bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of pharmacokinetics and biological activity of two IL-15 heterodimeric forms in mice and macaques (P6356)
Authors: Bergamaschi Cristina , Valentin Antonio , Kulkarni Viraj , Bear Jenifer , Rosati Margherita , Alicea Candido , Sowder Raymond , Chertova Elena , Lifson Jeffrey , Felber Barbara , Pavlakis George 
Published: January 2023

Abstract
IL-15 is a member of the γ-chain family of cytokine important for the proliferation and function of NK and T cells. IL-15 acts on the surface of the cell in complex with IL-15Rα to engage IL-15Rβγ complex in nearby cells. We recently showed that in both murine and human sera IL-15 is in complex with soluble IL-15Rα (sIL-15Rα), suggesting that IL-15/IL-15Rα heterodimer is responsible for IL-15 bioactivity in vivo. We have generated stable cell lines secreting high levels of fully processed human IL-15/sIL-15Rα cytokine. We also prepared an additional form of human glycosylated IL-15 heterodimer in which the C-terminus of sIL-15Rα is fused to the Fc region of human IgG1. The biochemical properties and bioactivity of these IL-15 heterodimers were tested in mice and macaques. IL-15/IL-15RαFc was characterized by an increased bioactivity that reflected its superior plasma half-life in mice, in comparison to IL-15/sIL-15Rα. However, delivery of these two IL-15 heterodimers in macaques failed to reveal any major differences in their pharmacokinetic and pharmacodynamic profile. In macaques, both IL-15 heterodimeric forms resulted in similar levels of plasma IL-15 and induced similar proliferation of NK, γδ and CD8+ T cells. Also, both IL-15 heterodimers were effective in reducing tumor burden in a colon carcinoma mouse model. These results provide important insights for the choice of IL-15 for clinical use, and suggest caution when interpreting data using IL-15/IL-15RαFc in mice.
Finding new receptors for serum amyloid A (P6362)
Authors: He Rong , Omer Linda 
Published: January 2023

Abstract
Serum amyloid A (SAA) is a major acute-phase protein with cytokine/chemokine-like properties. It can be expressed at sites of inflammation and induce the migration of immune cells to the inflammatory sites. SAA plasma concentration can be 1000 times higher in the patients with autoimmune diseases such rheumatoid arthritis, than in the healthy people. However, its precise role in inflammation and infection remains unclear. SAA is known to bind to several receptors such as FPRL1, TLR2, and TLR4, etc. It is possible that SAA also use other chemokine receptors to recruit immune cells during the inflammation. In this study, we used a mathematical approach called Natural Vector Method (NVM) and analyzed the genetic information of all major human chemokines (total 175) and SAA. SAA was found clustered with two chemokines based on both DNA and protein sequences: CXCL9 and CCL23. We hypothesized that SAA may use these chemokines’ receptors, CXCR3 and CCR1. We found that SAA indeed can induce MAP kinase ERK activation in the receptor over-expressed cell line. We will check other receptor-mediated cell functions such as intracellular calcium mobilization, to confirm that SAA can use these two receptors. We hope that our research work not only helps to understand the function of SAA, but also introduces a new way of finding receptors for the endogenous molecules.
KMT1E is a regulator of T cell development (P4542)
Authors: Martin Francis , Nicholson Thomas , Loureiro Joseph , Chen Taiping , Huang Qian 
Published: January 2023

Abstract
The histone methyltransferase KMT1E has a demonstrated role in pluripotency, embryonic stem cell development, and melanoma formation, yet its role in T cell development has not been investigated. As T-cell development involves many stages of lineage commitment, we hypothesized that KMT1E may have a role in regulating these commitment stages. KMT1E is dynamically regulated during the stages of T-cell development, peaking at the DN2 through DN4 stages and dramatically waning as lineage commitment occurs. In order to further query the role of KMT1E in thymocyte development, we created conditional knockout animals in which KMT1E is deleted specifically in the T cell compartment (where the Cre recombinase is driven by the Lck promoter). Deletion of KMT1E caused a profound reduction in the numbers of DN1 (Lin-/CD44+/CD25-) cells in the thymus and single positive CD4 and CD8 cells in the thymus and spleen. In order to elucidate the genetic changes induced by KMT1E that may influence the observed phenotype, we performed microarray experiments on thymocyte precursors from the wild type and conditional knockout animals. Deletion of KMT1E had a modest effect on global gene expression, with only a small subset of the genes being upregulated. Currently we are examining the role of these genes mediating KMT1E’s function in early T cell development.
The key role of Aquaporin 3 and Aquaporin 10 in the pathogenesis of pompholyx (P6372)
Authors: Soler David , Bai Xiaodong , Ortega Lina , Nedorost Susan , Cooper Kevin , McCormick Thomas 
Published: January 2023

