bluuebunny/crossref_metadata_2025_split huggingface dataset:
Failure of Rituximab in solid tumors is due to its inability to eliminate tumor evoked B regulatory cells (165.15)
Authors: Bodogai Monica , Lee Chang Catalina , Wejksza Katarzyna , Malchinkhuu Enkhzol , Chan Andrew , Biragyn Arya 
Published: January 2023

Abstract
We have previously shown that breast cancer generates regulatory B cells (tBregs) to convert Tregs and thereby to enable its metastasis. Thus, we decided to deplete tBregs using aCD20 antibody, a counterpart of the FDA approved strategy for the treatment of B cell malignancies (Rituximab). To our surprise, when tumor bearing mice were treated with αCD20 antibody, tumor progression was accelerated leading to increased lung metastasis. Thus, we hypothesized that tBregs may not be targeted by the antibody due to their low expression of CD20. Indeed, we found that B cell during their conversion to tBregs, downregulate their CD20 expression. Thus, tumor bearing mice treated with aCD20 antibody had enriched amounts of tBregs. We provide evidence that CD20 cannot be a target for the depletion of tBregs, explaining the failure of Rituximab to improve clinical outcomes in solid tumors. Instead, we developed an alternative strategy by in vivo targeting CpG through CXCR5 expressed by tBregs. We show that BLCArp-CpG inactivates tBregs, thereby reversing tumor metastasis. Taken together, suppressive B cells need to be controlled in solid tumors.
IL-2 withdrawal from human CD8+ T cell expansion in the presence of IL-7 enables retention of favorable functional and phenotypic characteristics for adoptive immunotherapy (165.2)
Authors: Ho Y. , Brooks Anna , Dunbar P. 
Published: January 2023

Abstract
Viral infection and reactivation of latent viruses are major causes of mortality and morbidity following haematopoietic stem cell transplantation. Adoptive immunotherapy with CD8+ T cells has proven efficacy in preventing or treating post-transplant viral infection, including therapy with resting T cells that undergo homeostatic expansion in vivo that follows transplantation. However T cells continuously expanded in vitro in IL-2 lose many characteristics associated with efficacy in vivo, and most IL-2-expanded cells die soon after infusion. Here we describe an alternative expansion protocol for human CD8+ T cells that only exposes the cells briefly to IL-2. Survival of the cells after IL-2 withdrawal relies on the continuous presence of IL-7, and the cells eventually come to rest in the cultures. In this system, timed exposure of naïve CD8+ T cells to IL-12 and IL-21 generates memory cells with competent effector functions upon rechallenge, specifically strong production of IFNγ, TNFα and IL-2. The memory cells generated also have acquired a favourable phenotype associated with early differentiation status by both cell surface markers (CCR7, CD62L, CD27 and CD28) and transcription factors (eg Tcf-1). Although our system has been piloted on the expansion of naïve CD8+ T cells, we propose that this alternative protocol could be used to generate resting antigen-specific memory cells with improved efficacy in preventing or treating viral disease in immunocompromised patients.
Induction of high levels of resistance to schistosome infection in buffalo vaccinated with a prime/boost regimen using a new delivery method. (166.14)
Authors: Li Changlin , Da'darah Akram , Li Yuesheng , Harn Donald 
Published: January 2023

Abstract
Schistosomiasis japonicum remains a serious zoonotoc disease of man and livestock, with water buffaloes accounting for about 75% of schistosome transmission to humans in China. A mathematical model of schistosome transmission suggests that a vaccine that induces 40% efficacy against infection, would significantly reduce transmission to humans. We tested the ability of SjC23, using four different vaccine delivery regimens, to induce the desired levels of efficacy in water buffalo. Comparing GLP-grade plasmid DNA Sj23-Hsp70 to our in-house produced DNA vaccine, we observed no differences in efficacy. Increasing the time between boosts from 1 to 3 months actually resulted in lower levels of efficacy, 37.2% and 31.5% compared with 41.2% and 45.8% adult worm burden and liver egg burdens respectively. Co-administration of an IL-12 plasmid DNA significantly enhanced SjC23 plasmid DNA vaccine efficacy. We then tested priming with SjC23 and SjCTPI plasmid DNAs, followed by a boost with recombinant SjC23 and rec SjCTPI, using our new vaccine delivery method. The prime/boost, new delivery method strategy yielded the highest levels of efficacy seen to date; 55% reduction in adult worms and 57% reduction in fecal egg hatching rates compared to levels in control vaccinated buffalo. Serological and immunological analyses are under way. We believe we can further enhance vaccine efficacy by priming with plasmid DNA vaccines delivered by electroporation.
Carbohydrate modification of novel polyanhydride nanoparticle adjuvants to promote pathogen-mimicking characteristics (166.5)
Authors: Phanse Yashdeep , Carrillo-Conde Brenda R. , Ramer-Tait Amanda , Roychoudhury Rajarshi , Pohl Nicola , Narasimhan Balaji , Wannemuehler Michael , Bellaire Bryan 
Published: January 2023

