bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergy between intraepithelial lymphocytes and lamina propria T cells drives inflammation during infection (161.12)
Authors: Egan Charlotte , Maurer Kirk , Cohen Sara , Mack Matthias , Simpson Kenneth , Denkers Eric 
Published: January 2023

Abstract
Oral infection of C57BL/6 mice with the protozoan parasite Toxoplasma gondii triggers severe necrotic lesions in the ileum within 7-10 days of cyst inoculation. Lesion development is mediated by Th-1 cytokines and CD4+ T cells. Pathology is associated with a shift in gut flora to predominantly gram-negative species and sub-epithelial bacterial translocation. As such, these features share striking similarity to inflammatory bowel diseases in humans, in particular Crohn’s disease. Recently, we uncovered an unexpected role for IFN-γ-dependent intraepithelial lymphocytes (IEL) in mediating ileal pathology after Toxoplasma infection. We show here that αβ and not γδ T cell receptor-positive IEL mediate intestinal damage. By adoptive transfer of mucosal T cells into naive Rag1-/- mice, we definitively establish that lesions are caused by pathogen-induced immunological factors rather than parasite-mediated tissue destruction. Furthermore, we demonstrate that IEL do not act alone to cause inflammatory lesions, but function to recruit CCR2-dependent CD4+ T lymphocytes from the lamina propria into the IEL compartment. Our data provide valuable new insight into mechanisms of intestinal inflammation triggered by microbial infection, findings that have important implications for understanding human inflammatory bowel disease.
Intranasal immunization of porcine reproductive and respiratory syndrome virus entrapped biodegradable PLGA- nanoparticles elicits virus specific cross-protective immune responses in pigs (161.21)
Authors: Dwivedi Varun , Manickam Cordelia , Binjawadagi Basavaraj , Patterson Ruthi , Dodson Katie , Gourapura Renukaradhya 
Published: January 2023

Abstract
Porcine reproductive and respiratory syndrome (PRRS) is an economically very important endemic chronic respiratory viral disease of pigs. Live PRRS virus (PRRSV) vaccines are not safe in pregnant sows and boars, and currently used killed vaccines are ineffective. In this study, killed PRRSV Ags were entrapped in poly-DL-lactide-co-glycolide (PLGA) nanoparticles (100-500nm by SEM) with an approximate 50% entrapment efficiency. Internalization and localization of nanoparticles-PRRSV Ags inside the endosomes of pig alveolar macrophages was demonstrated by confocal microscopy. Immune correlates of protection were analyzed in nanoparticles-PRRSV Ags immunized and genetically variant PRRSV challenged pigs, inoculated intranasally, at post-challenge day 15. In nanoparticles immunized pig lungs, reduced PRRSV load and reduced gross lung lesions were detected compared to pigs unimmunized or immunized with free killed PRRSV Ags and challenged. Immunologically, increased frequency of lymphocytes, CD4+, CD8+, γδ T cells, myeloid cells, and reduced frequency of Tregs were detected in lungs, blood, and tracheobronchial lymph nodes. In addition, increased secretion of cytokines, IFN-γ, IL-6, and reduced IL-10 and TGF-β by ex vivo restimulated mucosal immune cells was detected. Thus, our results suggested that mucosal delivery of nanoparticles- PRRSV killed Ags has the potential to control PRRS.
Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung (161.5)
Authors: Willinger Tim , Rongvaux Anthony , Takizawa Hitoshi , Yancopoulos George , Valenzuela David , Murphy Andrew , Auerbach Wojtek , Eynon Elizabeth , Stevens Sean , Manz Markus , Flavell Richard 
Published: January 2023