Abstract
Pompholyx (a.k.a dyshidrotic eczema) is a skin affliction without a compelling pathophysiological trigger. The disease is characterized by the sudden onset of blisters exclusively in the hands and soles that can expand and fuse, eventually leading to heavily dehydrated skin. Using immunofluorescence we found that the aquaglyceroporins Aquaporin 3 (AQP3) and Aquaporin-10 (AQP10) are aberrantly expressed across the suprabasal keratinocytes in the involved palm lesions of pompholyx patients compared to uninvolved skin and skin from healthy controls. AQP3 and AQP10 function as bi-directional transport channels for water and glycerol, and their activity is inhibited at acidic pH and favored at basic pH. The suprabasal keratinocyte presence of these two aquaglyceroporins may bridge the abundantly hydrated dermis and basal epidermis to the outer environment in pompholyx, creating a dehydrating osmotic gradient imbalance as a result from exposure to exogenous water. Since hands are typically exposed to water numerous times daily, this constant osmotic gradient imbalance may provide a mechanistic explanation for the extreme dehydration observed clinically in pompholyx skin patients, thus irreversibly altering the skin homeostasis and contributing to the chronic cutaneous inflammation of this disease.
Cutaneous immuno-surveillance and regulation of inflammation by group 2 innate lymphoid cells (P6374)
Authors: Roediger Ben , Kyle Ryan , Yip Kwok , Sumaria Nital , Guy Thomas , Mitchell Andrew , Tay Szun , Jain Rohit , Forbes-Blom Elizabeth , Chen Xi , Tong Philip , Bolton Holly , Paul William , Fazekas de St. Groth Barbara , Grimbaldeston Michele , Le Gros Graham , Weninger Wolfgang 
Published: January 2023

Abstract
Type 2 immunity is critical for defense against cutaneous infections, but also underlies the development of allergic skin diseases. We report the identification in normal murine dermis of an abundant, phenotypically unique group 2 innate lymphoid cell (ILC2) subset that depends on IL-7 and constitutively produces IL-13. Intravital multiphoton microscopy revealed that dermal ILC2 specifically interact with mast cells, whose function is suppressed by IL-13. Treatment of Rag1−/− mice with IL-2 led to a marked expansion of activated, IL-5-producing dermal ILC2, resulting in the development of spontaneous dermatitis characterized by eosinophil infiltrate and activated mast cells. Our data uncover a novel interactive pathway between two innate immune cell populations implicated in type 2 immunity, and demonstrate that ILC2 exhibit both pro- and anti-inflammatory properties.
Development and evaluation of an in vitro skin sensitization assay based on primary monocyte-derived dendritic cells (P6376)
Authors: Kuehnl Jochen , Gerlach Silke , Reuter Hendrik , Onken Stefan , Wenck Horst , Schepky Andreas 
Published: January 2023

Abstract
Allergic contact dermatitis is a delayed T-cell mediated allergic response associated with relevant social and economic impacts. Until now, animal experiments (e.g. the local lymph node assay) are supplying most of the data used to assess the sensitization potential of new chemicals. However, becoming effective in March 2013, the 7th amendment to the EU Cosmetic Directive introduced an animal testing ban for the endpoint skin sensitisation for cosmetic ingredients. In vitro alternative methods are thus being actively developed. Although promising results have been obtained with cell lines, their reduced functionality and inherent genomic instability led us to reinvestigate the use of peripheral blood monocyte-derived dendritic cells (PBMDCs) for the establishment of a reliable in vitro sensitization test. We successfully solved the issues associated with the use of primary cells (optimized cytokine concentrations, incubation time, readout, pooled vs. single donors and cytoxicity) resulting in a stable and reproducible protocol. Here, we report on the adaption of the protocol to the 96-well format, allowing for a higher and cost-effective throughput of test substances. Comparative analyses of the effect of several skin sensitizers on CD86 expression display similar results for 24- and 96-well format. Upscaling of the PBMDCs advances its applicability for the reliable detection of human skin sensitizers.
Asian sand dust induces autophagic markers and activates NF-κB in immune cells (P6377)
Authors: Song Yuan , Ichinose Taksmichi , Yoshida Yasuhiro 
Published: January 2023