Abstract
An imminent need exists to design improved adjuvants and vaccines to control emerging and re-emerging diseases. An ideal vaccine will mimic the way in which a naturally occurring infection induces a robust immune response yet avoids the undesirable effects of disease. To accomplish this, new adjuvants must engage pattern recognition receptors on antigen presenting cells (APCs). In this work, we employ a novel strategy to enhance the adjuvanticity of polyanhydride nanoparticles (NP) composed of 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG) and 1,6-bis(p-carboxyphenoxy) hexane (CPH) by decorating their surface with the pathogen associated molecular pattern di-mannose (diM) to confer “pathogen-like” properties. Co-incubation of diM-NP with APCs elicited significant increases in surface expression of antigen presentation and co-stimulatory molecules and secretion of proinflammatory cytokines. An 800% increase in uptake of diM-NP was also observed. Furthermore, the mechanism of NP uptake was actin mediated and clathrin dependent, as is the case for many bacterial pathogens. Together, our data show that diM-NP possessed similar patterns of intracellular fate, persistence and APC activation as did live, pathogenic Y. pestis and E. coli. The innovative combination of polyanhydride NPs and di-mannose modification provides mechanistic insight into the properties required for next-generation adjuvants to safely mimic the immune stimulating activities of bacterial pathogens.
The role of mannose binding lectin (MBL) in co-infection of pandemic H1N1 and Streptococcus pneumoniae (168.14)
Authors: Ling Man To , Han Yan , Tu Wen Wei , Ho Pak Leung , Lau Yu Lung 
Published: January 2023

Abstract
Pandemic H1N1 (pdmH1N1) influenza A virus caused massive outbreak in 2009 and currently circulates in the community worldwide. Recent studies on this pandemic revealed that most of the deaths were resulted from secondary bacterial pneumonia caused by common bacteria found in upper respiratory tract, such as Streptococcus pneumoniae. Previous studies have shown that mannose binding lectin (MBL) exhibits anti-viral and anti-bacterial effects in vitro and in vivo. However, the immunomodulatory role of MBL during pdmH1N1/ S. pneumoniae co-infection has not been reported before. In this study, we aim to compare the severity of pdmH1N1/S. pneumoniae co-infection with pdmH1N1 infection alone, and to elucidate the functional implication of MBL during co-infection. Our in vitro preliminary data showed that recombinant MBL could successfully bind to immobilized pdmH1N1 in a dose-dependent manner. However, recombinant MBL was found to be incapable of binding immobilized S. pneumoniae. WT and MBL KO mice were infected with a sublethal dose of pdmH1N1 and S. pneumoniae. Co-infection resulted in a more severe disease phenotype and mortality in mice. However, no significant difference in weight loss and survival rate was observed between WT mice and MBL KO mice. Taken together, these data suggest that MBL may play a more vital role in modulating the first pdmH1N1 infection before subsequent bacterial infection and may attenuate the severity of the co-infection.
The molecular mechanism of dengue virus-induced IL-10 production in monocytes (168.15)
Authors: Lin Chiou-Feng , Chuang Yi-Jui , Lin Yee-Shin , Wan Shu-Wen , Chen Chia-Ling 
Published: January 2023

Abstract
Dengue virus (DV)-caused anti-inflammatory IL-10 production is much higher in patients with severe dengue hemorrhagic fever and dengue shock syndrome than those with mild dengue fever; however, the regulation of IL-10 is still unclear. Here we showed that DV infection significantly increased IL-10 production and then caused suppressor of cytokine signaling 3 expression in human monocytic THP-1 cells. In DV-infected cells, activation of CREB determined IL-10 expression largely through cAMP-dependent protein kinase A (PKA)- and PI3K-regulated manners. Furthermore, sequential activation of cAMP and PKA facilitated PI3K/PKB signaling. Notably, DV infection caused glycogen synthase kinase (GSK)-3β inactivation in a PKA/PI3K-regulated manner and inhibiting GSK-3β considerably increased DV-induced IL-10 production following CREB activation. However, blocking the well-known DV receptors, including CD209 (DC-SIGN), CD29 (integrin β1), and CD61 (integrin β3), did not inhibit DV-induced IL-10. These results show a potent molecular basis for DV infection-induced IL-10 production in monocytes. The involvement of receptors related to signaling axis of cAMP, PKA, PI3K, PKB, GSK-3β, and CREB needs further investigation.
Mast cell-dependent inflammatory response during influenza A virus infection (168.31)
Authors: Graham Amy , Zickovich Julianne , Hilmer Kimberly , Obar Joshua 
Published: January 2023