Abstract
Mice with a functional human immune system have the potential to allow in vivo studies of human infectious diseases and to enable vaccine testing. To this end, mice need to fully support the development of human immune cells, allow infection with human pathogens, and be capable of mounting effective human immune responses. A major limitation of humanized mice is the poor development and function of human myeloid cells and the absence of human immune responses at mucosal surfaces such as the lung. To overcome this, we generated human IL-3/GM-CSF knock-in (hIL-3/GM-CSF KI) mice. These mice faithfully expressed human GM-CSF and IL-3 and developed pulmonary alveolar proteinosis due to elimination of mouse GM-CSF. We demonstrate that hIL-3/GM-CSF KI mice engrafted with human CD34+ hematopoietic cells had improved human myeloid cell reconstitution in the lung. In particular, hIL-3/GM-CSF KI mice supported the development of human alveolar macrophages that partially rescued the PAP syndrome. Moreover, human alveolar macrophages mounted correlates of a human innate immune response against influenza virus. hIL-3/GM-CSF KI mice represent a unique mouse model which permits the study of human mucosal immune responses to lung pathogens.
IL-17-secreting neutrophils represent a novel lung cell subset playing a critical role in the resolution of inhalational anthrax (161.6)
Authors: Anne Quesnel-Hellmann , Garraud Kevin , Cleret Aurélie , Mathieu Jacques , Fiole Daniel , Gauthier Yves , Tournier Jean-Nicolas 
Published: January 2023

Abstract
Background: The role of IL-17 and neutrophils in the lung has been described as two intricate but independent players, IL-17 triggering downstream recruitment of neutrophils. Methods: A/J, C57BL/6, IL-17RA-/-, CX3CR1+/gfp mice were infected intranasally by B. anthracis Sterne 7702, its toxin-defective derivative mutant RP42 and the fully virulent 17JB strains. Cytokine productions were evaluated in the broncho-alveolar lavage and the population identified by intra-cellular staining. Results: Here, we identify neutrophils as the primary IL-17-secreting cell subset in an inhalation model of anthrax infection. Using IL-17RA-/- mice, we confirm that IL-17A/F signaling is instrumental in the self-recruitment of this population. Moreover, we show that IL-17A/F axis is critical for survival to pulmonary infection as IL-17RA-/- mice become susceptible to intranasal infection by anthrax Sterne spores. Eventually, by depleting neutrophils in wild type and IL-17RA-/- mice, we demonstrate the crucial role of IL-17-secreting neutrophils for mouse survival after anthrax infection in the Sterne strain model. In accordance, following intranasal infection with a fully virulent strain, neutrophils prove to be critical for survival. Conclusion: This work demonstrates the very intricate role of both IL-17 and neutrophils in the clearance of pathogen and survival to pulmonary anthrax.
Bone marrow mesenchymal stem cells calibrate the innate immune tone by inducing monocyte emigration in response to circulating TLR-ligands (162.1)
Authors: Shi Chao , Jia Ting , Mendez-Ferrer Simon , Frenette Paul , Pamer Eric 
Published: January 2023

Abstract
Inflammatory (Ly6Chi CCR2+) monocytes provide defense against infections but also contribute to autoimmune diseases and atherosclerosis. Monocytes originate from the bone marrow and their entry into the bloodstream requires stimulation of CCR2 chemokine receptors by MCP1. How monocyte emigration from bone marrow is triggered by infections in anatomically remote sites remains unclear. We demonstrate that low concentrations of TLR ligands in the bloodstream drive CCR2-dependent emigration of monocytes from bone marrow. Bone marrow mesenchymal stem cells (MSCs) rapidly express MCP1 in response to circulating TLR ligands or systemic bacterial infection and induce inflammatory monocyte trafficking into the bloodstream. Targeted deletion of MCP1 from MSCs impaired monocyte emigration from bone marrow upon LPS stimulation and increased susceptibility to Listeria monocytogenes infection. Our findings suggest that bone marrow MSCs respond to circulating microbial molecules and regulate bloodstream monocyte frequencies by secreting MCP1 in proximity to bone marrow vascular sinuses.
IL-13 regulates the in vivo generation of IL-17 producing T cells (163.15)
Authors: Kinyanjui Margaret , Shan Jichuan , Fixman Elizabeth 
Published: January 2023

