bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting regulatory T cells in chronic inflammatory disease. (MPF2P.749)
Authors: Lieske Nora , Tonby Kristian , Kvale Dag , Dyrhol-Riise Anne , Taskén Kjetil 
Published: January 2023

Abstract
Human regulatory T cells (Tregs) are functionally characterized by their ability to suppress effector T cells in addition to having an essential role in maintaining immunological tolerance. Activated Tregs are upregulated in chronic inflammation and studies in human tuberculosis (TB) patients indicate that patients with active disease have increased frequency of Tregs in peripheral blood compared to patients with latent TB. Tregs also play a role in chronic viral infections. In HIV, Tregs control viral replication in early stages of the disease but limit immune activation and pathogen specific immune responses in later stages. The MAPK/ERK signaling pathway has been shown to be involved in the regulation of the FoxP3 transcription factor, the major regulator of Treg suppressive function. We aimed to target activation of disease specific Tregs by inhibition of the MEK signaling pathway based on the hypothesis that this would improve anti-HIV and anti-TB immunity. Upon stimulation of patient PBMCs with TB- and HIV-specific antigens in presence of MEK inhibitors, we observed significantly downregulated levels of FoxP3 in resting Tregs (CD45RA+FoxP3+) and a reduced number of activated Tregs (CD45RA-FoxP3++). Differential effects on production of IFNγ TNFα and IL-2 could be observed. In conclusion, MEK inhibitors modulate disease antigen-specific Treg activation which may have potential application in new treatment approaches where limiting Treg activity would be favourable.
Lung resident memory CD4 T cells promote chronic inflammation in allergic asthma (MUC1P.910)
Authors: Turner Damian , Goldklang Monica , Trischler Jordis , D’Armiento Jeanine , Farber Donna 
Published: January 2023

Abstract
Common household allergens, like infectious agents, are often encountered at epithelial barrier surfaces within the lung and can sometimes cause allergic asthma. Whereas lung resident memory T cells (TRM) protect against recurrent respiratory infection, allergen-induced CD4 TRM could have deleterious effects, initiating chronic inflammation and recurrent asthma symptoms. We sought to investigate whether lung CD4 TRM are generated in asthma and their role in the pathogenesis of allergic asthma. To this end, mice were inoculated intranasally with house dust mite (HDM) extract (a common household allergen) for three weeks to induce the characteristic symptoms of asthma. The sensitized mice were then rested for 4 weeks and the CD4 population within the lung analyzed. Chronic allergen exposure induces TRM-like CD4 T cells with the characteristic high expression of CD69. HDM-induced TRM are long-lived and persist for weeks in the lung parenchyma after cessation of HDM exposure. Lung CD4 TRM cluster around the bronchioles and are rapidly activated upon subsequent exposure to the allergen. This local activation of CD4 TRM was accompanied by activation of dendritic cells within the lung. These data suggest that early activation of allergen-induced lung CD4 TRM might be an initiating step in the cascade of events that are involved in recurrent asthma episodes.
Can human lung fibroblasts present antigen to autologous T cells? (MUC1P.911)
Authors: Hutton Andrew , Staples Dr Karl , Wilkinson Dr Tom , Warner Jane 
Published: January 2023

Abstract
HLF are a major structural cell in the lung, and their ability to influence CD4 T cells in an Ag-specific manner is unknown. Recurrent bacterial infections, a hallmark of COPD, may involve bacterial presence in the mesenchyme and HLF-Tcell interaction. We have investigated the effect of non-typeable H.Influenzae (NTHi) on HLF immune synapse molecule expression and their ability to stimulate T cells. Lung tissue from patients undergoing resection surgery was collagenase digested and CD45-CD90+ HLF were demonstrated to express HLA-DR at baseline. HLF outgrown from this tissue were cultured and stimulated with IFNγ and/or NTHi for 48h. IFNγ upregulated both ICAM-1 5.6-fold (P&lt;0.001, N=23) and HLA-DR 16.2-fold (P&lt;0.001, N=20). Exposure to NTHi increased ICAM-1 6.1-fold (P&lt;0.001, N=6) but not HLA-DR expression. HLF also expressed low levels of CD40 which increased 2.2-fold upon NTHi stimulation, but no detectable CD80 or 86 (N=5). To assess Ag presentation, HLFs were co-cultured with NTHi-specific autologous T cells overnight and cytokine production measured by FACS. Results indicate HLF preconditioned with IFNγ+NTHi could stimulate autologous T cells raised against NTHi Ags to produce IFNγ or IL-17A. Blocking experiments showed this stimulation to be reliant upon fibroblast HLA-DR expression. In conclusion, NTHi can cause HLF to present antigen to and activate autologous T cells. HLF-activated T cells may cause the lung damage associated with bacterial infections in COPD.
Microarray analysis of epithelial-to-mesenchymal transition genes suggests differential epithelial remodeling in human disease vs. mouse models of asthma (MUC1P.912)
Authors: Loffredo Lucas , Berdnikovs Sergejs 
Published: January 2023

