bluuebunny/crossref_metadata_2025_split huggingface dataset:
Eosinophil accumulation in postnatal lung is specific to the primary septation phase of development
Authors: Coden Mackenzie , Loffredo Lucas F , Jeong Brian M , Walker Matthew , Anekalla Kishore Reddy , Doan Ton , Rodriguez Raul , Browning Mandy , Nam Kiwon , Lee James , Abdala-Valencia Hiam , Berdnikovs Sergejs 
Published: January 2023

Abstract
Type 2 immune cells and eosinophils are transiently present in lung tissue not only in pathology but also during normal postnatal development. However, the lung developmental processes underlying postnatal airway recruitment of eosinophils after birth remain unexplored. We determined that in mice, mature eosinophils are recruited to the lung during P3–14, which corresponds to the primary septation/alveolarization phase of lung development. Developmental eosinophils peaked during P10–14 and exhibited Siglec-Fmed/highCD11c−/low phenotypes, similar to allergic asthma models. By interrogating the lung transcriptome and proteome during peak eosinophil recruitment in postnatal development, we identified markers that functionally capture mesenchymal-epithelial interface establishment (Nes, Smo, Wnt5a, Nog) and provisional extracellular matrix (ECM) deposition (Tnc, Postn, Spon2, Thbs2) as key lung morphogenetic events associating with eosinophils. We identifiedTenascin-C (TNC) as one of the key ECM markers in the lung epithelial-mesenchymal interface at the RNA and protein levels, consistently associating with eosinophils in development and disease. By RNA-seq analysis, naïve murine eosinophils cultured with TNC-enriched ECM significantly induced expression of Siglec-F, CD11c, eosinophil peroxidase, and other markers typical for activated eosinophils in development and allergic inflammatory responses. TNC knockout mice had an altered eosinophil recruitment profile in development. Collectively, our results indicate that lung morphogenetic processes associated with heightened Type 2 immunity are not merely tissue “background” but specifically guide immune cells both in development and pathology.
Human Chorionic Gonadotropin acts as a central regulator of adaptive immune responses during early pregnancy safeguarding fetal survival
Authors: Schumacher Anne , Zenclussen Ana 
Published: January 2023

Abstract
A perfect interplay between the endocrine system and the maternal immune system is pivotal for early fetal tolerance induction. Particularly, the placenta-derived hormone human chorionic gonadotropin (hCG) that is secreted during early pregnancy stages and is suggested to regulate pro- and anti-inflammatory maternal immune responses. However, the precise mechanisms underlying hCG-driven immunoregulation are far from being understood. Thus, we performed several studies to illuminate the participation of hCG in immunomodulation with a specific focus on T and B cell responses.
We included human and mouse material in our studies to analyze the influence of hCG on the generation, plasticity and functionality of regulatory T (Treg) cells, Th17 cells and B cells using different in vitro assays. In vivo, we applied hCG during the peri-implantation period into abortion-prone mice and analyzed Treg proportions and activity.
Our in vitro results revealed that hCG attracts human Treg, promotes formation of human and mouse Treg and increases T cell suppressive activity in both species. Moreover, hCG inhibits mouse Th17 differentiation and induces Th17 cells with anti-inflammatory phenotypes in the mouse system. Human B cells adopt a regulatory phenotype and start to secrete fetal-protective asymmetric antibodies upon hCG stimulation in vitro. In vivo, hCG application into abortion-prone mice restored Treg levels, augmented Treg suppressive activity and rescued fetuses from rejection.
In summary, our findings suggest that hCG contributes to early fetal tolerance induction by shifting maternal adaptive immune responses towards an anti-inflammatory profile.
Lymphocytes in autoimmune-resistant mice may protect the islets through IL-10 production
Authors: Whitesell Jennifer C , Lindsay Robin S , Yannacone Seth , Olivas-Corral Jessica , Lucas Erin , Friedman Rachel S. 
Published: January 2023

