bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stabilized lipid nanocapsules eliciting potent mucosal immune response (P4509)
Authors: Li Adrienne , Moon James , Irvine Darrell 
Published: January 2023

Abstract
We investigated the use of a novel lipid nanocapsule, Interbilayer-Crosslinked Multilamellar Vesicles (ICMV), for mucosal vaccine delivery. ICMV co-encapsulated with MPLA and/or polyI:C as adjuvants, was used to vaccinate mice using model antigen and SIV-gag epitopes. When delivered via the lungs, we found that ~60-fold more antigen transported to the draining lymph nodes than equivalent subcutaneous vaccination, mediated by the vast number of antigen presenting cells in the lungs. Potent CD8 T-cell response was elicited by ICMV pulmonary vaccine and established a substantially greater memory population than a soluble vaccine, with 5.2-fold and 4.8-fold higher frequencies of antigen-specific cells in lungs and spleen, at 11 weeks post-priming. T-cells primed by ICMV pulmonary vaccination were also found to be strongly biased toward an effector memory phenotype, and a 5-7-fold higher number of effector memory cells were found in both the local and distal mucosa compared to soluble vaccines. Protection against a viral challenge was observed in animals given ICMV pulmonary vaccine while animals that received subcutaneous ICMV or pulmonary soluble vaccines showed steady weight loss that led to 100% mortality by day 5 post challenge. These particles can be prepared using aqueous solution processing techniques currently used for production of commercial liposomal products. They can also be freeze-dried for long term storage and have shown to retain immunogenicity after 1 month.
Humoral immune responses elicited by the polyanhydride particle vaccine platform are facilitated by enhanced T follicular helper cell phenotype (P4511)
Authors: Huntimer Lucas , Ross Kathleen , Ramer-Tait Amanda , Narasimhan Balaji , Wannemuehler Michael 
Published: January 2023

Abstract
Previous studies have shown that the use of the polyanhydride nanoparticle (NP) vaccine platform provides innate immunomodulatory activity while also controlling antigen release kinetics that enhance antibody-mediated immunity. The goal of this project was to demonstrate that the increased antibody responses detected by utilizing NP-based vaccines induced of robust T helper cell responses to promote B cell activation and differentiation into antibody secreting cells. Using the ovalbumin (Ova) specific T cell (OT II) model, we evaluated the mechanisms associated with the expansion and activation of Ova-specific CD4+ T after immunization using three different polyanhydride NP formulations that contained encapsulated Ova. Significant expansion of CD4+ T cells occurred following immunization with Ova-loaded 20:80 CPH:SA or 20:80 CPTEG:CPH PNPs. Similar to Alum and MPLA adjuvanted responses, these NP regimen induced T follicular helper cells (CXCR5high PD-1high) that are important for initiating and maintaining germinal centers. Following a single administration, PNP vaccines induced robust Ova-specific IgG1 antibody titers. Upon secondary immunization, the NP vaccinated mice effectively responded with robust Ova-specific IgG1 and IgG2c antibody responses. The NP vaccinated mice presented with more antigen-specific Tfh (vα2+, vβ5+) CD4 T cells and more numerous germinal centers cells (B220+ CD23high PNA+) that supported more avid Ova-specific IgG1.
Analysis of the humoral immune response to HSV-2 glycoproteins in ACAM529-vaccinated mice. (P4519)
Authors: Hernandez Hector , Hamberger John , Lai Charles , Kleanthous Harold , Parrington Mark , Delagrave Simon 
Published: January 2023

Abstract
HSV-2 infection is a global, serious public health problem affecting over 530 million people. ACAM529, a vaccine candidate targeting genital herpes infections, is an HSV-2 virus rendered incapable of replication, through deletion of the genes UL5 and UL29. Blockage of viral DNA replication is expected to prevent true late gene expression, yet this vaccine successfully protected animals against infection and lethal challenge in preclinical studies (Delagrave et al., 2012, PLoS One, 7(10): e46714). Here we present the IgG responses against viral glycoproteins elicited by ACAM529 vaccination. We compare the ability of ACAM529 to generate IgG responses to gG and gD, two leaky late (γ1) HSV-2 antigens, and gC a true late antigen (γ2).
The role of antibody and CD4 follicular helper cells during malaria liver stage infection (P4485)
Authors: Keitany Gladys , Jang Ihn Kyung , Finney Olivia , Smithers Hannah , Wang Ruobing 
Published: January 2023