Abstract
Epithelial-mesenchymal transition (EMT) is the process by which epithelial cells revert to a less differentiated, mesenchymal phenotype; it occurs in maintenance of tissue homeostasis and is exaggerated in disease. EMT has been implicated in human asthma, although it is not clear whether this process is caused by inflammation or rather contributes to it. In allergen-induced murine models of asthma, EMT would be directly caused by inflammation; however, evidence for EMT in such models is lacking. To assess weight-of-evidence and causality for EMT, we contrasted gene expression between mouse models and human asthma samples, using data from 12 gene expression microarrays (GEO, NCBI). PCA analysis surprisingly discriminated human and mouse studies based on behavior of 8 classical EMT genes and 25 epithelial differentiation genes. Increased expression of Cdh2, Twist1, Twist2, Snai2 and Zeb1 supported existence of EMT in human asthma. Interestingly, the same genes did not change or decreased their expression in mouse models. Moreover, inducers of EMT Sox4, Fgf18 and Fgfr4 decreased and suppressor of EMT Runx3 increased expression in mice, consistent with mesenchymal-epithelial transition associated with repair. The fact that even chronic mouse models failed to recapitulate the EMT pattern seen in patients suggests that allergic inflammation alone is not sufficient to trigger persistent epithelial de-differentiation, implicating a missing component in the causation of EMT in asthma.
Development of a novel tool for Francisella tularensis immunology (MUC1P.915)
Authors: Place David , Kirimanjeswara Girish 
Published: January 2023

Abstract
Tularemia, an acute infection caused by Francisella tularensis, can manifest in various forms. Pulmonary tularemia developed after an aerosol exposure to the bacterium has a high risk of mortality in unvaccinated individuals. Therefore, development of a vaccine is of critcal importance but is hampered by a relative lack of understanding of the protective adaptive immune response. Absence of immunological tools to study protective T cell responses has been one of the key hurdles in establishing the profile of immune responses to F. tularensis. We have developed a novel F. tularensis LVS, which constitutively expresses a vgrG-OVA fusion protein containing the epitopes OVA257-264 and OVA323-339. This will allow researchers to study antigen-specifc T cell responses during infecton by F. tularensis. Robust expression of this construct was confirmed by immunoblot from bacterial lysates. An additional chromosomally-integrated expression construct is also being generated for more stable expression throughout in vivo infections. This new tool will allow us to study the memory response to Francisella vaccinaton in ways previously difficult to do. Inital experiments are underway using OT-I and OT-II transgenic mice to study the pathogen-specifc response to Francisella following vaccinaton by the intradermal and intranasal routes in order to determine the ideal conditons for improving survival after pulmonary challenge, which remains a concern in a potental bioterror atack.
In situ imaging unveiled location of protective endogenous CD8 T cell response in lung (MUC1P.916)
Authors: Gilchuk Pavlo , Guy Clifford , Hill Timothy , Rabacal Whitney , Sebzda Eric , Green Douglas , Joyce Sebastian 
Published: January 2023

Abstract
The anatomic distribution of protective endogenous memory CD8 T cell response in the lung—a common site of pathogen invasion—is poorly understood. We report that endogenous CD8 T cell memory installed by local pulmonary, but not systemic, vaccination resulted in faster viral control and enhanced protection to a lethal respiratory viral challenge in mice. Enhanced protection depended on elicitation of a distinct CXCR3LO resident CD8 T cell memory population (CD8 TRM) confined to the pulmonary interstitium. CD8 TRM sensed the pathogen and rapidly initiated a local immune response before inflammation-induced recruitment of lung vascular and/or circulating memory CD8 cells. Imaging of protective CD8 T cell response in lungs by exploiting in situ staining with fluorescent MHC class I tetramers coupled with Sheet Plane Illumination Microscopy (SPIM) platform uncovered that CD8 TRM are retained within immunologically correct locations, which include the delicate alveoli walls outside of the alveolar capillary network - the most vulnerable sites affected by lower airway infection. Such a location of memory CD8 T cell response may allow prompt surveillance of infected alveolar epithelium without need for the egress into the alveolar space. In sum, our study unveiled novel dimensional information of memory T cell response that localize to those anatomic sites of the lung that are critical for host defense.
Trace levels of staphylococcal enterotoxin bioactivity are concealed in a mucosal niche during pulmonary inflammation (MUC1P.917)
Authors: Menoret Antoine , Svedova Julia , Behl Bharat , Vella Anthony 
Published: January 2023