Abstract
We have identified T cells and B cells in the islets of autoimmune resistant mice, yet the role of these lymphocytes is unknown. In the islets of autoimmune resistant C57BL/6 mice, local antigen receptor signaling was assessed using Nur77-GFP mice. Nur77-GFP expression was increased in islet CD8+ T cells and B cells suggesting that these lymphocyte subsets receive local antigenic stimulus. Islet T cell and B cell populations expressed the regulatory cytokine IL-10, assessed using the B6.TIGER reporter mouse. T cell populations lacked expression of the pro-inflammatory cytokine IFN-γ. These findings indicate that islet T cell populations are likely playing a regulatory role. In addition, cultured whole islets produced IL-10 protein, but not IFN-γ protein. To test the stability of the islet lymphocyte populations under inflammatory conditions, mice were exposed to metabolic stress through a diet-induced obesity (DIO) model. Obesity and type 2 diabetes (T2D) are associated with circulating inflammatory cytokines. In T2D patients, islet lymphocytes have been identified, though the function of these populations is largely unknown. C57BL/6 mice were fed a high fat diet (DIO) or a matched control diet (Control) starting at 5 weeks of age, and then analyzed at 16–25 weeks of age. The number and phenotype of lymphocytes in the islets were similar in DIO and control mice. Notably, under the conditions of obesity-associated systemic inflammation, islet lymphocytes in the DIO mice maintained IL-10 production. From these data, we propose that islet lymphocytes play a regulatory role to protect the islets from systemic inflammation through IL-10 production.
Age-related changes in the immune phenotype of human memory CD4 T cells differ between colon and peripheral blood
Authors: Wilson Cara C , Dillon Stephanie 
Published: January 2023

Abstract
Gut lamina propria (LP) CD4 T cells are primarily tissue resident memory cells that are critical in maintaining gut homeostasis and responding to enteric pathogens. We established that aging altered the phenotypic and functional profiles of human small intestinal CD4 T cells. However, given site-specific differences in immune cell composition in the gut, it is difficult to extrapolate these findings to other locations. To probe the effect of aging on large intestine CD4 T cells, we used flow cytometry to analyze immune phenotypes of colon LP CD4 T cells from younger (34±2yrs mean±SEM; N=6) and older (80±2yrs, N=6) adults. Tissue-specificity of these profiles was determined by comparing to memory (CD45RA−) peripheral blood (mPB) CD4 T cells in a separate cohort of similarly aged persons (N=6/age group). Among younger samples, LP CD4 T cells expressed higher levels of co-inhibitory molecules CTLA4 and PD1, but had lower turnover (Ki67+) and IL2 receptor (CD25) expression relative to mPB CD4 T cells. Expression of activation (CD38, HLA-DR), senescence (CD57) and survival (Bcl2) markers were similar. Regarding age effects, frequencies of LP CD4 T cells (% of CD3 T cells) were similar between older and younger samples; mPB CD4 T cell frequencies were higher in older vs younger samples. Older LP CD4 T cells had lower CTLA4, PD1, CD38, CD25 and Ki67 and higher Bcl2 expression than younger LP CD4 T cells. Among mPB CD4 T cells, greater age was only associated with a higher CD57+ fraction. Thus, age effects differed between colon LP and mPB CD4 memory T cells. Loss of co-inhibitory markers, decreased turnover and increased survival of colon LP CD4 T cells may contribute to altered homeostasis, loss of protective immunity, and chronic inflammation in older people.
The role of old age on Mycobacterium bovis BCG vaccine-induced tissue immunity
Authors: Scordo Julia M , Piergallini Tucker J , Headley Colwyn A , Hodara Vida , Reuter Nicole , Papin James F , Turner Joanne 
Published: January 2023

Abstract
Infections account for one-third of deaths in elderly individuals. Vaccines are a primary tool to combat infection, yet they are less effective in the elderly population. While many groups have aimed to address this problem by studying vaccine-induced peripheral blood responses in the elderly, work from our lab demonstrates that immune responses to vaccination and infectious challenge differ between tissue sites and the periphery. To improve health outcomes in our aged population, we must study vaccine-responses in both the periphery and the local infection site (the tissue). We study this through a delayed-type hypersensitivity model of Mycobacterium bovis BCG vaccination and subsequent tuberculin skin test (TST) eight weeks after vaccination in adult and elderly baboons. Vaccination generates BCG-specific immune cells that are recruited to the skin upon TST challenge which we can study in skin biopsies reflecting tissue specific responses. Three days or one week after TST we examine BCG-specific memory responses in the skin biopsies. We also determine BCG-induced responses in the blood to compare tissue and systemic responses. We find increased oxidation and decreased production of cytokines, chemokines and growth factors in aged baboon skin at the site of TST challenge, despite no alteration in vaccine-induced peripheral blood responses between age groups. Based on these findings, we anticipate that alterations in the skin of aged BCG-vaccinated baboons will hinder T cell migration to and function in the tissue, thus decreasing vaccine-induced tissue immunity.
Human gingiva-derived mesenchymal stem cells are therapeutic in lupus nephritis through targeting of CD39-CD73 signaling pathway
Authors: Wang Julie , Dang Junlong , Zheng Song Guo 
Published: January 2023