Abstract
The lung is protected from pathogens by alveolar epithelial cells, tissue resident alveolar macrophages, dendritic cells, and mast cells. The role of the mast cell has been under explored during severe pulmonary viral infections. In mice that lack functional mast cells, pathological immune responses are altered depending on the influenza strain. We found that both A/WSN/33 (WSN) and A/PR/8/34 (PR8) influenza viruses generate significant immunopathology in C57BL/6 mice, but only WSN induced pathology was mast cell dependent. To assess the differences in mast cell dependent inflammation response due to influenza strain, we examined the ability of each strain to activate in vitro-derived bone marrow cultured mast cells (BMCMC). We found that WSN, but not PR8, influenza virus activated BMCMC to produce inflammatory cytokines/chemokines, anti-viral chemokines, and degranulate. Importantly, a recombinant PR8 virus that expresses the WSN hemagglutinin (HA) glycoprotein instead of its own could induce cytokine production in BMCMC, demonstrating an important role for the HA glycoprotein for mast cell activation. Mast cell infection and viral RNA synthesis and export were necessary for mast cell activation and occurred in a MAVS-dependent mechanism. Thus, we have identified a unique inflammatory cascade which could be targeted to limit morbidity following infection with influenza virus.
Elevated levels of circulating galectin-9, a novel immune-modulator, in acute dengue virus Infection reflects disease severity (170.18)
Authors: Chagan-Yasutan Haorile , Ndhlovu Lishomwa C. , Lacuesta Talitha Lea , Leano Prisca Susan A. , Telan Elizabeth Freda O. , Niki Toshiro , Hirashima Mitsuomi , Dimaano Efren M. , Hattori Toshio 
Published: January 2023

Abstract
Following a dramatic rise in incidence in recent decades, Dengue virus infection (DENV) is now a significant burden of disease in the tropics and major international public health concern. Currently no treatment or effective vaccine exists. The β-Galactoside-binding lectin, Galectin-9 (Gal-9), functions as pro-apoptotic agent and inducer of pro-inflammatory cytokines from T cells. Here, we sought to evaluate the role of Gal-9 in the pathogenesis of acute DENV in patients presenting with self-limiting dengue fever (DF) and more serious life-threatening dengue hemorrhagic fever (DHF). Blood samples were obtained from 65 patients (mean age: 23±4yrs) hospitalized with DENV from the San Lazaro Hospital, Manila, Philippines in 2010. Plasma Gal-9 was measured by an ELISA method at the critical phase (day4-5) and recovery phase (day7-8) of infection. Our results show that during the critical phase, Gal-9 levels were markedly elevated in DF (1758±1047pg/ml) and DHF(2730±1848pg/ml) compared to uninfected (363±280pg/ml) (p&lt;0.05) controls. These levels of Gal-9 were the highest ever observed in humans. During the recovery phase, Gal-9 levels significantly declined (1170pg/ml and 1140pg/ml) (p&lt;0.05) from peak levels in DF and DHF, respectively, but not to levels observed in uninfected donors. The above findings suggest that Gal-9 levels tracks disease severity during acute DEN, potentially mediate immuno-pathology associated with DHF, and may serve as an indicator of recovery from DENV.
Crucial role for IPS-1 signaling in mediating anti-viral responses and clearance of Respiratory Syncytial Virus (170.4)
Authors: Demoor Tine , Petersen Bryan , Morris Susan , Berlin Aaron , Schaller Matthew , Lukacs Nicholas 
Published: January 2023