Abstract
Pathogen and cellular by-products released during infection or trauma are critical for initiating mucosal inflammation. This was studied in mice undergoing pulmonary inflammation after Staphylococcal enterotoxin A (SEA) inhalation. A potent pro-inflammatory factor was detected using a sensitive bioassay suggesting the presence of an alarmin, a danger-associated molecular pattern (DAMP), and/or a cytokine. Highly purified bronchoalveolar lavage fluid (BALF) fractions obtained by sequential chromatography were screened for bioactivity and subjected to mass spectrometry. SEA was the only identified protein with known inflammatory potential, and unexpectedly, it co-purified with immunosuppressive proteins. Among them was lactoferrin, which inhibited SEA and anti-CD3/-CD28 stimulation by promoting T cell death and reducing TNF synthesis. Higher doses of lactoferrin were required to inhibit effector compared to resting T cells. This inhibition relied on the continual presence of lactoferrin rather than a programming event. The data show that bioactive SEA is constituted in a mucosal niche within BALF even after the initiation of inflammation. These results may have clinical value in human diagnostic settings since traces levels of SEA can be detected using a sensitive bioassay, and may help pinpoint potential mediators of lung inflammation when molecular approaches fail. Submitted to American Journal of Respiratory Cell and Molecular Biology.
Human HLA-G+ extravillous trophoblasts: immune activating cells that interact with decidual leucocytes (MUC2P.921)
Authors: Tilburgs Tamara , Crespo Angela , van der Zwan Anita , Moffett Ashley , Strominger Jack 
Published: January 2023

Abstract
Invading HLA-G+ extravillous trophoblasts (EVT) are believed to play a key role in the prevention of a maternal immune attack on foreign fetal tissues. EVT are difficult to study due to their low frequency and lack of proliferative capacity. Here highly purified HLA-G+ EVT and HLA-G- villous trophoblast (VT) were isolated. Culture on fibronectin increased HLA-G expression on EVT but differentiation from VT into EVT was not observed. Moreover microarray analysis demonstrated that VT and EVT have more than 4200 differentially expressed genes. Functional gene set enrichment analysis (GSEA) revealed a striking immune activating potential for EVT that is absent in VT. Co-culture of HLA-G+ EVT with sample matched decidual NK, macrophages, CD4+ and CD8+ T cells were established and demonstrated interactions of all leukocyte types with EVT. Interaction of EVT with CD4+ T cells resulted in increased proportion of CD4+CD25hiFOXP3+ Tregs and increased FOXP3 protein level in these cells. However, EVT did not enhance cytokine secretion in dNK whereas stimulation of dNK using mitogens or classical NK targets confirmed the distinct cytokine profiles of dNK and pNK. Thus EVT are specialized cells with an immune activating profile whose properties are not imitated by HLA-G expressing cell lines. Careful validation of EVT-leukocyte interactions using primary HLA-G+ EVT needs to be carried out to understand the unique contribution of EVT to the decidual immune response in human pregnancy.
Increased expression of antimicrobial peptides in the cervix during Trichomonas vaginalis infection (MUC2P.923)
Authors: Makinde Hadijat , Novak Richard , Landay Alan , Spear Gregory 
Published: January 2023