Abstract
Cell specific and cytokine targeted therapeutics have underperformed in systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs) have emerged as a novel therapy to address the dysregulation in autoimmune diseases but also have limitations. Human gingiva derived MSCs (GMSCs) are superior in regulating immune responses. Here, we demonstrate that the adoptively transferred GMSC home to and maintain in the kidney and have a robust therapeutic effect in a spontaneous lupus nephritis model. Specifically, GMSCs limits the development of autoantibodies as well as proteinuria, decreases the frequency of plasma cells and lupus nephritis histopathological scores by directly suppressing B cells activation, proliferation and differentiation. The blockage of CD39-CD73 pathway dramatically abrogated the suppressive capacities of GMSCs in vitro and in vivo and highlights the significance of this signaling pathway in SLE. Collectively, manipulation of GMSCs provides a promising strategy for the treatment of patients with SLE and other autoimmune diseases.
PT101: A Treg selective agonist IL-2 mutein therapy for autoimmunity
Authors: Higginson-Scott Nathan , Otipoby Kevin L. , Viney Jo 
Published: January 2023

Abstract
Regulatory T cells (Treg) play a critical role in immune homeostasis and are dysfunctional in many autoimmune diseases. Interleukin 2 (IL-2), via the heterotrimeric IL-2 receptor (CD25/CD122/CD132), drives the proliferation and function of Treg. CD25 loss-of-function in mice is associated with Treg deficiency and widespread autoimmunity. Low dose IL-2 expands Tregs and is being evaluated therapeutically, however it has a narrow selectivity window over conventional T cells and Natural Killer cells which is dose limiting. To enhance IL-2 selectivity for activating and expanding Treg, mutations can be introduced that create a dependency on CD25 binding for signaling through CD122/CD132 upon IL-2 facilitated CD25/CD122/CD132 trimer formation. We created PT101, a mutant IL-2 Fc fusion, containing a N88D mutation that significantly decreases CD122 binding affinity in addition to other mutations that increase CD25 binding affinity and introduce improved molecular stability and drug-like properties. We found that PT101 selectively induces STAT5 phosphorylation in human and cynomolgus monkey Tregs in vitro. In humanized NOD-scid IL-2Rg-null (NSG) mice and cynomolgus monkeys, single or multiple dose administration of PT101 dose-dependently and selectively expands Treg without significant effects on other immune cell types, and without eliciting proinflammatory cytokine production. A 1-month toxicity study in cynomolgus monkeys indicated that PT101 was safe and well-tolerated at 300× the minimum efficacious dose whilst maintaining its Treg selectivity. PT101 is being evaluated in a randomized, placebo-controlled, double-blind, single ascending dose-escalation trial in healthy volunteers.
High-content screening assay for compounds that enhance or inhibit leukocyte superoxide production to identify drugs for treating immune-mediated diseases
Authors: Wu Szu-Yu Szu , Shieh Chi-Chang K 
Published: January 2023

Abstract
Reactive oxygen species (ROS) are produced by cells to play important roles in the effector and regulatory functions of immune cells. Our previous studies revealed that ROS act as negative regulators in IL-1β-mediated inflammation. Enhanced severity of inflammation in immune-mediated arthritis was noted when leukocyte NADPH oxidase (NOX2), which mediates the production of ROS, was defective. We hence hypothesized that drugs that modulate the leukocyte ROS production may regulate the pathogenicity of immune-mediated arthritis. Here, we devised a high-content image assay using the dye H2DCF-DA for identifying LOPAC 1280 library compounds that may facilitate or suppress superoxide production in differentiated HL-60 (dHL-60) cells. ROS levels were measured after the cells were treated with phorbol 12-myristate 13-acetate (PMA) or menadione which may induce ROS production from NOX2 or mitochondria. From a screening of 640 compounds in a 3-point interpolate titration in cell-based imaging analysis, we identified 74 drugs that may enhance the ROS production and 72 compounds that may inhibit ROS production by PMA-stimulated-dHL-60 cells. The drugs that we identified included the agonist/antagonist of neurotransmitters and their receptors, ion channel blockers, serotonin antagonists, cell stress modulators and cell cycle inhibitors. To further clarified our hypothesis, we treated NOX2-deficient mice with menadione, which tended to increase the oxidant stress in the joint tissue. The severity of the immune-mediated arthritic joint was significantly suppressed after the treatment. This novel screening method hence may be used to identify potential drugs for treating redox-related inflammatory diseases.
Angiotensin-Converting Enzyme Inhibitor (ACEI) suppresses the expression of the MHC molecules in mucosal cells of the small intestine leading to the delayed onset of autoimmune type 1 diabetes mellitus in NOD mice
Authors: Hattori Masakazu , Ueda Aiko 
Published: January 2023

