bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic ethanol consumption increases susceptibility to influenza A virus infections via alteration of memory CD8 T cell responses
Authors: Zacharias Zeb Ralph , Legge Kevin L 
Published: February 2023

Abstract
Alcoholism is estimated to contribute to approximately 95,000 deaths within the United States per year making it the third leading preventable cause of death. These alcohol-related deaths are due, in part, to the increased risk of severe disease that human alcoholics have during bacterial and viral infections. Our laboratory has previously shown using a mouse model of chronic ethanol consumption that increased disease severity during a primary influenza A virus (IAV) infection is due to deficits in the developing IAV-specific CD8 T cell response. However, unlike mice, human alcoholics have likely been exposed to IAV prior to the onset of alcohol consumption. Therefore, we determined the effects of chronic alcohol consumption on pre-existing IAV immunity. Our results show that mice with established immunity to IAV that then chronically consumed alcohol (IAV-immune➞EtOH) exhibited increased morbidity and mortality to secondary heterologous IAV challenge compared to IAV-immune mice that then consumed water (IAV-immune➞H2O). IAV-immune➞EtOH mice also showed deficits in IAV-specific killing of target cells and a reduction in the number of IAV-specific CD8 T cells compared to IAV-immune ➞H2O mice. Finally, our results show that following a heterologous IAV challenge, the fold-increase of IAV-specific CD8 T cells within the lungs of IAV-immune➞EtOH was reduced compared to IAV-immune➞H2O mice. Interestingly, IAV-immune➞EtOH mice had reduced expression of CXCL10 and CXCL11 within their lungs, suggesting defects in cell trafficking. Overall, these data and our prior studies demonstrate that chronic alcohol consumption negatively impacts both the naïve and memory compartments of the CD8 T cell response to IAV infection.
IL-33 mediated stromal-myeloid cell crosstalk controls intestinal helminth infestation
Authors: De Martin Angelina , Scandella Elke , Lütge Mechthild , Perez-Shibayama Christian , Gil-Cruz Cristina , Engetschwiler Céline , Harris Nicola , Le Gros Graham S , Ludewig Burkhard 
Published: February 2023

Abstract
Interleukin-33 (IL-33) is a nuclear cytokine of the interleukin-1 family and is released upon cell damage thereby acting as an alarmin. IL-33 plays an essential role in promoting host-protective immune responses against helminth parasites at different mucosal surfaces including the intestine. However, early events after gastrointestinal nematode infection are poorly understood and the cellular source of IL-33 in the gut remains ill-defined. Here we show that Cxcl13-Cre-positive fibroblastic stromal cells (FSCs) of the lamina propria are the main source of IL-33 in the small intestine. Within the first days of nematode infection, lamina propria FSCs showed strongly increased IL-33 expression. Ablation of IL-33 in Cxcl-13-Cre-positive FSCs resulted in an increased infestation with the gastrointestinal nematode Heligmosomoides polygyrus bakeri. We found that myeloid cells were recruited to the site of worm invasion early after infection and that the upregulation of a distinct set of inflammatory cytokines was dependent on FSC-derived IL-33. Collectively, these data unveil that IL-33-mediated crosstalk between stromal and myeloid cells is a critical event during the initial immune response against gastrointestinal nematodes.
Immunotargeting of T Follicular Helper (TFH) Cells for SLE Treatment
Authors: Papillion Amber M , Bachus Holly , Ballesteros-Tato Andre 
Published: February 2023

Abstract
T follicular helper (TFH) cells promote antibody (Ab) responses by providing both survival and differentiation signals to B cells. As such, the expansion of self-reactive TFH cells contributes to auto-Ab production and correlates with disease severity in SLE. Importantly, blockade of TFH activity prevents auto-Ab production and disease progression in lupus-prone mice. Thus, TFH cells have been suggested as a target for treating SLE. Unfortunately, there are currently no therapies to selectively deplete TFH cells in vivo. We have previously identified IL-2 as a critical factor that suppresses TFH cell responses in vivo. In agreement with its negative role in TFH cell development, we show here that low-dose recombinant IL-2 (rIL-2) treatment prevents self-reactive TFH cell responses in lupus-prone mice. Importantly, this effect is independent of TREGS. Thus, our results demonstrate a novel immunosuppressive function of IL-2 that is independent of its role in regulatory T cell homeostasis. In addition, we demonstrate that rIL-2 can be targeted to TFH cells by adding an IL-6 blockade. Altogether, our data suggest that TFH cell suppression following low-dose IL-2 treatment is a significant mechanism underlying the immunosuppressive effects of low-dose rIL-2 immunotherapies.
Skin delivery of hapten and neurokinin-1 receptor antagonists by microneedle arrays targets neurogenic inflammation and prevents contact dermatitis
Authors: Bandyopadhyay Mohna , Morelli Adrian E , Erdos Geza , Sumpter Tina L , Tkacheva Olga , Shufesky William , Falo Louis D , Larregina Adriana T 
Published: February 2023