Abstract
Several features associated with allergic airways disease are regulated by the Th2 cytokine IL-13. IL-17 is also known to regulate aspects of allergic disease since production of IL-17 is associated with severe asthma and correlates with an increase in airway neutrophilia. The mechanism by which these IL-17 producing cells develop during airways disease is still unclear. To better understand what factors regulate the development of IL-17 producing cells we used an acute model of IL-13-induced airway inflammation in which IL-13 was intranasally administered to anaesthetized mice. As expected, administration of IL-13 induced airway eosinophilia, airway hyperresponsiveness, and mucus production. In addition, IL-13 induced airway neutrophilia as well as increases in expression of neutrophil chemokines. IL-13 also induced increased mRNA expression of IL-17 and IL-6 in the lung. Intracellular cytokine staining of bronchoalveolar lavage cells showed that IL-13 increased the number of IL-17+ve cells when compared to control. These cells did not produce IL-22 or IFN-gamma and were identified as either CD4 or γδ T cells. Animals were then treated with IL-13 in the presence of BrdU to follow development of IL-17 expresing cells in vivo. The majority of these cells incorporated BrdU suggesting that these IL-17+ve cells proliferated in the lung. Further studies to characterize these IL17+ve T cells are under way.
Assessment of the role of basophils in promoting allergen-specific T-cell proliferation in allergic patients (163.3)
Authors: Eckl-Dorna Julia , Ellinger Adolf , Pavelka Margit , Blatt Katharina , Valent Peter , Womastek Irene , Valenta Rudolf , Niederberger Verena 
Published: January 2023

Abstract
The long standing view that basophils mainly play an effector role in allergy by releasing histamine and eicosanoids upon crosslinking of FcϵRI receptor bound immunoglobulin E with specific allergen has recently been challenged. Studies in mouse models indicated an additional role of basophils as antigen presenting cells (APCs) in the initiation of Th2 immunity. However, so far this question has not been addressed in allergic patients. Here we compared basophils and professional APCs with regards to their capacity in promoting in vitro T-cell proliferation upon allergen challenge. T-cells isolated from allergic patients were either cultured alone, together with APCs depleted of basophils or with purified basophils in the presence or absence of allergen. Proliferation was measured by 3H-thymidine incorporation. Stimulation with allergen-induced proliferation in both total PBMCs used as controls and T-cells co-cultured with APCs. In contrast, T-cells co-cultured with basophils did not proliferate in response to allergen stimulation. Addition of cytokines promoting basophil survival to the cultures did not have relevant effects on their capacity to promote T-cell proliferation. In summary, our data indicate that basophils do not play an important role in promoting T-cell proliferation in vitro upon allergen challenge in allergic patients.
Prevention of autoimmune myocarditis by angiotensin inhibition (164.13)
Authors: Schuessler Teresa , Engman David 
Published: January 2023

Abstract
Myocarditis, inflammation of the heart, is one of many cardiac pathologic states that can ultimately lead to heart failure. A variety of infectious and noninfectious agents can cause myocarditis, and certain individuals will develop autoimmune responses to various cardiac antigens. To study the autoimmune aspects of the disease, an animal model of experimental autoimmune myocarditis (EAM) has been developed in which immunization of susceptible mouse strains with cardiac myosin induces cardiac inflammation, hypertrophy, and fibrosis through mechanisms dependent on CD4+ T cells. We tested the ability of the antifibrotic, angiotensin-converting enzyme (ACE) inhibitor captopril to inhibit the massive fibrosis that develops during EAM. To our initial surprise, not only did captopril prevent fibrosis, but also it prevented inflammation primarily. Captopril treatment did not appear to directly affect T cell function, since T cells from captopril-treated mice proliferated and secreted proinflammatory cytokines. However, preliminary data indicate that immune cells from spleens of captopril-treated mice show reduced ability to transmigrate across endothelium ex vivo, suggesting that ACE inhibition somehow affects cell trafficking into the myocardium. Current studies are underway to further elucidate the mechanisms by which ACE inhibition mediates these effects with respect to how ACE and ACE products provide proinflammatory signals during EAM.
Docosahexaenoic acid modulates CD4+ T cell differentiation and is protective in experimental autoimmune encephalomyelitis (164.18)
Authors: Kong Weimin , Yen Jui-Hung , Adhikary Sabina , Ganea Doina 
Published: January 2023

