bluuebunny/crossref_metadata_2025_split huggingface dataset:
Liver-primed CD8+ T cells are dysfunctional but gain Treg activity on T effectors via the Lag-3 and Tim-3 inhibitory pathways (105.4)
Authors: Dolina Joseph , Krueger Peter , Hahn Young 
Published: January 2023

Abstract
The liver maintains a tolerogenic site as a result of constant exposure to bacterial constituents and food-derived antigens and facilitates the establishment of persistent infections by viruses such as hepatitis C virus (HCV). In these studies, we employ a murine model of intravenous (IV) adenovirus infection specifically targeting the virus to the liver. During IV infection, intrahepatic CD8+ T cells display an inability to produce proinflammatory cytokines and lyse targets compared to other sites of virus delivery (subcutaneous and intranasal). Notably, IV adenovirus infection results in local intrahepatic antigen presentation responsible for limiting the CD8+ T cell immune response. CD8+ T cells mounted by the IV infection demonstrate up-regulation of PD-1, Lag-3, and Tim-3 on their surface, correlating to IL-10 production. Tim-3 and Lag-3 blockade in vitro boosts IFN-γ and attenuates IL-10 production of αCD3-activated CD8+ T cells. Importantly, the liver-generated CD8+ T cells also appear to have a Treg function on the priming of antigen-specific T cells in vitro and in vivo. These results suggest that specific inhibitory pathways and IL-10 signaling are co-dependent. The presence of IL-10-producing CD8+ T cells in the livers of chronic HCV patients implicates that liver-primed CD8+ T cells play a pivotal role in dampening hepatic T cell responses in the local microenvironment.
Inhibition of p38 MAPK activity in mononuclear phagocytes abrogates HIV gp120-induced neurotoxicity while triggering expression of numerous anti-viral and cytoprotective factors. (105.42)
Authors: Kaul Marcus , Sejbuk Natalia , Maung Ricky , Medders Kathryn 
Published: January 2023

Abstract
Macrophages produce neurotoxins upon infection with HIV-1 or exposure to its envelope protein gp120. Both stimuli lead to activation of p38 mitogen-activated protein kinase (MAPK). In order to study the basis for the neurotoxic phenotype of monocytic cells that is initiated by HIV/gp120 and prevented by inhibition of p38 MAPK, we performed a genome-wide gene expression analysis. We treated monocytic THP-1 cells for 4 h or 24 hr with HIV gp120 (1 nM) in the presence or absence of the p38 MAPK inhibitor (SB203580; 10 μM) and subsequently isolated RNA. Microarray analysis indicated that HIVgp120 moderately affected gene expression in comparison to the p38 MAPK inhibitor. Blocking p38 MAPK suppressed some cytokines but, surprisingly, also significantly increased others, such as CCL3, CCL4 and CCL5, all of which have anti-HIV activity and protect against gp120 neurotoxicity. Using a multiplex protein array, we confirmed expression changes for thirteen cytokines. Thus, p38 MAPK signaling is critical for the neurotoxicity of HIVgp120-exposed monocytic cells but only moderately alters gene expression. In contrast, inhibition of p38 MAPK substantially changes gene and protein expression, including increases in potentially neuroprotective chemokines. Thus, inhibition of p38 MAPK may not only protect from HIVgp120-induced neurotoxicity of mononuclear phagocytes by interrupting toxic signaling pathways but also by inducing an array of potentially cytoprotective factors.
Effective control of influenza A virus infection by boosting γδ-T-cell immunity with pamidronate (106.13)
Authors: Tu Wenwei , Zheng Jian , Liu Yinping , Peiris Malik , Lau Yu-Lung 
Published: January 2023

Abstract
Influenza remains a global threat to public health. There are few antiviral drugs for treating influenza and the emergence of antiviral resistance has further limited the available therapeutic options. Furthermore, antivirals are not invariably effective in severe influenza, such as that caused by H5N1 viruses. Thus, there is an urgent need to develop alternative therapeutic strategies. Pamidronate has been commonly used to treat osteoporosis by enhancing human Vγ9Vδ2-T-cell immunity. Using Rag2-/-γc-/- mice reconstituted with human peripheral mononuclear cells (huPBMCs) as a model, we demonstrate that the treatment of pamidronate decreases disease severity and/or mortality caused by human seasonal H1N1 and avian H5N1 influenza virus, and controls the lung inflammation and viral replication. Importantly, pamidronate has no such effects in influenza virus-infected Rag2-/-γc-/- mice reconstituted with Vγ9Vδ2-T-cell-depleted huPBMCs. Our results demonstrate that pamidronate can control human and avian influenza A virus infections through a Vγ9Vδ2-T-cell dependent mechanism in vivo. This study provides proof-of-concept of a novel therapeutic strategy for treating influenza by targeting the host rather than the virus, thereby reducing the opportunity for the emergence of drug-resistant viruses. This ‘new application of an old drug’ potentially offers a safe and readily available option for treating influenza.
TLR and ODN agonists used as adjuvants enhance the protection elicited in mice by a vaccine formulated with the Chlamydia trachomatis MoPn rMOMP (106.17)
Authors: Chang Chunmei , Jain Pooja , Pal Sukumar , Tifrea Delia , de la Maza Luis 
Published: January 2023