Abstract
Upon replication of Respiratory Syncytial Virus (RSV), double-stranded viral RNA can be detected in the endosomes via Toll-like receptor 3 (TLR3) signaling or by the cytoplasmic helicases retinoic acid inducible gene I (RIG-I) and melanoma differentiation-associated gene (Mda5). The latter interact downstream with IFNβ promoter stimulator (IPS-1). We previously demonstrated that TLR3 deficiency worsens RSV-induced lung pathology, yet leaves viral clearance intact. The present study examined the importance of IPS-1 signaling for anti-viral responses in primary cultures of alveolar epithelial cells (AECs), in dendritic cells (DCs), and macrophages (mΦ), as well as in vivo using IPS-1 knockout (KO) mice. In AECs, RSV induced IFNβ, IL6, CXCL1, CCL2 and CCL5 in an IPS-1 dependent manner. In DCs, the expression of IFNβ and CCL2 also required IPS-1. Conversely, RSV-induced cytokine and chemokine expression was enhanced in IPS-1 KO mΦ, while T-cells of infected IPS-1 KO mice showed a predominant Th1 profile with increased IFNγ. Plaque assays revealed higher RSV titers in IPS-1 deficient mice, accompanied by more severe granulocytic infiltration. Our data suggest a significant contribution of the IPS-1 pathway to the RSV-induced type I interferon response and inflammatory cytokine/chemokine production. Future experiments, using bone marrow chimeras, will help to elucidate the role of IPS-1 in both the structural and hematopoietic mediated response to viral infection.
Differential and temporal immunomodulation of α4 integrin receptors on memory T cells by Bordetella pertussis and Bordetella parapertussis infection in mice (173.24)
Authors: Nguyen Tuan , Ravindra Dipti , Ferguson Ryan , Kwong Brian , Waheed Sana , Tarlton Nicole , Abramson Tzvia 
Published: January 2023

Abstract
The hallmarks of B. pertussis (Bp) infection are extreme lymphocytosis and delayed recovery, which are linked to pertussis toxin (PTX). We hypothesize that PTX interferes with imprinting of α4 integrins on T-cells leading to their compromised homing to respiratory mucosa. In a murine model, immunofluorescence of lung sections implies a delayed recruitment of leukocytes in Bp but not in B. parapertussis (Bpp) and B. pertussis PTX mutant (BpTOX6) on day 5 p.i; lymphocyte recruitment is restored at day 25 p.i in Bp. At day 5 p.i, in Bpp and BpTOX6 models we reveal by flow cytometry an increase of blood memory CD4+ cells (CD44high and CD45RBlow) that express α4β1, α4β7; the respective cells are reduced in Bp infection. However, their frequency is increased at day 25 p.i, confirming delayed immune response. In vitro assays reflect a PTX-mediated inhibition of blood lymphocytes α4 integrins dependent adhesion and migration toward VCAM-1. In Bp, a high percent of lung dendritic cells (DC) expressing MHC-II and CD86 persists through day 25 p.i; however, the percent of CCR7+ DC in Bp is lower than that in Bpp at day 5 p.i. Lastly, after co-culturing with isolated Bp-lung DC from day 5 p.i for 4 days, a reduced percent of allogeneic CD4+ cells expresses α4β1, α4β7 compared to the respective models with Bpp or BpTOX6. We conclude that α4 integrins play an important role in memory CD4+ cell migration in Bordetellae, and that PTX interferes with their imprinting early in Bp infection.
Vitamin E Isoforms Differentially Regulate Intercellular Adhesion Molecule-1 Activation of PKCα in Human Microvascular Endothelial Cells (173.25)
Authors: Abdala-Valencia Hiam , Berdnikovs Sergejs , Cook-Mills Joan 
Published: January 2023

Abstract
Leukocytes bind to ICAM-1 on endothelial cells during leukocyte transendothelial migration. ICAM-1 is reported to activate endothelial cell xanthine oxidase (XO), protein kinase C(PKC) and ERK1/2, but the PKC isoform and the pathway involving these signals is not known. PKCα can be directly regulated by vitamin E, but it is not known whether vitamin E regulates ICAM-1 activation of PKC. Therefore, we identified an ICAM-1 signaling pathway and determined whether these signals are regulated by the vitamin E isoforms d-α-tocopherol and d-γ-tocopherol. In primary cultures of TNFα-stimulated human microvascular endothelial cells, ICAM-1 crosslinking activated the PKC isoform PKCα but not PKCβ. ICAM-1-activated XO stimulated ERK1/2 activation that then induced activation of PKCα. ICAM-1 crosslinking did not induce oxidative activation of PKCα. D-α-tocopherol inhibited ICAM-1 activation of PKCα but not the upstream signal ERK1/2. The d-α-tocopherol inhibition of PKCα was ablated by the addition of d-γ-tocopherol. In summary, ICAM-1 activation of XO and ERK1/2 stimulates endothelial PKCα without oxidation of PKCα. ICAM-1 activation of PKCα is inhibited by d-α-tocopherol and this inhibition is ablated by d-γ-tocopherol. These data are consistent with PKCα antagonist and agonist functions of d-α-tocopherol and d-γ-tocopherol, respectively, during ICAM-1 signaling.
Lymph Node Trafficking of Regulatory T Cells Is Prerequisite for Immune Suppression (173.40)
Authors: Huang Miao-Tzu , Chiang Bor-Luen 
Published: January 2023