Abstract
Contact dermatitis (CD) is a chronic inflammatory disease caused by type-1 immunity. Skin exposure to haptens stimulates the secretion of Substance-P (SP) and initiates the neurogenic inflammation that intensifies CD. Neurokinin-1 receptor (NK1R)-signaling by SP or hemokinin-1 (HK1) amplifies immune responses. Nonetheless, the role and therapeutic implications of the NK1R-SP-HK1 axis in CD remain unclear. We show that SP, HK-1 and the NK1R are required for CD. Specific deletion of the NK1R in keratinocytes decreased the rapid release of IL-1β and IL-6 at the site of contact sensitization which impaired the innate and adaptive immunity of CD whereas deletion of the receptor in dendritic cells (DC) prevented only the adaptive immune response of the disease. Therefore, we hypothesized that blockade of NK1R during sensitization would be a feasible immunosuppressive intervention to treat CD. We developed a system of microneedle arrays (MNA) that co-deliver hapten and NK1R antagonists into mouse skin. This immunosuppressive approach resulted in decreased skin migration and lymph node homing of stimulatory dermal DC transporting the hapten from the sensitization site. Conversely, the immunosuppressive MNA did not affect the migration and lymph node homing of epidermal Langerhans cells (LC), and depletion of LC resulted in loss of the NK1R antagonist beneficial effects. In addition, immunosuppressive MNA caused deletion of hapten-specific T cells and increased T-regulatory cells, which prevented CD-onset and -relapses in a hapten-specific manner. Our findings indicate that immune-regulation by engineering localized skin neuroimmune-networks can be used to treat cutaneous diseases that, like CD are caused by type-1 immunity.
A novel application of chimeric antigen receptor (CAR) T cells for treating severe allergic diseases
Authors: Christie Karen Michelle , Fay Brittany L , Ma Zhengyu (Mark) 
Published: February 2023

Abstract
IgE suppression by Omalizumab has shown to be highly efficacious at controlling severe allergic asthma. The antibody-based drug, however, has a relative short half-life and requires repeated administrations resulting in high costs. To develop a therapy that can suppress IgE with a single treatment, we designed an adoptive T cell therapy (ACT) approach that targets the source of IgE, IgE-expressing B cells. To this end, we constructed chimeric antigen receptors (CARs) that recognize the extracellular membrane-proximal domain (EMPD) of membrane IgE (mIgE), which is exclusively expressed on all IgE-producing B cells. EMPD exists only on mIgE but not on secreted IgE, therefore EMPD-specific CARs cannot be blocked by secreted IgE. Two peptides composing the EMPD region were used to create four hybridomas that produced EMPD-specific monoclonal antibodies. The variable regions were cloned and used to construct single chain variable fragments (scFvs) for second generation CARs including the 4-1BB co-stimulatory domain. EMPD-specific CARs were efficiently expressed on primary human T cells through lentiviral transduction. One of the CARs, 2E3E10, produced potent cytotoxicity and IFN gamma in response to U266 cells and Daudi cells expressing mIgE. The response to U266 cells was especially impressive since the expression level of mIgE is very low. The results show proof of concept that redirecting T cells with EMPD-specific CARs can mediate potent T cell response and eliminate mIgE-expressing B cells. Exploiting the ability of CAR-expressing T cells to continuously eliminate IgE-expressing B cells, this cell-based immunotherapy approach has the potential to control severe allergic diseases with a single treatment.
Generation of PT101, a highly selective IL-2 mutein for treatment of autoimmune diseases
Authors: Visweswaraiah Jyothsna , Sampson Erik R , Kiprono Timothy , Petaipimol Parika , Monsef Adrianne , Kis-Toth Katalin , Otipoby Kevin L , Sundy John , Higginson-Scott Nathan , Viney Joanne L 
Published: February 2023