Abstract
Protective anti-inflammatory effects of DHA were reported in clinical studies and animal models of colitis, sepsis, and stroke. In the present study, we investigated the effects of DHA on the function of bone marrow-derived dendritic cells (DC) in CD4+ T cell stimulation and differentiation. Pretreatment of DC with DHA prevented LPS-induced DC maturation, maintaining an immature phenotype characterized by low expression of costimulatory molecules and lack of proinflammatory cytokine production (IL-12p70, IL-6 and IL-23). DHA-treated DC were poor stimulators of antigen-specific T cells in terms of proliferation and Th1/Th17 differentiation. This was associated with an increase in p27(kip1), a cell cycle arresting agent. In contrast, T cells co-cultured with DC-DHA express higher levels of TGFβ and Foxp3, without exhibiting a functional Treg phenotype. In addition, DHA prevents up-regulation of VCAM-1 and ICAM-1 in bEND.3 cells (mouse brain microvascular endothelial cell line). Here we report for the first time a beneficial effect of dietary n-3 fatty acids in experimental autoimmune encephalomyelitis (EAE), a model for human multiple sclerosis. The beneficial effect of DHA in EAE was associated with reduced numbers of IFNγ- and IL-17-producing CD4+ T cells in both spleen and CNS.
Interleukin-7 promotes autoimmune disease by enabling memory T cells to escape PD-1-mediated tolerance (164.21)
Authors: Dooms Hans , Penaranda Cristina , Kuswanto Wilson , Hofmann Jerry , Kenefeck Rupert , Narendran Parth , Walker Lucy , Bluestone Jeffrey , Abbas Abul 
Published: January 2023

Abstract
An important challenge in the therapy of immune-mediated inflammatory diseases is to control established disease, largely because autoreactive memory T lymphocytes are difficult to suppress or eliminate. Memory T cells depend on interleukin-7 (IL-7) for their generation and maintenance and genomic studies have associated the cytokine’s receptor, IL-7Rα, with increased risk for autoimmune diseases such as type 1 diabetes. Here we show that IL-7Rα blockade reverses hyperglycemia in the non-obese diabetic (NOD) mouse model of type 1 diabetes. Diabetogenic memory T cells deprived of IL-7 signals remained present in the lymphoid organs but expressed the inhibitory molecule Programmed Death 1 (PD-1), which is critical for preventing autoimmunity. Blocking the interaction of PD-1 with its ligand, PD-L1, in cured mice rapidly induced hyperglycemia, demonstrating that this mechanism inhibited memory responses to pancreatic islets after IL-7Rα blockade. Conversely, IL-7 suppressed PD-1 expression after T cell activation, indicating that IL-7 contributes to the pathogenesis of autoimmune diabetes by keeping memory T cells in a functionally competent, tolerance-resistant state. Our data uncover a novel link between IL-7 and the PD-1/PD-L1 tolerance pathway and identify IL-7Rα blockade as a potential therapeutic approach to induce PD-1-mediated inhibition of pathogenic memory T cells in established T cell-dependent inflammatory diseases.
Novel, orally active proteasome inhibitor, CEP-18770, protects and treats disease in preclinical mouse models of lupus nephritis (164.3)
Authors: Seavey Matthew , Lu Lily , Stump Kristine , Wallace Nate , Ruggeri Bruce 
Published: January 2023

