Ampligen) (89.49)
Authors: Silvestre Isabel , Marshall Maria , Hagen Kathryn , Pfost Max , Strayer David , Peterson Daniel , Hudig Dorothy , Mikovits Judy 
Published: January 2023

Abstract
Chronic Fatigue Syndrome (CFS) is a debilitating disease of unknown etiology that affects ~17 million people worldwide. Patients suffer persistent viral infections and may develop hematopoietic malignancies. The patients have reduced Natural Killer (NK) cell activities which could contribute to the diseases, and, if restored, potentially reduce symptoms. We characterized the in vitro effects on NK cells of the interferon inducer poly (I): poly (C12U) (Ampligen) which in some CFS patients abates disease symptoms. The 30 CFS patients were infected with the gammaretrovirus xenotropic murine leukemia virus-related virus (XMRV). We cultured their peripheral blood mononuclear cells with the drug for 24 hrs and monitor NK activity to K562 cells by flow cytometry, concurrently measuring degranulation by externalization of CD107a, and expression of Grz B and perforin. Treatment markedly increased CD107a externalization in the NK cell population as indicated by 5-fold increases in CD107a-positive cell frequencies and 3-fold increases in their CD107a MFI, with slight positive shifts in intracellular Grz B and perforin. In contrast, T cells showed little change in CD107a externalization. Our results suggest that degranulation rates may be more affected than the levels of cytotoxic proteins, indicating a novel mechanism by which NK activity was affected by the drug. The increase in degranulation per NK cell indicates a mechanism by which Ampligen treatment can improve NK cell function.
Immunoregulatory Activities of Self-Nanoparticle Forming CpG ODN (89.52)
Authors: Gursel Ihsan , Tincer Gizem , Karatepe Kutay , Gursel Mayda 
Published: January 2023

Abstract
CpG ODN patterned after bacterial DNA can be harnessed in different clinical settings to provide an advantage to host. Several challenges hampers utilization of synthetic ODNs in the clinic. There are at least three distinct classes of CpGODNs displaying differential immune activation. Of note, the efficacy of these synthetic ODNs is reduced under physiological conditions due to premature clearance, nuclease digestion and low levels of internalization. Moreover, D-ODN as one of the most potent IFNα inducer has a large-scale production problem due to 3’polyG-runs hampering its entry into clinics. A novel class of ODN (NP-ODN420) devoid of polyGs that can undergo nanoparticle formation necessary for its IFNα induction is designed. Ex vivo stimulation of mouse splenocytes and in vivo administration of NP-ODN420 have revealed that it exhibits higher immunostimulatory potential due to higher internalization and nuclease resistance. The PO backbone is at least as potent as its more stable counterpart with the modified PS backbone. Furthermore, it combines superior properties of conventional classes of K and D-ODNs. These results have been reproduced in human peripheral blood mononuclear cells by various assays. NP-ODN420 induced significantly higher level of Th1-mediated anti-Ova response than conventional ODNs. In the tumor xenograft model, it promoted partial remission of the tumors. This knowledge will pave the way for more effective immunotherapeutic approaches.
Cigarette smoke modulates release of CXCL8 through the inflammasome signaling in human bronchial epithelial cells (16HBE14o) (89.57)
Authors: Mortaz Esmaeil , Kraneveld Aletta , Nijkamp Frans , Folkerts Gert 
Published: January 2023

Abstract
Chronic obstructive pulmonary disease (COPD) is a major health problem and cigarette smoke (CS) is the main risk factor for the development of COPD. Exposure to cigarette smoke activates inflammatory cells for production of CXCL8 with accompanying damage to the lung epithelium and recruitment of macrophages and neutrophils. The Inflammasome is a multiprotein complex consisting of caspase-1, and NALP molecules and promotes the maturation of inflammatory cytokines such as interleukin 1-β and IL-18. The role of IL-1β in induction of CXCL8 has been reported. The epithelium is a barrier to the entry of pathogens, and as a dynamic system for host response. The epithelium can produce natural antimicrobial factors and release pro-inflammatory cytokines. Therefore it is thought that the airway epithelium plays a role in modulating innate immunity. In this study we studied the effects of CS on the regulation of CXCL8 release via inflammasome signaling by HBE-14o cell lines. We found that in HBE-14o preincubation with anti-caspase-1 (Z-VAD-FMK) suppressed the release of CXCL8 induced by CSE. Moreover, CSE induced maturation of IL-1β (17 KD) and activates NALP3 molecules which is demonstrated by Western blotting. In conclusion this study indicates that inflammasome signaling may directly or indirectly promote the production of CXCL8 by human bronchial epithelial cells.
Stat3 and Th17-mediated colitis promotes regional tumorigenesis in response to a common commensal bacterium: role of Foxp3+ Treg/Th17 balance (90.17)
Authors: Geis Abby , Wolfe Jamie , Wu Shaoguang , Wu Xinqun , Pardoll Drew , Sears Cynthia , Housseau Franck 
Published: January 2023