Abstract
Chlamydia trachomatis (CT) is the most common sexually transmitted bacterial pathogen in the World and there is an urgent need for a vaccine to prevent these infections. To determine what type of adjuvant better enhances the immunogenicity of a vaccine, we formulated the CT recombinant major outer membrane protein (rMOMP) with several TLR and NOD agonists including: Pam2CSK4 (TLR2/6), Poly(I:C) (TLR3), Monophosphoryl lipid A (TLR4), Flagellin (TLR5), Imiquimod R837 (TLR7), Imidazoquinoline R848 (TRL7/8), CpG-1826 (TLR9), M-Tri-DAP (NOD1/NOD2) and muramyldipeptide (NOD2). Groups of female BALB/c mice were immunized i.m. with rMOMP and one of those adjuvants and were challenged i.n. with 104 CT MoPn inclusion forming units (IFU). Following the challenge the mice were weighed and, at 10 days post-infection (p.i.), they were euthanized, their lungs weighed and the number of IFU in the lungs determined. Based on the IgG2a/IgG1 ratio in sera collected the day before the challenge, mice immunized with rMOMP-Pam2CSK4 showed a strong Th2 bias. Furthermore, these mice develop a robust cellular immune response with high CT-specific T cell proliferation and levels of IFN-γ. In addition, based on changes in body weight, weight of the lungs and number of IFU recovered from the lungs, mice immunized with rMOMP-Pam2CSK4, were significantly better protected than mice immunized with the other adjuvants. In summary, Pam2CSK should be considered as a good candidate adjuvant for a CT vaccine.
A live-attenuated HSV-2 ICP0- virus elicits 10 to 100 times greater protection against genital herpes than a glycoprotein D subunit vaccine (106.22)
Authors: Halford William , Gershburg Edward , Wilber Andrew , Rakowski Brandon 
Published: January 2023

Abstract
Many herpes simplex virus 2 (HSV-2) vaccines rely on combinations of HSV-2’s glycoprotein D (gD-2) and a potent adjuvant. The Simpilirix™ vaccine is a gD-2 subunit vaccine that recently failed in human clinical trials (Science, 2010, 330:304). We have proposed that immunization with an ICP0- mutant virus, HSV-2 0ΔNLS, would be more effective (PLoS ONE, 2010, 5:e12251). The current study was initiated to test this hypothesis. Mice immunized with a gD-2 subunit produced high titers of gD-2 antibody, but were poorly protected against HSV-2 challenge of the vagina or eyes (survival rate = 3 of 45). In contrast, 114 of 115 mice immunized with HSV-2 0ΔNLS survived the same HSV-2 challenges, and protective immunity endured for 6 months. We present several lines of evidence that immunization with HSV-2 0ΔNLS was 10- to 100-fold more protective against HSV-2 infection than a gD-2 subunit. We conclude that a gD-2 vaccine does not protect mice or humans from HSV-2 infections, and infer that live-attenuated HSV-2 would be 10 to 100 times more effective in preventing genital herpes.
Comparison of parenteral delivery routes of ACAM529, a replication-defective vaccine against genital herpes (106.24)
Authors: Hernandez Hector , Zhou Changhong , Mundle Sophia , Hamberger John , Catalan John , Pougatcheva Svetlana , Anderson Stephen , Londono-Hayes Patricia , Kleantous Harold , Delagrave Simon 
Published: January 2023