Abstract
The liver stage malaria provides an excellent target for malaria vaccine: eliminating the parasite at this stage using immunization with attenuated parasites that arrest in the liver results in long-term sterile protection. This immune response has been associated with CD8 T cells, as well as antibodiesdirected against the sporozoite. In this study, we hypothesized that genetically attenuated pasite (GAP) immunization induces T follicular helper cells (Tfh), which in turn induce memory B cells responses, leading to long-lived and high avidity functional antibodies to pre-erythrocytic malaria. Using immunization with GAP that arrest during late liver-stage development, we showed that immunization induces high titer antibodies, and that these antibodies can inhibit parasite growth in liver cells in vitro by 99%. To understand the induction of the antibody response, we characterized both the B cell response and the Tfh response in the liver, the spleen and the lymph nodes. Furthermore, in order to determine the localization of the priming of the response, immunization via mosquito bite and intravenous injection were compared. Understanding the role of Tfh in liver stage malaria and how they are induced will be crucial in designing an effective antibody based malaria vaccine.
AERAS-402/Ad35 vaccine induces CD4+ and CD8+ responses in HIV-infected, BCG-vaccinated adults (P4487)
Authors: Hokey David , Pandian Ramanan , Graves Andrew , Churchyard Gavin , Snowden Peggy , Douoguih Macaya , Landry Bernard 
Published: January 2023

Abstract
One-third of the world's population is estimated to be infected with TB. The WHO no longer recommends that the currently available TB vaccine, BCG, be given to infants born to HIV+ mothers due to safety concerns. An improved vaccine that is effective and safe for HIV+ infants is needed to protect this vulnerable population. AERAS-402 is a novel replication deficient Ad35 TB vaccine candidate that expresses a fusion protein of the Mtb antigens 85A, 85B, and TB10.4 and has been shown to safely induce CD8+ T cell responses in healthy adults. This study examined the safety and immunogenicity of a single IM dose of AERAS-402 in HIV+ adults. No vaccine-related serious adverse events were reported, suggesting the vaccine is safe in this population. CD4+ and CD8+ T cell responses were evaluated using ICS. Prior studies in healthy adults revealed primarily CD8+ responses to vaccination with AERAS-402. Vaccination of HIV+ adults resulted in the elicitation of both CD4+ and CD8+ responses of ~0.1% to 0.2% of the parent population largely directed to 85A and 85B. CD4+ responses were primarily polyfunctional (IFN-γ, IL-2, and TNF) and bifunctional (IL-2 and TNF) while CD8+ responses were largely bifunctional (IFN-γ and TNF) and monofunctional (IFN-γ) with lower levels of polyfunctional cells observed. Together the data suggest that vaccination with AERAS-402 in HIV+ adults is safe and immunogenic, resulting in a mixed CD4+ and CD8+ multifunctional T cell response to encoded antigens.
Thwarting HIV evasion of antibody avidity with novel antibody architectures (P4489)
Authors: Galimidi Rachel , West Anthony , Bjorkman Pamela 
Published: January 2023

Abstract
Despite decades of effort, no current vaccine elicits neutralizing antibodies at concentrations blocking HIV infection. In addition to structural features of HIV's envelope spike that facilitate antibody evasion, a hypothesis for the ineffective immune response lies in the low density and limited mobility of HIV envelope spikes, which impedes bivalent binding by antibodies, reducing avidity, minimizing the potential for high affinity binding and virus neutralization. We intend to engineer anti-HIV reagents that bind with high avidity to single spikes, overcoming potential problems with the low density of HIV spikes. Here, we demonstrate a strategy to use dsDNA as a rigid molecular ruler to map epitopes on the HIV envelope protein to gain insight into the relatively unknown spatial environment of the spike trimer. Upon determining the optimal separation distance between epitopes, the dsDNA linker will be replaced with a structured protein linker. This technique should allow for the development of a novel multivalent antibody reagent improving binding and increasing avidity. Optimal HIV binding proteins will be trimerized by attaching a trimerization motif, reducing the concentration required for sterilizing immunity. To date, we have several bispecific DNA reagents that have the ability to neutralize various strains of HIV with greater potency than its individual components. These results demonstrate the promise for discovery of optimal anti-HIV reagents using this technology.
HIV-1 gag specific exosome-targeted CD8+ T cell based vaccine stimulates specific CTL responses leading to long-term immunity (P4493)
Authors: Wang Rong , Xiang Jim 
Published: January 2023