Abstract
The lower genital tract is a unique mucosal environment and further studies are needed to define the types of immune responses that occur during genital infections. We investigated the expression of antimicrobial proteins/peptides (AMP) and cytokines produced in response to Trichomonas vaginalis (TV) infection. A cohort of women (30 TV+, 30 TV-) aged 18-45 that was at high risk of acquiring HIV was studied. mRNA was isolated from cervical cytobrush samples, reverse transcribed, and real time PCR used to determine AMP and cytokine expression. Cytokines were measured by ELISA in cervical vaginal lavage (CVL). TV+ samples had significantly higher mRNA levels of S100A7, S100A8, S100A9 and Muc1 than TV- samples. In contrast, lactoferrin was lower in the TV+ group. For defensins (HBDs), mRNA for HBD4 was significantly higher in TV+ samples, while HBD103 was lower in TV+ samples, but there was no difference in HBD1. Cathelicidin was not different between TV+ and TV- samples. mRNA for RegIIIγ was detected in only four samples. Although a role in inducing expression of AMPs has been shown for IL-22 and IL-17A, these two cytokines, as well as IFNγ, were not different in TV+ and TV- groups. However, IL-17 protein, but not IL-22 was higher in TV+ CVL samples (p &lt; 0.05). Our data identify AMPs that have altered expression in the cervix during TV infection suggesting that these AMPs might have an important role in immunity against TV infection.
Role of NK cells in IFN-epsilon-mediated protection against female reproductive tract infection (MUC2P.925)
Authors: Hansbro Philip , Mayall Jemma , Mangan Niamh , Starkey Malcolm , Kim Richard , Hertzog Paul , Horvat Jay 
Published: January 2023

Abstract
Chlamydia trachomatis is the most common bacterial STI and frequently results in reproductive tract (RT) sequelae such as pelvic inflammatory disease and infertility. However, the immune processes involved in the clearance and immunopathology of Chlamydia infection are not well understood. In previous studies we showed that IFN-ε, a novel type I IFN that is exclusively and constitutively expressed in the female RT, plays an important role in protecting against Chlamydia infections. Here, we examined the effects of IFN-ɛ on cellular responses in the female RT in order to elucidate the mechanisms by which IFN-ɛ protects against Chlamydia infections. Female WT and IFN-ε-/- C57BL/6 mice were pre-treated with progesterone and infected intra-vaginally with Chlamydia muridarum or sham-infected. Uterine horns were harvested and the effects of IFN-ε deficiency on Chlamydia infection, immune factor expression and cellular infiltration were assessed using real-time qPCR and flow cytometry. We show that IFN-ε-/- mice have increased Chlamydia 16S expression in the upper RT which correlated with fewer NK cells and tissue-resident uterine NK cells at 3 days post infection. IFN-γ+ CD45+ cells were also decreased in the infected IFN-ε-/- mice, of which over 60% were NK cells. These changes were associated with reduced iNOS and STAT1 expression. These findings suggest that IFN-ε may protect against Chlamydia RT infections by potentiating the recruitment of protective IFN-γ-producing NK cells.
Impacts of ethanol and nicotine withdrawal on fecal immunoglobulin A levels in rats (MUC3P.947)
Authors: Harris Henry , Lingg Ryan , Hayes Dayna , Redmond Sarah 
Published: January 2023

Abstract
Alcohol and nicotine are both well known to cause depression of immune response; however, the effects of withdrawal from these substances have not been extensively explored. The impacts of exposure may arise from direct depression of the immune system or from the stress associated with exposure and withdrawal. In this study the immune response of adult male Rattus norvegicus was tested following exposure to both alcohol and nicotine, alcohol alone, nicotine alone, or neither (n=4/group). Nicotine or saline was administered 3 times per day for 10 days (0.3 mg/kg in saline; subcutaneous). Alcohol (25%w/v in nutritionally complete diet; intragastric) or isocaloric dextrose-containing diet was administered during days 7-10 of nicotine administration following the same thrice-daily schedule. Fecal samples were collected 4, 7, 11 and 14 days post exposure and fecal extractions were tested via ELISA to measure immunoglobulin A (IgA) levels. The effects of ethanol exposure, nicotine exposure, time post-exposure, and the interactions of the three were tested using a 3-way ANOVA. There was a significant decrease in IgA levels across groups on day 7 (p = 0.015), followed by an increase in IgA levels measured on day 10 in ethanol exposed groups (p = 0.011). This fluctuation in mucosal immunity following binge exposure to ethanol suggests that the impacts of even short term alcohol use impact the immune response during a withdrawal period.
Maximal use systemic exposure study evaluating AN2728, a novel boron-based small molecule, for the treatment of pediatric and adolescent subjects with mild-to-moderate atopic dermatitis (THER2P.959)
Authors: Kircik Leon , Call Robert , Tschen Eduardo , Draelos Zoe , Van Syoc Merrie , Zane Lee , Hebert Adelaide 
Published: January 2023