Abstract
Human herpes simplex viruses (HSV types 1 and 2) constitute the primary cause of genital ulcer disease. Genital herpes is the most prevalent sexually transmitted infection and is found throughout the world. Available treatments for HSV-infected patients are not 100% effective and cannot prevent acquisition of infection. ACAM529 is an HSV-2 virus made replication-defective by deletion of the genes UL5 and UL29. ACAM529 is propagated in a complementing cell line expressing the deleted genes (Da Costa et al., J. Virol.2000). Here we present the comparison of three routes of administration of ACAM529. We measured immunogenicity as well as protective efficacy in the mouse vaginal challenge model. ELISA and neutralizing antibody titers, as well as protection against morbidity, mortality and viral shedding of the challenge virus indicate that two doses of ACAM529 delivered intramuscularly are optimal.
Intranasal norovirus vaccination shows efficacy in preventing acute gastroenteritis following a live GI.1 NoV challenge (106.5)
Authors: Bargatze Robert , Bernstein David , Harro Clayton , Al-Ibrahim Mohamed , Chen Wilbur , Ferreira Jennifer , Estes Mary , Graham David , Richardson Charles , Mendelman Paul , Atmar Robert 
Published: January 2023

Abstract
NoVs are a common cause of both epidemic and endemic AGE. Currently, no vaccine is available to prevent illness. Vaccination with an IN GI.1 NoV virus-like particle (VLP) vaccine (adjuvanted with chitosan and monophosphoryl lipid A) was followed by a homologous viral challenge. The trial employed a randomized, double-blind, placebo-controlled design for assessing safety, immunogenicity and efficacy against AGE and infection. Two-doses of vaccine or placebo IN 3 weeks apart were administered to healthy adults 18-49 years of age. At least 3 weeks later ~10 HID50 of a GI.1 challenge virus was administered to subjects who were then monitored for illness and infection. Two doses of the NoV VLP vaccine were administered to 90 subjects with the vaccine being well tolerated. The per protocol (PP) population was 77 of the 84 persons who completed the challenge. Of the 84, 64% of vaccinees had a &gt;4-fold serum IgA response, none receiving placebo. In the PP analysis the incidence of AGE decreased from 69% to 37% by vaccination and infection was reduced from 82% to 61%. Efficacy against illness was 47% (95% CI, 15-67%) and against infection was 26% (95% CI, 1-36%) relative to placebo and severity of illness was also reduced. Of note, protection from NoV illness and infection correlated with the level of 50% HBGA blocking activity prior to challenge. We report that a NoV vaccine candidate can prevent AGE and that an IN-delivered vaccine can prevent illness due to an enteric pathogen.
Assessment of T cell-mediated immunity by ELISPOT in preclinical studies of dengue in cynomolgus macaques (106.6)
Authors: Moldovan Ioana , Brewoo Joseph , Osorio Jorge , Tary-Lehmann Magdalena 
Published: January 2023

Abstract
We used ELISPOT assays to assess frequencies and cytokine signatures of dengue-specific T cells in preclinical studies. Cynomolgus macaques were either infected with one of the four wild type (wt) dengue viruses or immunized with a tetravalent, chimeric dengue vaccine (DENVax). Peripheral blood mononuclear cells (PBMC) were separated, cryopreserved at different timepoints of the studies and tested in the ELISPOT assay for recall responses to live dengue viruses (DENV). We show that dengue antigen-specific T cells can be consistently detected after the second infection or booster vaccination. In a third study three formulations of DENVax, based on the DENV-2 backbone, were tested. Upon stimulation with live DENV-2, PBMC from animals immunized with any of three DENVax formulations induced significant (p&lt;0.05) higher levels of IL-2 compared to the controls. T-cell mediated IFN-γ responses were also significantly higher in DENVax-immunized macaques compared to the control group. IFN-γ responses in macaques receiving DENVax formulations 2 or 3 were significantly increased (p&lt;0.05) after the second vaccination, whereas animals immunized with formulation 1 didn’t show any augmentation after the second immunization. Consistently, control animals failed to induce IL-2 or IFN-γ responses before wt virus challenge. These data show that DENVax had an efficacy in preclinical dengue studies and support the further evaluation of this vaccine in human clinical trials.
Kallikrein gene modified mesenchymal stem cell transplantation protected mice from anti-GBM induced and lupus nephritis (107.10)
Authors: Li Quanzhen , Li Yajuan , Shao Xinli , Ramin Indu , Yan Mei , Min So , Du Yong , Mohan Chandra 
Published: January 2023