Abstract
It is well going to know that several particles modulate immune responses and phagocytosis may induce activation in antigen-presenting cells. Asian sand dust (ASD), which is derived from air pollutants in East China that migrate to Japan and ASD is concerned about influence for health. Our group has reported that ASD induced inflammatory responses in lung tissue and causes respiratory diseases in mice. In the last meeting, we reported that the effect of ASD on the immune system in vivo. In this study, we examined the effect of ASD in vitro. Cell lysates were prepared from freshly isolated splenocytes of ICR mice and resolved by western blotting. Immunoblotting demonstrated that ASD induced autophagic-marker LC3-II expression and decreased the level of p62 especially in CD11b+ cells. Cell activation of splenocytes was evaluated by a cell viability assay. The cell viability assay showed mitogen-induced proliferation of splenocytes is inhibited by ASD treatment. In addition, an electrophoretic mobility shift assay demonstrated increased activated-NF-κB in bone marrow derived macrophage after ASD treatment. Taken together, these results suggest that ASD activates immune cells, and may modulate cell survival or activity.
Immune cell profiles in response to silver nanoparticles associated with medical devices (P3357)
Authors: Zelikoff Judith , Willis Daniel , Degheidy Heba , Zhang Qin , Umbreit Thomas , Goering Peter 
Published: January 2023

Abstract
Silver nanomaterials are increasingly being used as antimicrobial agents in medical devices, yet their effects on immunocompetence are unclear. This study investigated modulation of immune cell profiles and cell activation by exposure to silver nanoparticles (AgNP). Mice were injected iv (each day for 2 d) with 66 or 300 µg of either 20 or 110 nm AgNP (or sodium citrate) and sacrificed 1 d later. Flow cytometric analysis revealed that injection of 66 µg of 20 nm AgNP increased Th2 cells and decreased effector memory cells, while exposure to the same dose of larger-sized AgNP had no effect on numbers of CD3+,CD4+, Th1, Th2, Th17 cells, CD4/CD8 ratio, or total memory/naïve/central memory/effector memory cells compared to controls. At 300 µg, 20 nm AgNP significantly decreased the number of naïve CD4+ cells and CD3+CD4- cells (i.e., cytotoxic T cells), while increasing central memory cells, activated central memory cells, effector memory cells, activated effector memory cells, total memory cells, and natural killer cells. A somewhat different cell profile was observed following exposure to the same dose of 110 nm AgNP including an increase in activated CD11c+ cells (macrophages). Taken together, these data indicate that systemic AgNP exposure can modulate the immune system in a dose-dependent manner, with smaller size particles leading to more drastic effects. Overall, these studies have policy implications and demonstrate the need for protecting already vulnerable individuals.
Longitudinal tracking of immune cell subsets and phenotypes in cynomolgus monkeys following immunization with two model antigens (P3369)
Authors: Casey Kerry , Wang Shu , Gallagher Sandra , Stern Jessica , Xiong Ximing , Manetz Scott , Grant Ethan , Herbst Ronald , Carter Laura L. , Ettinger Rachel 
Published: January 2023

Abstract
Antigen immunization studies in cynomolgus monkeys (cyno) provide an opportunity to study in vivo immune responses in a higher order species. Such models can also be useful for testing candidate immunomodulatory drugs which lack rodent cross-reactivity. Here, we have optimized and validated eight, 6-7 color panels of cyno-human cross-reactive antibodies allowing extensive flow cytomtric phenotyping of immune cell populations under steady state, Tetatanus Toxoid (TT), or Keyhole limpet hemocyanin (KLH) primed conditions. Comparisons were made between fresh & overnight cells in Na/Hep tubes to cells phenotypically stabilized in Cytochex tubes. We followed 17 distinct lymphocyte subsets including T, B & NK cells and tracked their activation status over 85 days following primary or secondary immunization. Similar to humans, cyno B & T cell compartments demonstrated a history of prior stimulation evidenced by elevated memory:naive cell ratios and significant baseline expression of CD95, GrB, Ki-67, PD-1, CXCR3, CCR6 and CD11c. In response to immunization, frequencies of circulating Ki67+ B & T cells increased, followed by an elevation of T dependent Ab titers. Changes in Th1 and Th17 subset frequencies as well as CD25 and CD69 expression following immunization were also observed. Direct application of these Ab panels to leukocytes from Rheumatoid Arthritis patients has recapitulated published observations supporting the utility of modeling immune responses in cyno.
IgG 4-RSD involving the pleura (P3373)
Authors: Kohli Ritesh , Chowdhary Harjinder 
Published: January 2023