Abstract
Since therapeutic blockade of the cellular proteasome has previously demonstrated preclinical efficacy against inflammatory diseases, the evaluation of a novel, orally active proteosome inhibitor, CEP-18770, was tested in models of systemic lupus erythematosus (SLE). Age matched, 8-week old (MRL/lpr) or 8 months old (NZM) mice with established SLE or lupus nephritis (LN), respectively, were treated with CEP-18770 either 3mg/kg 1-2x/wk, iv, or orally at 10mg/kg. Reference agent, bortezomib, was provided at 0.5mg/kg, 1x/wk, or 0.3mg/kg 1-2x/wk. Standard of care agents included dexamethasone or cyclophosphamide. Mice were monitored for clinical, pathological and immunological changes. Reductions in the frequencies of specific anti-chromatin, smith and dsDNA antibody secreting cells (ASC) and levels of the corresponding antinuclear antibodies (ANA), followed CEP-18770 treatment and were accompanied by decreases in spleen ASCs, plasma cells, and serum cytokines (IL-12, IL-17A, IL-1β, TNFα). CEP-18770-treatment also mitigated the incidence of renal histopathology, and subsequently, proteinuria, in both models. CEP-18770 treatment also extended survival for both models over bortezomib. Proteasome inhibition and IκBα accumulation in target tissues followed administration of CEP-18770 and bortezomib. CEP-18770 was equivalent to treatment with bortezomib; however, CEP-18770 resulted in greater tolerability and rate of response resulting in greater SLE disease stability overtime.
Egr-2 is a tumour repressive gene (165.1)
Authors: Miao Tizong , Wang Ping 
Published: January 2023

Abstract
EGR-2, a zinc finger domain containing transcription factor, plays an important role in the development of both centre never system and T lymphocytes. However, the mechanism of action is unknown. To investigate Egr-2 function in lymphocytes, we have developed lymphocyte specific Egr-2 KO (Knockout) and Tg (Transgenic) mice. In the absence of Egr-2, the homeostasis of T cells is disregulated with hyper-proliferation of effector phenotype cells. In addition to the increased effector phenotype lymphocytes, the development of spontanouse B and T cell lymphoma in Egr-2 KO mice has been found at later age. More than 30% Egr-2 KO mice aged more than 12-months developed either T or B cell lymphoma. Oncogene-database (Oncomine gene expression database) search showed that the expression of Egr-2 is either suppressed or deleted in haematopoietic tumours. To explore anti-tumour function, Egr-2 was transfected into HKE 293 and mouse melanoma B16 cell lines, respectively. The transfected cells exhibited small cell body and stopped cell division. In the undergoing mechanism study, we found that 1), The expression of p53 was increased in lymphocytes from Egr-2 Tg mice and p53 was phosphorylated in Egr-2 transfected HKE293 cells.2), Egr-2 binds to c-Jun, the key components of AP-1; 3), Egr-2 strongly inhibited STATs transcriptional activity. Our results suggest that tumour suppressive role of Egr-2 involved in multple cell signalling pathways.
Combining gp96-Ig vaccination and mTL1A-Ig fusion protein boosts anti-tumor immunity. (165.10)
Authors: Khan Samia , Schreiber Taylor , Deyev Vadim , Podack Eckhard 
Published: January 2023