Abstract
Mesenchymal stem cells (MSC) have been reported to be an attractive cell source for treatment of renal diseases. Recently, we reported that kallikreins (klk) play renoprotective role in anti-GBM-induced and lupus nephritis. Here, we investigated whether MSCs could be used as vehicle to deliver klks into injured kidneys and play synergetic protective role against experimental glomerulonephritis. Human KLK1 gene was incorporated into genome of mouse bone marrow-derived MSCs via retroviral vector pMSCV and a stable cell line, hKLK1-MSC, was established and proved to express high level hKLK1. NZW mice with anti-GBM induced nephritis were injected with 105 hKLK1-MSCs (i.v.) and hKLK1 expression was detected from blood and kidneys 2 weeks after injection. Comparing with MSCs injected mice, the hKLK1-MSCs treated mice showed significantly reduced proteinuria (0.188 mg/24 h vs. 0.766 mg/24 h, p&lt;0.05), serum BUN (5.9 mg/dl vs. 12.5 mg/dl, p&lt;0.05) and ameliorated renal pathology (p&lt;0.05). hKLK1-MSC transplantation significantly reduced mesangial cell (MC) proliferation, monocyte/macrophage infiltration and mesangial matrix accumulation. Using the same strategy, we treated the B6.Sle1.Sle3 mice with hKLK1-MSCs and proved that hKLK1-MSCs reduced the renal injury caused by spontaneous lupus nephritis. In conclusion, our results indicate that Kallikrein modified mesenchymal stem cell transplantation is a potent therapeutic strategy for the treatment of immune-mediated and lupus nephritis.
Adeno-associated virus-mediated CCL11 shRNA reduced lung inflammatory responses in a mite allergen-sensitized mouse model (107.13)
Authors: Wu Chia-Jen , Huang Wen-Chung , Lin Chun-Yen , Kuo Ming-Ling 
Published: January 2023

Abstract
Asthma is considered as a chronic pulmonary inflammatory disease, characterized by eosinophilia. Lung epithelium cells secrete CCL11, the major chemokine for the recruitment of eosinophils. Hybrid adeno-associated virus serotype 2/9 might achieve long-term gene delivery specifically to lung epithelium cells. Thus, this study tested whether hybrid AAV2/9 virus carrying shRNA specific for CCL11, sh47 and sh137, could reduce eosinophilia in a mite allergen-sensitized mouse model. Both sh47 and sh137 viruses significantly reduced CCL11 level in CCL11-transformed NIH 3T3 cells, compared with others. Both viruses were delivered into Dp2 (group 2 allergen of Dermatophagoides pteronyssinus) sensitized mice before first challenge. The results showed that sh47 virus significantly reduced airway resistance, airway hyperresponsiveness, CCL11 levels and eosinophilia in the lungs of Dp2-sensitized mice. Th2 cytokines were also significantly reduced in the bronchoalveolar lavage fluid and Dp2-stimulated mediastinal lymphocytes of sh47 virus-treated mice. However, serum levels of Dp2-specific IgG1 and IgE as well as Th2 cytokine levels in Dp2-stimulated splenocytes culture supernatants were at the comparable levels to the untreated group. The results suggest that sh47 virus relieved local instead of systemic inflammatory responses. Therefore, the hybrid AAV2/9 viral vector, which is preferable to target lung epithelia cells, might be applied as a novel therapeutic approach for asthma.
Disease-specific regulation of antibody-mediated immune diseases by the pathogenic antibody Fab fragments (107.15)
Authors: Yoshino Shin 
Published: January 2023

Abstract
Ag-specific immunotherapies for Ab-mediated diseases including asthma and rheumatoid arthritis have been unavailable. In the present study, we investigated whether Ab-mediated asthmatic responses as well as arthritis in mice were able to be Ag-specifically regulated by the pathogenic Fabs. Asthmatic responses were induced in BALB/c mice by i.p. injection of anti-OVA Abs followed by intratracheal (i.t.) challenge with OVA. Arthritis was induced in DBA/1J mice by i.v. injection of anti-OVA Abs and then by intraarticular injection of OVA. Fabs from anti-OVA Abs were prepared by digestion with immobilized papain and purified. Anti-OVA Fabs were i.t. administered at the same time or 30 min before OVA challenge to test their effect on asthmatic responses. To test the effect of anti-OVA Fabs on anti-OVA Ab-induced arthritis, the Fabs were i.v. injected immediately after administration of the intact Abs.The results showed that treatment with anti-OVA but not control Fabs was followed by a marked decrease in specific airway resistance (sRaw). The decrease in sRaw in anti-OVA Fabs-treated animals was associated with the suppression of infiltration of eosinophils in bronchoalveolar lavage fluids. Treatment of anti-OVA Ab-induced arthritis with anti-OVA Fabs was also followed by the significant inhibition of joint inflammation. Therefore, asthmatic responses and arthritis induced by the respective pathogenic Ab appear to be Ag-specifically downregulated by the Ab Fabs.
Oenothein B isolated from Epilobium angustifolium enhances cytokine and pathogen-induced IFNγ production by bovine mononuclear cells (108.1)
Authors: Ramstead Andrew , Kimmel Emily , Schepetkin Igor , Quinn Mark , Jutila Mark 
Published: January 2023