Abstract
IgG4-RSD is a novel clinical entity that shows IgG4 producing plasma cells in affected organs with fibrotic and sclerotic changes, and elevated serum IgG4 levels. IHerein, we report one case of IgG4-RLD, presenting with pleural effusion, with lab values showing high IgG4 levels and pleural biopsy showing infiltrated plasma cells with strong immunoreactivity for IgG4. A 55year old Caucasian female, nonsmoker with no significant past medical history presented to the clinic for b/l hand swelling and occasional dyspnea. Physical examination was unremarkable except for decreased breath sounds left lung, and b/l hand swelling.There was no evidence of synovitis involving hands or any other joints. Range of motion was normal. The routine blood tests Immunological markers were normal except high IgG-4levels Pleural fluid aspiration was suggestive of exudative effusion. Pleural biopsy was performed that was suggestive of massive lymphoplasma cell infiltration in the pleura, with immunostaining revealing predominant IgG4 positive plasma cells greater than 30hpf.He was started on steroid therapy with clinical significant improvement in few weeks. IgG4RSD is an unrecognized condition about which knowledge is now growing rapidly., Acknowledging that IgG4RSD may present as pleural effusion is essential for early management and preventing complications
Phospholipase D1 regulates the extent of TCR-induced lytic granule release by CD8+ CTL (P1390)
Authors: Radoja Sasa , Ma Jennifer 
Published: January 2023

Abstract
Regulation of lytic activity in CD8+ CTL remains incompletely understood despite the importance of this effector T cell function in immune response to intracellular pathogens and tumors. One important aspect involving the regulation of T cell effector function is the spatio-temporal regulation of DAG metabolism in T cells. Based on the involvement of phospholipase D (PLD) isoforms in DAG metabolism-related regulation of vesicular trafficking in other cells types, we reasoned that these enzymes might regulate lytic function in CD8+ T cells. By combining the use of pharmacological inhibitors and siRNA-mediated knockdown, we showed that PLD1 isoform modulates lytic function in primary mouse CD8+ CTL. Surprisingly, PLD1 knockdown in CTL lead to the enhancement of lytic activity despite its inhibitory effect on conjugate formation. The observed phenotype was not due to increased levels of expression of lytic molecules but was due to an increased release of lytic granule contents in response to TCR engagement. At the same time, overexpression of PLD1 in CTL resulted in the inhibition of lytic activity that coincided with an accumulation at the immunological synapse of both phosphatidic acid (PA), a byproduct of PLD1, and actin. Thus, PLD1 regulates the degree of lytic response in CD8+ CTL, potentially via PA-mediated induction of actin polymerization at the synapse, which could serve as a molecular gate that controls the extent of lytic granule release toward target cells.
Vitamin D3 is necessary for human dendritic cells to respond to bacterial products (P1372)
Authors: Brosbol-Ravnborg Anne , Bundgaard Bettina , Höllsberg Per 
Published: January 2023