Abstract
Tumor necrosis factor 25 (TNFR25) and its natural ligand, TL1A, inhibit the suppressive activity of regulatory T cells (Tregs) and block de novo biogenesis of antigen specific induced Treg (iTreg). TL1A/TNFR25 co-stimulates CD4+ and CD8+ T cells and promotes proliferation and cytokine production in the presence of antigen. Due to the role of TNFR25 as a co-stimulator of T cells, we hypothesize that combination therapy with g96-Ig vaccination will enhance the robust expansion of CD8 CTL observed with vaccine alone. As expected, gp96 vaccine with TNFR25 agonistic antibody, 4C12, enhanced CD8 CTL expansion and tumor rejection as compared to vaccine only. Here we genetically engineered murine TL1A-Ig fusion proteins that differ in retention of the cleavage site in the extracellular domain fused to the C-terminus of mIgG1 Fc. The in vitro potencies of the TNFR25 agonist fusion proteins were confirmed by caspase activation and binding assays. Apparent molecular weights were measured as 447 and 152 kDa by gel filtration, and biological half life was determined as 7 hours in mice. In vitro, mTL1A-Ig with anti-CD3 caused rapid proliferation of all CD4+ T lymphocytes, including CD4+FoxP3+Tregs. Enhanced antigen specific CTL expansion was observed in the spleen and peritoneal cavity when naïve mice were treated with vaccine and mTL1A-Ig. We will optimize dose and scheduling of mTL1A-Ig injection, which can be utilized in combination with the vaccine to enhance therapeutic benefit.
The pro-apoptotic effect of vitamin C on colon cancer cell lines, HCT116 via the regulation of SIRT1 expression (165.11)
Authors: Yu Yeon-sil , Bae Seyeon , Kim Hyemin , Kong Joo Myung , Kim Hang Rae , Kang Jae Seung , Hwang Young Il , Lee Wang Jae 
Published: January 2023

Abstract
Vitamin C is an essential nutrient for living organisms to protect from oxidative stress. In addition, It shows potent anti-tumor activity through the enhancement of immune system. However, there are few reports regarding the direct cytotoxic activity on tumor cells and its related mechanisms. Therefore, we investigated the direct cytotoxic activity of vitamin C on tumor cells especially through the regulation of SIRT1. Since It is generally known that the activity of SIRT1, a NAD-dependent deacetylase, is related with the survival and proliferation of tumor cells, we have first investigated whether vitamin C shows an anti-tumor effect through the regulation of SIRT1 activity in HCT116s. As a result, we found that extensive apoptosis is occurred in HCT116 in company with the suppression of SIRT1 mRNA expression by the treatment of vitamin C. Even though it is known that SIRT1 expression is regulated by p53, we could not find any differences between p53 wild type HCT116 and p53 null type HCT116. To clarify the direct regulatory effect of vitamin C on SIRT1 activity, we examined the change of phosphorylation on SIRT1 after treatment of vitamin C. We observed that vitamin C suppressed the phosphorylation of SIRT1 on the both of ser27 and ser47 residues. Taken together, our data suggest that vitamin C induces apoptosis in HCT116 via the down-regulation of SIRT1 expression and suppression of its phosphorylation.
CXC chemokine receptor 3 deficiency promotes cutaneous tumor formation (165.14)
Authors: Masui Yuri , Kai Hiromichi , Kadono Takafumi , Sato Shinichi 
Published: January 2023

Abstract
CXC chemokine receptor 3 (CXCR3), G protein-coupled, seven-transmembrane receptor, binds and is activated by the three IFN-γ-inducible C-X-C chemokines; MIG/CXCL9, IP-10/CXCL10 and I-TAC/CXCL11. CXCR3 is expressed on natural killer cells, plasmacytoid dendritic cells, myeloid dendritic cells, B cells, activated T cells, proliferating endothelial cells, and preferentially expressed by Th1-polarized activated/memory T cells. Although recent studies have correlated the expression of CXCR3 and its ligands with a variety of diseases or pathological states, little has been known about the engagements of CXCR3 in cutaneous immune responses, especially cutaneous anti-tumor immunity. In this study, we injected B16 murine melanoma cells into the skin superficial to the ear cartilage of CXCR3-deficient mice. The tumor formation in the ears from CXCR3-deficient mice was accelerated compared to that from C57BL/6 mice. Local cytokine mRNA expression levels of the ear tumors were measured by real-time PCR and immunohistochemical analysis was performed to evaluate leukocyte subsets within the tumors. Thus, CXCR3 may play an important role in tumor immunity.