Abstract
Regulatory T cells (Treg) are vital for immune homeostasis and are dysfunctional in autoimmunity. Interleukin 2 (IL-2) drives the proliferation and function of Tregs via its heterotrimeric receptor (CD25/CD122/CD132). Low dose IL-2 is being evaluated for treatment of autoimmune diseases and has been shown to expand Tregs, yet it has a small selectivity window over conventional T cells (Tconv) and natural killer (NK) cells. To enhance IL-2 selectivity, mutations can be introduced to reduce its CD122/CD132 affinity thus creating a CD25 dependency for signaling through CD122/CD132 upon IL-2 facilitated CD25/CD122/CD132 trimer formation. Using structure guided approach, we introduced mutations in IL-2 that significantly decreased CD122 affinity in addition to mutations that increased CD25 affinity. Finally, we explored other mutations, orientation, and linkers to generate a potent, selective molecule with drug-like manufacturability. These structure activity relationship efforts culminated in the generation of PT101, a mutant IL-2 Fc fusion that was selective in activating and expanding Tregs. PT101 selectively induced STAT5 phosphorylation in human and non-human primate (NHP) Tregs in vitro. In humanized mice and NHPs, administration of PT101 dose-dependently and selectively expanded Treg without significant effects on other immune cell types, nor eliciting proinflammatory cytokine production. In a Phase 1a clinical trial, PT101 was well-tolerated and selectively expanded total Tregs by up to a mean maximum of 3.6-fold. There was no evidence of expansion of NK cells nor pro-inflammatory Tconv at any dose studied. Clinical trials in patients with ulcerative colitis and systemic lupus erythematosus are planned with PT101.
IRAK4 degradation abrogates cytokine release and improves disease endpoints in murine models of IL-33/36- as well as Th17-driven inflammation
Authors: Hubeau Cedric J , Campbell Veronica , Lee Albert , Lurier Emily , Skouras Stephanie , Mayo Michele , Fitzgerald Michael , Wang Amy , Chen Dapeng , Rong Haojing , Zheng Xiaozhang , Chesworth Richard , Gollob Jared , Mainolfi Nello , Slavin Anthony 
Published: February 2023

Abstract
Interleukin-1 receptor associated kinase 4 (IRAK4) plays a critical role in TLR and IL-1R mediated inflammation through its catalytic and scaffolding functions, making it an attractive target for the treatment of immune-inflammatory diseases. Kymera has developed oral heterobifunctional molecules that selectively target IRAK4 for degradation by the ubiquitin-proteasome pathway. These degraders have broad and potent activity in-vitro against LPS + IL-1β-induced proinflammatory cytokine and chemokine production that is superior to IRAK4 kinase inhibitors. We evaluated their efficacy in comparison to kinase inhibition in-vivo in both mechanistic, and disease models of skin and CNS inflammation. IRAK4 degraders were administered to mice in models of skin inflammation induced by either IL-33 or IL-36, as well as in an EAE model of Th17-mediated CNS inflammation. In IL-33- and IL-36-induced skin inflammation, IRAK4 degradation resulted in dose-dependent decreases in ear thickness as well as local and systemic cytokines/chemokines that was superior to kinase inhibition. In MOG-induced EAE, IRAK4 degradation was superior to kinase inhibition and significantly reduced disease scores to levels comparable to a S1P receptor agonist. These data demonstrate the broad activity of IRAK4 degradation and its superiority over kinase inhibition in alleviating inflammation induced by IL-1 family cytokines as well as antigen-dependent Th17-mediated inflammation in models relevant to human disease.
PLXDC2 activation by PX-69 ameliorates rheumatoid arthritis through activation of novel immunometabolic mechanisms
Authors: Tubau-Juni Nuria , Leber Andrew , Maturavongsadit Panita , Chauhan Jyoti , Hontecillas Raquel , Bassaganya-Riera Josep 
Published: February 2023