Abstract
Background: Differentiated DCs are matured in the presence of lipopolysaccharide, a product of gram-negative bacteria. We hypothesized that additional bacterial products are able to cause DC maturation and that 1,25-dihydroxyvitamin D3 is capable of regulating this process by controlling cytokine secretion. Methods: DCs were differentiated and matured from human monocytes in the presence or absence of vitD3. DC maturation was induced by lipopolysaccharide and peptidoglycan. DC differentiation and maturation were monitored by morphology change and expression of surface molecules. Cytokine secretion of IL-6, IL-8, IL-10, and IL-12p70 was measured by ELISA. Expression of vitD3 receptor in DCs was determined by Western blotting. Results: The presence of vitD3 inhibited LPS-induced DC maturation, including formation of dendrites on DCs consistent with the phenotype of immature DCs. VitD3 was necessary for LPS- and PGN-induced secretion of IL-6, IL-8 and IL-10, whereas vitD3 inhibited LPS-induced secretion of IL-12. Furthermore, both LPS and PGN could act in synergy with vitD3 to increase the expression of the vitD3 receptor in DC. Conclusions: The presence of vitD3 was necessary for LPS- and PGN-induced secretion of IL-6, IL-8 and IL-10 in DCs. The expression of vitD3 receptor in LPS- or PGN-matured DC was enhanced in a synergy with vitD3. Elucidating the mechanisms behind this may be of importance for understanding the role of vitD3 during induction of peripheral tolerance.
Retinoic acid-rich microenvironment provides clonal survival cues for tumor and bacteria-specific CD8+ T cells (P1376)
Authors: Guo Yanxia , Pino-Lagos Karina , Noelle Randolph 
Published: January 2023

Abstract
While studies have implicated a role of vitamin A (VA) in host resistance to infectious disease, little is known as to the role of VA and its active metabolite, retinoic acid (RA) in host defense against cancer. Herein, it is shown for the first time that local RA production within the tumor microenvironment (TME) is increased up to 5-fold compared to naïve surrounding tissue, with a commensurate increase in RA signaling to regionally infiltrating tumor-reactive T cells. Conditional disruption of RA signaling in CD8+ T cells using a dominant negative Retinoic Acid Receptor α (dnRARα) illustrated that RA signaling is required for tumor-specific CD8+ T cell expansion/accumulation and protective anti-tumor immunity. Specific deletion of RARα, RARβ and RARγ in CD8+ T cells further demonstrated that RARα is required for CD8+ T cell survival, whereas RARβ is indispensable for bacteria-specific CD8+ T cell expansion in response to bacterial infection. These studies established a novel function of RA essential for both anti-tumor and infection CD8+ T cell immunity.
Inhibition of acetylcholinesterase regulates the anti-microbial immune response (P1378)
Authors: Fernandez-Cabezudo Maria , Al-Barazie Ray , al-Ramadi Basel 
Published: January 2023

Abstract
We have previously demonstrated that inhibition of the enzyme acetylcholinesterase, leads to an enhancement of animal survival following an oral infection with a lethal strain of S. typhimurium, a Gram-negative, facultative, intracellular pathogen. We hypothesized that the resultant increase in acetylcholine levels modulates the macrophage inflammatory response to infection. In this study, we assessed the potential of modulating the host’s immune response following a lethal bacterial infection. BALB/c mice were orally infected with a virulent strain of S. typhimurium, following which they were injected i.p. with the acetylcholinesterase inhibitor paraxon. The start of paraoxon injection varied from 30 minutes to 24 hrs post bacterial infection and repeated daily for 7 consecutive days. In contrast to control group which exhibited 10% survival, animals treated with paraoxon up to 6 hrs post infection showed 50% overall survival. Enhanced survival observed in this group correlated with a more robust inhibition of bacterial proliferation in systemic target organs. Furthermore, preliminary evidence from flowcytometric analysis of mesenteric lymph nodes and spleen cell populations revealed an increase in T lymphocyte ratios as well as upregulation of IFN gamma-regulated activation markers on B and T lymphocytes in the paraoxon-treated group. These findings underscore the importance of the neural-immune axis in regulating immunity to bacterial infection.
Expression of interferon-inducible genes is influenced by sex hormones and gender in SLE (P1380)
Authors: Hossain Awlad , Hahn Bevra , Singh Ram 
Published: January 2023

Abstract
Women may be more susceptible than men to SLE and other autoimmune diseases in part because many healthy women have higher interferon regulated genes and fewer regulatory T cells. Similarly, female BWF1 lupus mice have increased expression of interferon genes compared to age and sex- matched males. Estradiol regulates interferon-inducible genes differentially in healthy controls and in SLE, with higher induction of IFN-inducible genes in the SLE population. Plasma 17b-estradiol levels are significantly increased in female SLE patients compared to healthy females (p&lt;0.01). Testosterone (100 pg/ml) significantly increased FoxP3 expression in CD4+CD25+hi cells from women with SLE (p&lt; 0.03). Estradiol increases proinflammatory cytokines and positively correlated with plasma levels of IL-6/ IL-21 and miR21, miR25 and miR186.