Abstract
The limitations of highly active anti-retroviral therapy (HAART) have necessitated the development of alternative therapeutics for human immunodeficiency virus type-1 (HIV-1)-infected patients with dysfunctional dendritic cells (DCs) and CD4+T cell deficiency. We have recently demonstrated that Con A stimulated non-specific CD8+T cells could uptake OVA pulsed DC-derived exosome (EXO), act as CD8+Tc antigen presenting cells (Th-APCs), and capable of stimulating DC- and CD4+T cell-independent OVA-specific CTL responses leading to long-term immunity. This formed the new concept novel EXO-targeted CD8+T cell vaccine. The extreme conservation and intolerance of escape variants in HIV-1 Gag p24 make it a potential target for vaccine design. In this study, we constructed adenoviral vector AdV-gag and expression vector pEGFP-gag both expressing Gag. We generated Gag specific EXO-targeted T (Gag-Texo) cell vaccine by using C57BL/6 mouse CD8+ ConA T cells with uptake of AdV-gag transfected bone marrow DC (DCgag) released EXOgag. We then generated BL6-10gag cell lines by transfection of B16 melanoma cell line (BL6-10) with pEGFP-gag. We demonstrated that Gag-Texo vaccine is capable of stimulating efficient Gag-specific CD8+ CTL responses in vivo, leading to antitumor immunity against Gag expressing B16 melanoma (BL6-10 gag) in animal studies. Therefore, this novel HIV-1-specific EXO-targeted Gag-Texo vaccine may be useful in induction of efficient CTL responses in AIDS patients.
R-spondin3 prevents mesenteric ischemia/reperfusion-induced tissue damage by tightening endothelium and preventing vascular leakage (P5060)
Authors: Kannan Lakshmi , Kis-Toth Katalin , Thai To-Ha , Sehrawat Seema , Mayadas Tanya , Dalle Lucca Jurandir , Tsokos George 
Published: January 2023

Abstract
Inflammation and vascular injury triggered by ischemia/reperfusion (I/R) represent a leading cause of morbidity and mortality in a number of clinical settings. Wnt and its homologue partners R-spondins, in addition to regulating embryonic development have recently been demonstrated to serve as wound-healing agents in inflammation-associated conditions. Here we ask whether R-spondins could prevent inflammation-associated tissue damage in ischemic disorders and thus investigate the role of R-spondin3 (R-spo3) in a mouse model of mesenteric I/R. We demonstrate that R-spo3 ameliorates mesenteric I/R-induced local intestinal as well as remote lung damage by suppressing local and systemic cytokine responses and deposition of IgM and complement in intestinal tissues. We show that decreased inflammatory response is accompanied by the tightening of endothelial cell junctions and reduction in vascular leakage. We further provide evidence that R-spo3 preserves endothelial barrier function by maintaining VE-cadherin expression at adherens junction and decreasing the formation of stress fibers. We thus conclude that R-spo3 stabilizes endothelial junctions and inhibits vascular leakage during I/R and thereby mitigates the inflammatory events and associated tissue damage. Our findings, for the first time, demonstrate a protective effect of R-spo3 in I/R-related tissue injury and suggest a mechanism by which it may have these effects.
Inhibition of ADAM10 and 8 reduces transendothelial migration of the monocytic cell line THP1 in vitro (P5066)
Authors: Hess Franz , Alert Henriette , Prüssmeyer Jessica , Ludwig Andreas 
Published: January 2023

Abstract
Metalloproteases of the A Disintegrin And Metalproteases (ADAM) family are important molecular mediators of inflammation. ADAMs participate at all stages of inflammation via the proteolytic cleavage of cell surface molecules. It has been shown that leukocyte expressed ADAM8 and ADAM17 are important during the initial rolling of leukocytes on the endothelium. However, the role of leukocyte expressed ADAMs in transendothelial migration and chemotaxis remains to be investigated and in particular it is still unclear to what extent ADAM10 and ADAM9 contribute to leukocyte migration. In this study we show that treatment of leukocytes with a pharmaceutical ADAM10 inhibitor reduced both the in vitro transendothelial migration and the chemotaxis of the monocytic cell line THP1. The combined pharmaceutical inhibition of both ADAM10 and ADAM17 did not further suppress leukocyte migration in either experimental setting. The subsequent analysis of THP1 cells with a gene silencing of ADAM8, 9, 10 or 17 in transendothelial migration and chemotaxis experiments revealed that ADAM8 and ADAM10 are critically involved in THP1 cell migration. While ADAM9 did not seem to be required ADAM17 was only ofminor importance for the migration of THP1 cells. This study analyses the role of the four proteases ADAM8, 9, 10 and 17 in the migration of leukocytic cells. It shows that ADAM8 and ADAM10 are crucial for the in vitro transendothelial migration and chemotaxis of the monocytic cell line THP1.
Hydrogen peroxide as a signal induced cellular functions of macrophage in oxidative stress (P5038)
Authors: Wu Yu-Sheng , Chen Shiu-Nan 
Published: January 2023