Abstract
Enterotoxigenic Bacteroides fragilis (ETBF) is an inducer of inflammatory diarrheal disease with acute colitis, and may even be linked to chronic colitis and colorectal cancer in humans. The pathogenesis of ETBF can largely be attributed to the secretion of a toxin, BFT (B. fragilis toxin), which has a profound effect on the colonic microenvironment. BFT promotes cleavage of E-cadherin, activates NF-kB and Wnt/b-catenin signaling, and stimulates the secretion of pro-inflammatory cytokines, such as IL-6, IL-8, and TNF-a. The inflammation associated with ETBF is characterized by widespread colonic Stat3 activation and IL-17 cytokine secretion. In Min mice, the Th17-mediated inflammation promotes the formation of distal colon tumors, as demonstrated by reduced tumorigenesis in response to IL-17 blockade. Our research has been focused on elucidating the immunologic differences between the distal and proximal colon in an attempt to determine why tumorigenesis is so regional. We have found that the proximal colon has a greater density of Foxp3+ Tregs than the distal colon. Furthermore, preliminary data suggests that the Th17 cytokines are differentially expressed in the two regions. We propose that increased Treg density in the proximal colon restrains Th17-mediated inflammation relative to the distal colon. We are currently studying the relationship between the Treg cells and infiltrating effector cells and how that affects tumorigenesis in response to ETBF.
Identification, phenotype, migration, and function of c-kit-expressing dendritic cells in vivo (91.12)
Authors: Oriss Timothy , Krishnamoorthy Nandini , Poe Stephanie , Yarlagadda Manohar , Qi Zengbiao , Ray Prabir , Ray Anuradha 
Published: January 2023

Abstract
We previously reported c-kit induction on total lung DCs by in vitro treatment with Th2/Th17- (ovalbumin plus cholera toxin; OVA/CT) but not Th1-inducing (CpG) factors. Furthermore, we showed that c-kit plays a contributory role to Th2, and in particular to Th17, immune responses. Therefore, we sought to determine what, if any DC subset(s) upregulate c-kit after in vivo treatment. A basal level of c-kit expression was found on CD11c-positive, low autofluorescent DCs expressing CD11b/CX3CR1, which was upregulated following intratracheal administration of OVA/CT. Surprisingly, OVA/CpG also upregulated c-kit on CD11b/CX3CR1 DCs in vivo to an extent even greater than OVA/CT. DC expression of c-kit was highest where MHC Class II expression was also highest (i.e. following OVA/CpG treatment) suggesting that it may be linked to the activation state. However, c-kit on DCs migrating to the lung-draining lymph nodes (LNs) was markedly higher on cells from OVA/CT- versus OVA/CpG-treated animals. LN resident DCs also expressed c-kit, but it was not different between naïve and treated animals. Importantly, c-kit does appear to have functional consequences since c-kit-deficient DCs induce less IL-17 production in particular from naïve T cells, possibly due to their own decreased production of IL-6. These data suggest that c-kit expression, and possibly interaction with its ligand, stem cell factor, is important for migration to draining LNs and for skewing naïve T cell priming by DCs.
Mast Cells Expression of the ADAM-10 Protease is Inhibited BY IL-10 and TGFb1 (91.13)
Authors: Ryan John , Vance Bretton , Williams Kathryn , Morales Johanna 
Published: January 2023