Abstract
Angiotensin-converting enzyme (ACE) exists in the kidney, lung and small intestine of the NOD mouse (autoimmune type 1 diabetes animal model). ACE changes Angiotensin I to Angiotensin II. ACE exists in the small intestinal epithelial cells and villi, and digests the protein antigen molecules in the small intestine. ACE plays an important role in the antigen presenting process in the mucosal immune system of the duodenum and jejunum. To examine the role of ACE in the development of type 1 diabetes of the NOD mouse, ACE-Inhibitors (ACEI): captopril (CA) or enalapril maleate (EM) was dissolved in a drinking water at the concentration of 12.5mg/ml and given daily to 28-day-old NOD females and males ad libitum (89 females and 70 males in CA, 72 and 52 in EM, 120 and 87 in water control group, respectively). The animals were screened for the development of diabetes twice a week for 7 months and subjected to the Life Table analysis. The incidence of diabetes in our NOD/Kmc colony is 83% in females and 40% in males at 210 days of age.
The EM-treated NOD mice showed a significant delay of the onset of diabetes at 120 days of age in comparison with the controls (25% vs. 45% in females, p=0.002; 0% vs. 8% in males, p=0.037). The CA treatment was ineffective to delay the onset of diabetes. The histopathological examination of the pancreata showed that the EM-treated females had more islets without lymphocytic infiltration than the CA-treated or the water-control females.
The mRNA expression of MHC K and A genes was suppressed in the duodenum and jejunum of the NOD mice by EM- or CA-water for 14 days. Flow cytometric analysis showed suppression of the MHC K and I-A expression in the pancreatic lymphocytes of the EM- and CA-treated mice in comparison with the control mice.
Defining the role for the gut microbiome in the clinical efficacy of sulfasalazine therapy for IBD associated spondyloarthritis
Authors: Lima Svetlana Ferreira , Longman Randy , Rupert Amanda , Viladomiu Monica , Marderstein Andrew , Putzel Gregory , Funez-dePagnier Gabriela , Woo Viola , Metz Maeva L , Scherl Ellen J , Chou Lance 
Published: January 2023

Abstract
Spondyloarthritis (SpA) is the most common extra-intestinal manifestation of inflammatory bowel disease (IBD). Sulfasalazine (SAS) is one of the earliest medications used in IBD and its efficacy in spondyloarthritis is thought to depend on its antibacterial properties. Therefore, our study aims to diagnostically evaluate the role for the fecal microbiome in clinical response to SAS and identify microbial and immunologic therapeutic targets associated with clinical response.
We have longitudinally followed IBD-SpA patients subjected to SAS therapy. Clinical data, including validated IBD and joint disease activity scores, and fecal samples from 19 patients were collected at baseline and at week 2 and 12 after SAS initiation. Metagenomic sequencing was used to define the effect of SAS on the IBD-SpA fecal microbiome and to evaluate its relationship with joint symptoms improvement. Gnotobiotic mouse models were used to test the sufficiency of the SAS effect observed in patients.
Fecal microbiome of SAS-responders was distinct from that of non-responders and 6 pre-treatment microbial markers (including Faecalibacterium prausnitzii) predicted SAS-response (AUC: 0.9). SPF mice and germ-free mice colonized with patient microbiota revealed that SAS selectively reduced mucosal-associated bacteria. Gnotobiotic mouse models revealed a critical role for A. muciniphila in modulating mucosal inflammation.
Our study reveals the ability of SAS to selectively target mucosal-associated bacteria and modulate the inflammatory impact of IBD-SpA associated pathobionts. This study highlights the potential use of microbial-based diagnostic tools to improve drug efficacy and therapeutic strategies for IBD-SpA.
Macrophage migration inhibitory factor-2 of Wuchereria bancrofti suppressed the DSS-induced colitis in a mouse model by promoting alternative activation of peritoneal macrophages and increasing the number of Treg cells in the colon
Authors: Chauhan Nikhil , Khatri Vishal , Prasanna Kumar S B , Malendez Valeria , Kalyanasundaram Ramaswamy 
Published: January 2023