Abstract
Rheumatoid arthritis is a chronic inflammatory disorder that affects up to 1% of the population worldwide characterized by the increased presence of infiltrating immune cells, activation of inflammatory cytokine cascades, oxidative stress, abnormal proliferation of fibroblast-like synoviocytes (FLS) and neovascularization at the joint synovium. Plexin domain containing 2 (PLXDC2) is a transmembrane receptor with antioxidant, antiangiogenic and immunomodulatory properties that provide therapeutic activity in animal models of autoimmune disease, including rheumatoid arthritis. PLXDC2 activation suppresses glycolytic metabolism, while decreasing cytokine and chemokine secretion and production of superoxide species, in immune cells and FLS. In a rat model of collagen-induced arthritis, oral administration of the lead PLXDC2-binding agonist, PX-69, ameliorates disease severity, resulting in decreased clinical scores and paw size. Similarly, hind ankles presented structure preservation, reduced cartilage damage and decreased immune cell infiltration and number of blood vessels in the PX-69-treated group relative to vehicle. Immunologically, PX-69 treatment resulted in a 2-fold decrease of TNFα-producing cells while upregulating the proportion of IL-10+ myeloid cells and regulatory T cells in draining lymph nodes. In synovial tissue, pharmacological activation of PLXDC2 provided greater than 50% reduction in expression of inflammatory mediators (TNFα, IL1β, IL6, Cxcl1) and markers of synoviocyte activation (c-myc, c-fos). These results support the role of PLXDC2 signaling in controlling rheumatoid arthritis and validate PLXDC2 as a novel target for the treatment of this disabling inflammatory disorder.
BET inhibitors synergize with anti-PD1 in rescuing T cell exhaustion in acute myeloid leukemia by increasing TCF1 expression
Authors: Romine Kyle Alexander , Cho Hyun-jun , Kosaka Yoko , Flynn Patrick , Coy Jesse , Byrd Kaelan , Newman Matthew , Lind Evan 
Published: February 2023

Abstract
Acute myeloid leukemia (AML) is an aggressive myeloid lineage white blood cell cancer with an extremely poor prognosis that occurs most frequently above 60 years of age. The current standard of care consists of an intensive induction chemotherapy regimen. Many patients cannot withstand this intensive treatment regimen and rely on other targeted therapies such as small-molecule inhibitors, which inhibit specific oncogenic proteins, but these are not durable. Immunotherapies, which block stimuli that inhibit T cell functions, have had great success in achieving durable remissions in metastatic melanoma. Studies have shown that AML patients exhibit markers of immune suppression by the tumor microenvironment such as increased levels of PD1/LAG3+ exhausted T cells as well as regulatory T cells and myeloid-derived suppressor cells. In addition, inhibitors targeting the BET proteins family, which are histone readers, potently target leukemia cells by reducing myc but also increase IFNy and IL-2 production in T cells by inhibiting BATF, a negative regulator of TCF1. TCF1 is a critical factor in effector memory T cells and TCF1+ T cells are the primary expanders with aPD1. We therefore hypothesized that BETi and aPD1 would synergize in treating AML by modulating both tumor intrinsic and extrinsic factors (enhanced T cell activity). T cells derived from an immune competent FLT3-ITD/TET2/Lys-Cre AML mouse model show significant proliferative dysfunction and enhanced exhaustion markers, but are rescued by ex vivo treatment with BETi + aPD1. Further, In vivo treatment with this novel drug combination showed enhanced reduction of leukemic blasts, increased T cell proliferation, and in vitro expansion of TCF1+ effector memory CD8 T cells.
STING agonism combined with arginase and PTGES/COX2 inhibitors for improved anti-tumor immunotherapeutic benefit
Authors: Filderman Jessica , Chelvanambi Manoj , Storkus Walter J 
Published: February 2023