Abstract
Treg cells are well known to suppress the activation of immune competent cells by direct cell contacts or by production of immune modulatory cytokines. However, the anatomic sites where Treg cells exert optimal immune regulation are unclear. Trafficking of Treg cells to either the lymph nodes or the peripheral tissues was reportedly essential for their immune suppression function and a consensus regarding this aspect is elusive. To address this issue, we investigated the transmigration characteristics of Treg cells by using the shear-stress flow assay. We found that Treg cells exhibited a significantly decreased adhesion to either IL1-beta-activated endothelial monolayer or ICAM-1/ E-selectin-coated surface as compared to activated effector T cells. The less transmigration capacity of the Treg cells suggests probable preferential localization of these cells during the exertion of immune regulation. In vivo, adoptively transferred Treg cells were able to inhibit footpad inflammation; however, pretreatment of the Treg cells with anti-CCR7 or anti-CD62L blocking antibodies prevented trafficking of Treg cells into the draining lymph nodes and abrogated their immune suppression effect during footpad inflammation. Our findings demonstrate a crucial role of lymph node localization for Treg cell immune suppression and suggest a hierarchy of the anatomic sites in Treg cell-mediated immune regulation.
IL-2/15 receptor signal strength controls T lymphocyte proliferation and metabolism in a quantitatively distinct manner. (174.8)
Authors: Arneja Abhinav , Lauffenburger Douglas , White Forest 
Published: January 2023

Abstract
IL-2 and IL-15 signal through a heterotrimeric surface receptor complex (IL-2/15R) composed of an α, a β, and the common gamma (γc) chain. Signaling occurs through the shared β and γc chains, and the α-chains function as high affinity ligand capture agents. Despite sharing signaling chains and pathways, IL-2 and IL-15 have non-redundant roles in T cell biology. In vitro, although IL-2 and IL-15 function as equivalent mitogens, they greatly differ in their activities as growth factors. T cells cultured with IL-2 are larger in size, show increased protein synthesis, and increased amino-acid uptake compared to T cells cultures in IL-15. In vivo, IL-2 is critical for the initial clonal expansion and retraction of activated T cells, whereas, IL-15 is in the differentiation, and maintenance of memory T cells. The mechanism through which IL-2 and IL-15 can trigger distinct phenotypes while initiating identical signaling pathways remains elusive. Our results show that T cell proliferation and metabolism are controlled in a quantitatively distinct manner through IL-2/15R signal strength independent of the cytokine identity. Proliferation is controlled by signal strength in a digital manner, whereas cell size and metabolism are controlled in an analog fashion. These results suggest that IL-2 and IL-15 can trigger distinct phenotypes by differentially regulating the strength of IL-2/15R signal, without activating distinct biochemical signaling pathways.
JAK-STAT pathways are involved in the BAFF signaling of peripheral monocytes of patients with primary Sjögren’s syndrome. (174.9)
Authors: Yoshimoto Keiko , Tanaka Maiko , Kojima Masako , Ogata Hideko , Suzuki Katsuya , Kameda Hideto , Abe Tohru , Takeuchi Tsutomu 
Published: January 2023

Abstract
Background and Purpose: We have demonstrated that peripheral monocytes of patients with primary Sjögren’s syndrome (pSS) produces abnormally high amount of IL-6 in vitro upon stimulation with soluble BAFF (sBAFF). We have also found that this production is strongly suppressed by a JAK3 inhibitor. In the present study, we have further investigated a regulatory mechanism of the production of IL-6 by sBAFF-stimulated pSS monocytes. Materials and Methods: Peripheral monocytes of pSS patients and age-matched normal individuals were stimulated in vitro with sBAFF in the presence or absence of a JAK3 inhibitor. The expression levels of IL-6 and STAT protein families were analyzed by ELISA and/or quantitative RT-PCR.. Results and Discussion: The elevated production of IL-6 by sBAFF-stimulated pSS monocytes was strongly suppressed by a JAK3 inhibitor in a dose dependent manner. Quantitative PCR analysis indicated that stimulation of pSS monocytes with sBAFF remarkably induced the expression of JAK3 as compared with the control monocytes. Similarly, the expression levels of STAT3 and STAT4 in pSS monocytes were increased upon stimulation with sBAFF, while those of STAT5 and STAT6 did not change under the same conditions. Moreover, the JAK3 inhibitor suppressed the elevated expression of STAT4. Taken together, these data suggest that a JAK3-STAT4 pathway may be involved in the production of IL-6 by BAFF-stimulated peripheral monocytes.