Abstract
Experiments performed to show that one of the respiratory oxygen species, hydrogen peroxide was an attractant factor for macrophage that consequently affects the phagocytosis of macrophage and gene expression. Results obtained from the present study also show that LPS-induced inflammation would cause hepatocytes to produce hydrogen peroxide which subsequently attract macrophage migration to the inflamed region and promote scavenging function. Furthermore, this reaction is suggestive of macrophage interacts with oxidative stress which promotes the transcription factors activity to cause inflammation responses and suggested hydrogen peroxide act as cellular messenger to affect permeability of calcium ion channel to increase intracellular Ca2+ concentration as a migration messenger
Differential regulation of pro-inflammatory necrosis in males and females by Poly (ADP-Ribose) Polymerase-1 and 17β estradiol (P5074)
Authors: Jog Neelakshi , Caricchio Roberto 
Published: January 2023

Abstract
Cell death can be divided into the anti-inflammatory apoptosis and the pro-inflammatory necrosis. Necrosis as apoptosis, is a regulated form of cell death, and Poly-(ADP-Ribose) Polymerase-1 (PARP-1) and Receptor-Interacting Protein (RIP)1 are two of the mediators. We previously showed that absence or inhibition of PARP-1 protects mice from immune mediated nephritis. Surprisingly, this protection showed a sex-bias, with only male mice being protected. Several studies have shown that the response of males and females to stress differs, although the basis for this sexual dimorphism remains to be determined. We hypothesized that these differences may be due to an inherent difference in the cell death program between the two sexes. We show here that in an immune mediated nephritis model, females show increased apoptosis compared to males. Treatment of males with estrogens inhibited necrosis but induced apoptosis to levels similar to those observed in females. Although PARP-1 was activated in both males and females, absence or inhibition of PARP-1 reduced necrosis only in males. Inhibition of RIP1 with Necrostatin-1 did not show sex bias. We demonstrate here that males and females are prone to different types of cell death. Our data also suggest that estrogens and PARP-1 are two of the mediators of sex-bias in cell death. We therefore propose that clinical targeting of cell death should differ based on sex and could lead to better treatments for each gender.
Positive allosteric modulation of M1 muscarinic acetylcholine receptors suppresses lethal peripheral inflammation (P5082)
Authors: Pavlov Valentin , Ochani Mahendar , Dancho Meghan , Al-Abed Yousef , Nathanson Neil , Tracey Kevin 
Published: January 2023

Abstract
Peripheral inflammation can be regulated by activation of brain muscarinic acetylcholine receptor (mAChR)-dependent signaling functionally associated with a vagus-nerve mediated anti-inflammatory circuit (Proc Natl Acad Sci USA, 2006, 5219; Brain Behav Immun, 2009, 23:41). Here, we studied the specific role of the M1 mAChR subtype in this regulation by utilizing BQCA, a highly specific allosteric M1 mAChR activator that crosses the blood-brain barrier. Single drug (5,10 or 20 mg/kg, i.p) administration in mice 1h prior to endotoxin (8 mg/kg, i.p.) dose-dependently reduced serum and splenic TNF levels and significantly improved survival in mice as compared to vehicle-treated controls. Pharmacological blockade of brain mAChRs significantly abolished BQCA anti-inflammatory effects. Furthermore, BQCA (20 mg/kg, i.p.) significantly reduced serum and splenic TNF levels in wild type mice, but failed to alter TNF levels in M1 KO mice. Together these results indicate the anti-inflammatory role of increased functional activity of endogenous acetylcholine on the M1 mAChR by selective allosteric receptor activation. Our findings are of interest for further development of BQCA and other centrally-acting allosteric activators of the M1 mAChR as a novel class of experimental anti-inflammatory therapeutics.
Selenoprotein activity alters eicosanoid biosynthesis in macrophages (P5042)
Authors: Mattmiller Sarah , Sordillo Lorraine , Carlson Bradley 
Published: January 2023