Abstract
Tertiary lymphoid structures (TLS) are non-encapsulated immune cell aggregates that form at sites of chronic inflammation. Recent studies have shown that the presence of TLS in human tumors predicts extended survival and superior response to interventional immunotherapy. Our lab has recently demonstrated that treating mice bearing established tumors with agonists of STING, a cytosolic dsDNA sensor, leads to an inhibition in tumor growth in association with tumor vascular normalization, immune cell recruitment, and local formation of non-classical TLS within the tumor microenvironment. However, STING agonism also results in the upregulated expression of compensatory immune regulatory molecules, including ARG2 and enzymes involved in the production of immunosuppressive prostaglandins (i.e. PTGES and PTGS2/COX2), yielding an overall sub-optimal therapeutic paradigm. We are currently determining if combined treatment with STING agonists along with pharmacologic inhibitors of ARG2 and/or PTGES/COX2 results in improved control of tumor growth, increased formation of TLS, and more robust anti-tumor immune responses in vivo in murine melanoma models.
Targeting cancer cell kinase PERK incites antitumor immunity by inducing immunogenic cell death and reprograming tumor-linked immunosuppressive myelopoiesis
Authors: Mandula Jessica , Mohamed Eslam , Sierra-Mondragon Rosa , Chang Shiun , Jimenez Rachel , Satyajit Das , Rodriguez Paulo 
Published: February 2023

Abstract
The tumor microenvironment incites sustained endoplasmic reticulum (ER) stress in infiltrating T and myeloid cells, which impairs their antitumor potential through intrinsic activation of PKR-like endoplasmic reticulum kinase (PERK). Nonetheless, the immunomodulatory role of PERK activation in the tumor cell compartment remains unknown. Using multiple melanoma models, we established that PERK ablation (PERKKO) in cancer cells culminates in caspase-independent immunogenic cell death (ICD) in response to ER stress. In vivo, PERKKO cells underwent ICD and released immunostimulatory factors including HMGB1, ATP, calreticulin and type I interferons which provoked a dramatic anti-tumor response and induction of the abscopal effect. Immunologically, PERKKO tumor cells undergoing ICD spurred influx of CCR2-dependent monocyte-derived dendritic cells (MoDCs) and tumor infiltration of activated antigen-specific T cells. Moreover, PERK deletion in tumor cells triggered systemic expansion of myeloid precursors and promoted their differentiation into MoDCs via type I interferon signaling. Notably, MoDC-induced T cell responses in PERKKO tumors impaired B16-F10 tumor progression and enabled complete rejection of BrafV600E-SM1 tumors. Substantiating the translational potential of our work, inhibition of PERK in melanoma-bearing hosts resulted in significant anti-tumor effects. Also, TCGA analyses of melanoma patients showed that PERK signaling or repressed ICD marker expression coincided with shorter overall survival. Collectively, these results demonstrate that targeting PERK in tumor cells can offer the dual benefit of inducing ICD and reprogramming myelopoiesis to drive protective antitumor immunity.
A DNA nanorobot targeted release aTIGIT improves the immunosuppressive state and synergizes the anti-tumor effect of aPD-1
Authors: hou yuchen , Feng Hao , zuo xiaolei , Xia Qiang 
Published: February 2023

Abstract
Immune checkpoint inhibitor (ICIs) therapies have become the prominent breakthrough in the treatment of hepatocellular carcinoma (HCC). Dual blockade of TIGIT and PD-1 have promising results achieving synergistic antitumor effects for ICI-resistant HCC. However, immune-related adverse events (irAEs) and immune cell depletion in tumor microenvironment affect the clinical use of ICIs therapies. DNA nanobots have shown excellent potential as targeted release drug delivery systems in vivo. Here, using DNA origami we constructed an autonomous DNA robot to transport TIGIT antibodies to tumor site. The Pb (2+) dependent DNAzyme GR5 was used to achieve the aTIGIT free-loaded in DNA cargoes. The nucleolin-targeting aptamer serves both as a targeting domain and as a molecular trigger for the open of the DNA cargoes in tumor microenvironment. The CpG oligodeoxynucleotides (ODNs) responsible for immunostimulatory in tumor site by activation of TLR9, producing high-level secretion of various pro-inflammatory cytokines including tumor necrosis factor (TNF)-R, interleukin (IL)-6, and IL-12. DNA gel electrophoresis and TEM showing the structure of the nanobots. FRET efficiency verified the open of the cargoes regulated by nucleolin aptamer. Confocol microscopy showing the targeting of the nanobots to nucleolin-positive HCC cells. Cy5-modified oligonucleotides were conjugated to aTIGIT and the UV-Vis spectrometry results showed that aTIGIT was free-loaded and protected by the DNA cargoes. Tumor-bearing mouse model will be established to evaluate the synergistic antitumor effect of the DNA nanobots for aPD-1 in vivo. Our DNA nanorobot provide a safe and high efficient immunostimulatory delivery system for ICIs therapies.