Abstract
In this study, we cloned the homologue of macrophage migration inhibitory factor (MIF) secreted by the human filarial parasite Wuchereria bancrofti (rWbaMIF-2) and evaluated its potential in ameliorating inflammation in a dextran sulfate sodium salt (DSS)-induced colitis model. DSS administration resulted in substantial loss of body weight along with bloody diarrhea, severe inflammation in the colon and reduced length of the colon in just under 7 days. Treatment with rWbaMIF-2 reversed the clinical symptoms in DSS administered mice, characterized by no blood in the stools, minimal inflammation on the colon wall and the mice maintained normal colon length. rWbaMIF-2 treatment downregulated TNF-α, IL-6, IFN-γ, IL-1β, IL-17A, and NOS2 genes in the colon tissue and upregulated the percentage of IL-10 producing Treg and B1 cells in the colon and peritoneal cavity. Thus, one of the mechanisms by which rWbaMIF-2 induce its anti-inflammatory effect appeared to be by promoting the infiltration of IL-10 producing Treg cells into the colon. Further analysis showed alternative activation of F4/80+ large peritoneal macrophages (LPMs) with increased expression of arginase (p≤0.05) and reduced expression of iNOS, MPO activity, TNF-α, IL-6 and TLR4 in LPMs following rWbaMIF-2 treatment. Thus, for the first time, we demonstrate here that rWbaMIF-2 treatment can activate LMP macrophages alternatively and promote infiltration of Treg cells into the colon to suppress inflammation in a colitis model. These studies also demonstrate the potential of developing rWbaMIF-2 as a small molecule therapeutic agent for colitis and other inflammatory conditions. Studies funded by NIH RO1 AI116441.
Metabolite changes and anti-inflammatory effects of Astragalus membranaceus Radix by fermentation with Aspergilus strains
Authors: Lee Sung Hyen , Park Shin-Young , Lee Da-Bin , Lee Eun-Jung , Song Bit-Na , Park Bo-Ram , Choi Ji-Ho , Lee Eun-Byeol 
Published: January 2023

Abstract
Astragalus membranaceus (AM) is an edible medicinal resource in Korea, which has been traditionally used for cardioprotective, anti-inflammatory and longevity effects. This study was conducted to investigate metabolic changes and anti-inflammatory effects of AM by fermentation.
AM was fermented with three microorganisms of Aspergilus strains isolated from Nuruk at 30□ for 6 days (FAM). The metabolites changes in pre and post fermentation of AM were analyzed by LC-MS. The pro-inflammatory factors such as tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and nitric oxide (NO) were measured in lipopolysaccharide (LPS)-induced RAW 264.7 cell line.
As a result, the 28 identified metabolites in AM between pre and post fermentation process were detected in this study. The data revealed that the levels of sucrose and astraglaloside IV and calycosin decreased throughout the process while LPC and huangqiyenin B levels increased as expected and were the highest among the metabolites after the fermentation. The FAM reduced IL-1β, IL-6, TNF-α and NO production without cytotoxicity. The results suggest that the fermentation process with Aspergilus strains can increase the functional metabolites and control the inflammatory factors in FAM. We expect the biotransformation technique of flavonoids in Astragalus membranaceus Radix may be used in the field of a healthy food industry.
Anti-CD19 CAR-T cell therapy for Systemic Lupus Erythematosus in a mouse disease model
Authors: Jin Xuexiao , Lu Linrong 
Published: January 2023

Abstract
Dysregulated B cell activation plays pivotal roles in systemic lupus erythematosus (SLE), which makes B-cell-depletion a potential strategy for SLE treatment. The clinical success of anti-CD19 chimeric antigen receptor (CAR) T cells in treating B-cell malignancies has attracted the attention of researchers. In this study, we aimed to investigate the feasibility of applying anti-CD19 CAR-T cell therapy into SLE treatment in a mouse disease model. We have constructed murine anti-CD19 CARs with either CD28 or 4-1BB as the intracellular costimulatory motif and evaluated the therapeutic functions of corresponding CAR-T cells by infusing them into MRL-lpr mice. We found that adoptive transfer of anti-CD19 CAR-T cells was able to achieve sustained B-cell-depletion in MRL-lpr mice. More importantly, transferring syngeneic anti-CD19 CAR-T cells can not only prevent disease pathogenesis before the onset of disease symptoms but also have substantial therapeutic benefits in disease treatment at a later stage after disease progression. Comparing to CAR-T cells with CD28 as a costimulatory motif, CAR-T cells with 4-1BB costimulatory motif work better for mouse SLE treatment. In summary, our study claimed that anti-CD19 CAR-T cell therapy worked effectively in treating murine SLE, indicating its potential in treating human patients in clinic.