Abstract
Selenium (Se) exerts anti-inflammatory properties largely through the activity of antioxidant selenoproteins. However, the effect of reduced selenoprotein activity on the eicosanoid signaling network is unknown. Therefore, the objective of this study was to characterize the biosynthesis of eicosanoids that enhance or resolve inflammation as a function of selenoprotein activity. Macrophages cultured in Se-sufficient or Se-deficient media or macrophages obtained from selenoprotein conditional knockout mice were used to assess inflammatory markers and eicosanoids. Reduced selenoprotein activity significantly increased free radical accumulation, pro-inflammatory cytokines, and cyclooxygenase and lipoxygenase enzyme expression. Reduced selenoprotein activity significantly diminished the production of anti-inflammatory eicosanoids, lipoxin A4 and protectin, hydroxyl eicosanoids from arachidonic acid, and hydroxyl and ketone eicosanoids from linoleic acid (LA). Since LA is a predominant lipid in the western diet and LA-derived metabolites were produced in substantial amounts by macrophages, studies are currently underway to determine the inflammatory effect of the LA ketone, 9oxoODE. Future studies aim at determining if LA eicosanoids are oxidized by lipoxygenases or by non-enzymatic means when selenoprotein activity is reduced. A better understanding of how Se regulates eicosanoid biosynthesis may uncover nutritional intervention strategies to counteract uncontrolled inflammation.
Ethanol extract of Alismatis Rhizoma reduces acute lung inflammation by suppressing NF-κB and activating Nrf2 (P5044)
Authors: Kwun Min Jung , Kim Kyun Ha , Choi Jun-Yong , Lee Jang Hoon , Joo Myungsoo , Han Chang Woo 
Published: January 2023

Abstract
The tuber of Alisma orientale has an anti-inflammatory effect. Here, we investigated a possible underlying mechanism and a protective effect on acute lung injury (ALI). A. orientale tuber was extracted in 80% ethanol and dried. The powder of the ethanol extract of A. orientale tuber (EEAO) was dissolved in PBS. The effect of EEAO on NF-κB and Nrf2 activities was analyzed with RAW 264.7 cells. The effect of EEAO on lung inflammation was determined by histologic and molecular biological analyses of the lung tissue of C57BL/6 mice that were gavaged once a day with 0.3 or 1.2g/kg of EEAO for 14 days, prior to an intranasal administration of LPS (0.01g/kg) for inducing ALI. EEAO pre-treatment of RAW 264.7 cells suppressed NF-κB activity and the expression of its dependent genes including COX-2, IL-1β and iNOS. Similar treatment enhanced Nrf2 activity and the expression of Nrf2-regulated genes including NQO-1, HO-1 and GCLC. LPS instillation induced acute neutrophilic lung inflammation, which was significantly suppressed by pre-treatment with EEAO. Analysis of the lungs revealed that EEAO pre-treatment induced the expression of Nrf2-regulated genes, with concomitant down-regulation of inflammatory gene expression. EEAO attenuated lung inflammation in LPS-induced ALI mice, which was associated with differential regulation of NF-κB and Nrf2 activities. We suggest that EEAO can be developed as a potential therapeutics for the treatment of ALI.
IL-33- and IL-25-responsive innate lymphoid cells are present in human peripheral blood. (P6237)
Authors: Bartemes Kathleen , Fox Stephanie , Kita Hirohito 
Published: January 2023

Abstract
Recent advances in the initiation and maintenance of type 2 immune responses have highlighted a new cell type, the type 2 innate lymphoid cell (ILC2). Studies using mouse models show that ILC2s mediate helminth clearance in the gut and development of airway hyperresponsiveness in the lung. Further, the epithelium-derived cytokines IL-25 and IL-33 are integral to this process. However, how ILC2s contribute to chronic human airway diseases such as asthma and how IL-25 and IL-33 mediate that effect are not well characterized. Here we show that human peripheral blood mononuclear cells (PBMCs) respond to IL-33 or IL-25 stimulation by making IL-5 and IL-13. CD3+ and CD16+ PBMCs are not required. Furthermore, an ILC2-like cell that is lineage-negative and CD44+CD127+ST2+ is present in the peripheral blood of a subject with asthma. IL-5 production was induced by IL-33 or IL-25 in PBMCs from normal individuals as well as from patients with allergic rhinitis or allergic asthma, however, PBMCs from the group with asthma released significantly higher amounts. Our data suggests that the number and function of ILC2s is greater in patients with allergic asthma than in healthy subjects or patients with allergic rhinitis. Thus, ILC2s may be involved in the development of type 2 airway diseases.