Abstract
AN2728, a novel boron-based compound, inhibits phosphodiesterase-4 and reduces proinflammatory cytokine production possibly associated with atopic dermatitis(AD). This open-label maximal-use study evaluated systemic exposure, PK, and safety of AN2728 Ointment, 2% BID for 28 days in children and adolescents with mild-to-moderate AD(N=34; 3 cohorts based on age and minimum % treatable body surface area [%BSA] affected: 2-5y [≥35%]; 6-11y [≥35%]; 12-17y [≥25%]). Disease severity was measured using Investigator’s Static Global Assessment (ISGA; 0, clear to 4, severe), signs/symptoms score (0, none to 3, severe) and %BSA affected. At day 29, 65% of subjects had ISGA scores of clear or almost clear and 47% had scores of clear or almost clear and a ≥2-grade improvement vs baseline. Marked reductions vs baseline were seen for AD signs and symptoms (pruritus, erythema, lichenification, excoriation, exudation) throughout treatment. Mean pruritus scores improved by ~60% vs baseline as early as treatment day 5. Mean %BSA affected decreased by 78% after 4 weeks of treatment. The most common treatment-related adverse events were application site reactions (n=12) which generally were mild or moderate and resolved spontaneously. One patient withdrew due to application site pain. PK results showed low AN2728 blood levels similar to those previously seen in adults after adjusting for %BSA treated. AN2728 Ointment, 2% may be safe and effective in subjects aged ≥2 years with mild-to-moderate AD.
Adoptive cellular gene therapy for the treatment of experimental autoimmune polychondritis ear disease (THER2P.966)
Authors: Zhou Bin , Liao Yonggan , Guo Yunkai , H Tarner Ingo , Liao Chunfen , Chen Sisi , Habiby Kermany Mohammad , Tu Hanjun , Zhong Sen 
Published: January 2023

Abstract
Clinical therapy of autoimmune diseases used to be limited to non-specific immune-suppressive agents and was, for the most part, based on chance observations. Currently, gene therapy research aims at achieving higher specificity and thus less adverse side effects. This concept comprises the adoptive transfer of autologous T-cells that have been retrovirally transduced ex vivo to express and deliver immune-regulatory gene products to sites of autoimmune inflammation. In the animal model of collagen-induced autoimmune polychondritis ear disease (CIAPED), the adoptive transfer of IL-12p40 expressing collagen type II (CII)-specific CD4+ T-cell hybridomas resulted in a significantly lower disease incidence and severity compared with untreated or vector-only treated animals. In vivo cell detection using bioluminescent labels showed that transferred CII-reactive T-cell hybridomas accumulated in inflamed ear lobes in mice with CIAPED. In vitro analysis demonstrated that IL-12p40-transduced T-cells did not affect the antigen-specific T-cell activation or systemic anti-CII antibody responses. However, IL-12p40-transduced T-cells suppressed IFN-γ and augmented IL-4 production, indicating its potential to act therapeutically by interrupting Th1-mediated inflammatory responses via augmenting Th2 responses. These results indicate that the local delivery of IL-12p40 by T-cells could inhibit CIAPED by suppressing autoimmune responses at the site of inflammation.
Neuroprotective effects of bee venom phospholipase A2 mediated by the suppression of neuroinflammatory responses in the 3xTg AD mouse model of Alzheimer’s disease (THER2P.967)
Authors: Bae Hyunsu , Ye Minsook , Lee Chanju , Chung Hwan-Suck , Shim Insop 
Published: January 2023

Abstract
Alzheimer’s disease (AD) is a severe neuroinflammatory disease. CD4+Foxp3+ regulatory T cells (Tregs) play a pivotal role in maintaining immune tolerance in various inflammatory diseases. In this study, we sought to determine whether bee venom PLA2 promotes cognitive function in and modulates the patho-immunological features of AD in 3xTg-AD mice. PLA2 treatment significantly enhanced the cognitive function of the 3xTg-AD mice and increased glucose metabolism, as assessed with 18F-2 fluoro-2-deoxy-D-glucose ([F-18] FDG) positron emission tomography (PET). The levels of amyloid beta (Aβ) deposits in the hippocampus were dramatically decreased following PLA2 treatment. This neuro-protective effect of PLA2 was associated with microglial deactivation and a reduction in CD4+ T cell infiltration. Interestingly, the neuroprotective effects of PLA2 were abolished in Treg-depleted mice. Therefore, the present studies strongly suggest that the modulation of peripheral immune tolerance by Treg might contribute to the neuroprotective effect of PLA2 in the 3xTg AD mice.