Abstract
Asthma is an inflammatory lung disease that is caused in part by mast cell activation via IgE and antigen. B cell-mediated IgE secretion is suppressed by the low affinity IgE receptor, CD23. Recent data have demonstrated that CD23 function can be blocked by its cleavage with the protease ADAM-10. We demonstrate that mouse mast cells abundantly express surface ADAM-10 in vitro and in vivo. ADAM-10 surface expression is suppressed by the cytokines IL-10 and TGFb1, with approximately 50% inhibition after 3 days of culture. IL-10-mediated effects were Stat3-dependent and correlated with reduced ADAM-10 mRNA. These data suggest that IL-10 and TGFb1 may suppress allergic disease in part by reducing the effects of ADAM-10, allowing for CD23-mediated negative feedback. Supported by NIH grants 1R01 AI59638 and U19A1077435.
Antigen persistence and the control of local T cell memory by migrant respiratory dendritic cells following acute virus infection (92.11)
Authors: Kim Taeg , Hufford Matthew , Sun Jie , Braciale Thomas 
Published: January 2023

Abstract
Acute viral infections induce robust adaptive immune responses resulting in virus clearance. Recent evidence suggests that there may be depots of viral antigen which persist in draining lymph nodes following virus clearance and could therefore affect the adaptive immune response and memory formation. The nature of these residual antigen depots, the mechanism of antigen persistence and impact of the persistent antigen on memory T cells remains ill-defined. Employing a murine model of influenza virus infection of the respiratory tract, we have identified respiratory dendritic cells (RDC) as an essential cell responsible for both sampling and presenting residual viral antigen. RDC in the previously infected lung capture residual viral antigen deposited in an irradiation resistant cell type(s) and transport the viral antigen to the local lymph nodes draining the site of infection where the migrant RDC present the antigen to T cells. Furthermore, we demonstrate that there is preferential localization of memory T cells to the DLN following virus clearance as a consequence of presentation of residual viral antigen by the migrant RDC to T cells in the DLN. This enriched population of antigen-specific T cells maintained in the antigen draining LN would likely provide a more rapid and robust recall T cell response to a re-infection.
Immune Response to Seasonal Influenza Vaccination (92.18)
Authors: Ramakrishnan Amritha , Altoff Keri , Pekosz Andrew , Bream Jay 
Published: January 2023

Abstract
The emergence of new pandemic strains of influenza highlights the need to better understand the immune response to vaccination in order to develop novel vaccine strategies. The goal of our study was to identify and assess novel markers of immune activation after vaccination. To this end, 100 healthy adults who received either the seasonal Live Attenuated Vaccine (LAIV) or the Inactivated Vaccine (TIV) were enrolled from 2006-2008. First, we measured the serum antibody titers against vaccine strains of the virus. We found that while TIV induced a robust increase in anti-influenza serum antibody titers, LAIV induced only a modest increase. We next measured the levels of 10 cytokines in the serum of vaccine recipients. Vaccination with TIV resulted in a significant reduction in the levels of TNF-α while LAIV had no effect on any of the measured cytokines. Finally, we assessed the ability of seasonal vaccination to induce neutralizing antibody titers against the pandemic 2009 H1N1 strain. Vaccination with TIV was able to induce a significant increase in cross reactive antibodies against different seasonal H1N1 strains but not against the 2009 pandemic H1N1 strain. In all, these data suggest that 1) different influenza A vaccine formulations induce unique cytokine responses in the periphery and 2) seasonal influenza vaccination does not illicit strong cross-reactive serum antibodies with 2009 H1N1.
Failure to generate protective T-cells coupled with enhanced inflammation exacerbates lung damage in a pediatric model of influenza infection (92.21)
Authors: Verhoeven David , Farber Donna 
Published: January 2023

Abstract
Influenza virus causes severe morbidity/mortality in young children; however the exact mechanisms driving increased pathogenesis in children, as compared to adults, is not fully defined. We determined that pediatric mice (21 days old), were actively generating memory T-cells as would be expected in young children, while memory populations were firmly established in older “adult” mice. We infected pediatric and adult mice with influenza PR8 and found pediatric mice had elevated morbidity as measured by enhanced weight loss and lower oxygen saturation levels throughout infection thus modeling higher morbidity observed in children. Early viral loads were comparable but pediatric mice failed to clear virus by 10 days post-infection that coupled with apoptosis and poor lung recruitment of the responding T-cells while adult mice generated a strong antiviral response and cleared virus. In contrast to adult mice, IL-10 was not detected in the lungs of pediatric mice thus favoring a pro-inflammatory environment predominated by innate anti-viral responses. In addition, pediatric mice had extensive lung damage and pathology throughout infection that coupled with higher levels of pro-inflammatory innate cytokines. Reciprocal T-cell transfers revealed that both the T-cells and the inflammatory lung environment contribute to lung damage in pediatric mice. Therefore, this study highlights the key inflammatory mechanisms that drive enhanced morbidity in children infected with influenza.
Development and differentiation of memory CD8+ T cells in influenza infection (92.25)
Authors: Rutigliano John , Morris Melissa , Doherty Peter , Thomas Paul 
Published: January 2023