Abstract
Mycobacterium avium subsp. paratuberculosis is an intracellular pathogen that has been implicated in Johne’s disease in cattle and possibly Crohn’s disease in humans. Cells expressing the NK cell activating receptor NKp46 have been shown to play an important role in mycobaterial infections in cattle by producing IFNγ and lysing infected monocytes. Therefore, compounds that enhance the activity of these cells may be useful in the treatment of these types of pathogens. Oenothein B is an immunomodulatory tannin isolated from Epilobium angustifolium plants and shown to have antitumor properties. This compound is known to activate myeloid cells, as well as NK cells, NKT cells, and γδ T cells. Previous work from our laboratory has shown that certain tannins have the ability to enhance the response of innate lymphocytes to secondary stimuli. Here, we report that oenothein B is capable of priming bovine peripheral blood mononuclear cells to produce increased levels of IFNγ in response to the IFNγ-inducing cytokine IL-18. This enhanced response is dependent upon the presence of cells expressing NKp46. Our preliminary results also suggest that oenothein B is able to enhance IFNγ production in response to M. avium subsp. paratuberculosis infected monocytes. This demonstrates that priming of innate lymphocytes by supplementation with specific polyphenols may be a useful strategy to enhance immunity to certain intracellular pathogens.
NKT cells are essential for innate immune control of vaccinia viral infection in vivo (108.3)
Authors: Novy Patricia , Yang Yiping 
Published: January 2023

Abstract
The role of natural killer T (NKT) cells during the innate immune response to pathogen remains incompletely defined. We previously showed that early control of vaccinia virus is critically dependent on the activation of natural killer (NK) cells. Here we show that in CD1d-deficient hosts, early control of vaccinia virus is compromised. This defect in viral clearance corresponds to an insufficient NK cell response, as NK cells from CD1d-deficient hosts have reduced production of the effector molecules IFN-γ and Granzyme B. Furthermore, NK cells from infected CD1d-deficient mice fail to lyse target cells when used in a chromium release assay. These data suggest a role for NKT cells in NK cell activation. In vitro, NK cell activation in response to vaccinia is dependent on both dendritic cells (DC) and NKT cells. We observe that NKT cells produce high levels of IFN-γ in response to vaccinia virus, and the production of IL-12 by DC is dependent on NKT cell presence. Direct contact between NKT cells and DC is required to fully license them to effectively activate NK cells, a phenomenon that may be attributed to upregulation of activating NK ligands RAE-1 and MULT-1 on DC surfaces. Overall, our data show that NKT cells are required for the activation of NK cells during vaccinia infection and suggest that NKT cells license DC to optimally activate NK cells. These data indicate that NKT cells are key players in the early generation of an innate immune response to viral infection.
Spaceflight alters expression of microRNA during T cell activation (109.16)
Authors: Hughes-Fulford Millie , Boonyaratakanakornkit Jim , Chang Tammy , Li Chai-Fei 
Published: January 2023

Abstract
Returning astronauts have experienced altered immune function and increased vulnerability to infection during spaceflights dating back to Apollo and Skylab suggesting that immune-suppression is a major barrier to safe, long-term human space habitation and travel. We present definitive evidence that early signal transduction events are inhibited by the microgravity (ug) environment of spaceflight. Human leukocytes were stimulated with T cell mitogens onboard the International Space Station using a 1g centrifuge as the Earth’s 1g control. Microarray analysis demonstrated significant (p&lt; .05) differential expression of 54 genes in ug vs 1g conditions. Fifty percent of the genes most significantly inhibited in ug as compared to 1g showed marked over-representation of NFKB binding sites in their promoter regions. Qrtpcr confirmed that upregulation of key genes in the NFKB pathway were inhibited in ug. Inhibition of the NFKB pathway leads to activation dysfunction during spaceflight. Lack of immune response in microgravity occurs at the cellular level. In our recent spaceflight studies of early T cell activation, we have discovered that the expression of miRNAs in both man and mouse require gravity for appropriate regulation. MiRNAs expressed during activation in normal gravity (g), were down regulated in spaceflight. These data suggest that gravity may regulate T-cell activation by two separate mechanisms; promoter regions and microRNA.