Abstract
Many questions still linger regarding the development and differentiation of memory CD8+ T cells during influenza infection. Previously, it has been shown that an inverse relationship exists between virus inoculum size and the CD8+ T cell response. To this end, we examined the development and differentiation of CD8+ T cell memory populations based on specificity and effector function in a mouse model system comparing high and low pathological infections of influenza. Our findings reveal that viral titer was not the determining factor in the outcome of disease. Instead, differences in CD8+ T cell inflammation and effector function were observed for each infection dose, and these differences correlated with disease outcome. These phenotypic and functional analyses have revealed distinct effector memory CD8+ T cell populations in the context of influenza infection.
Escaping neutralization and gaining adaptation of highly pathogenic avian influenza (HPAI) H5N1 virus in interspecies evolution. (92.5)
Authors: He Wei , Li Zheng , Liu Zhonghua , Zhang Linqi , Su Yuelong , Gao George F , Li Zi , Cui Lianxian 
Published: January 2023

Abstract
Limited amount of mutations in hemagglutinin (HA) of highly pathogenic avian influenza (HPAI) virus H5N1 would greatly facilitate cross-species transmission of avian influenza virus from birds to human. Neutralizing antibodies (nAbs) and receptor adaptation could drive interspecies transmission. In order to investigate the contemporaneous strain-specific and cross-strain nAb response against H5N1 pseudotype viruses and HA proteins, 10 human sera and 4 bird sera were collected to analyze their neutralization and binding activities using 4 H5N1 Has. Neutralization and binding activities of mAbs against QH and XJ H5N1 Has were observed. We found that some mutations appear in the outside of the receptor binding domain (RBD) of H5N1 hemagglutinin (HA), for example at aa 90 on QH H5N1 HA, which might induce a conformational change of the RBD to escape from nAb and change receptor preference simultaneously. These mutations were deemed as “key events” particularly during interspecies transmission to ensure the original invasion successful. They were the result of positive selection caused by antibodies. Some mutations in the RBD that only induce the change of receptor preference were deemed as “maintaining adaptation” to ensure influenza variants circulating in a new species. They were the result of adaptation caused by receptor. Our results suggest that continuing appearance of these two types of mutation made the variants persist in new species.
IL-33 administration promotes both Th2 and Th17 responses and improves resolution during influenza infection (92.7)
Authors: Wissinger Erika , Vekaria Seema , Edwards Lorna , Lyonga Daphne , Godlee Alexandra , Lloyd Clare , Liew Foo , Hussell Tracy 
Published: January 2023

Abstract
A number of acute and chronic immunopathological diseases are driven by excessive Th1 cytokine responses. During influenza infection, Th1 cells and CTL dominate in the lungs. Whilst important for viral clearance, these cells may also cause damaging immune pathology. We now show for the first time that a newly-described cytokine, IL-33, drives Th2 cell polarization during influenza infection, and may be used to counter excessive pathology caused by Th1 cells. We show a change in expression of both endogenous IL-33 and its receptor, ST2L, in the influenza-inflamed lung. IL-33 administration improves resolution of disease and reduces the number of TNF-α and IFN-γ-secreting CD4 and CD8 T cells in the airways of influenza-infected animals. Critically, this reduction in anti-viral T cell number does not impair viral clearance nor alter the recall response. Surprisingly, IL-33 treatment during influenza infection also promotes Th17 cell development. Our data suggest that IL-33 mediates these effects via respiratory epithelium-derived TSLP. This interaction drives a Th17-promoting cytokine cascade involving IL-23 and IL-21. Though viral-induced illness is lessened by IL-33 treatment alone, further improvements are observed when IL-33 is given in combination with IL-17A depletion. These results have important implications for pathologies associated with both Th1 and Th17 cytokine profiles and may explain how an increase of IL-33 correlates with a worsening of disease.