bluuebunny/crossref_metadata_2025_split huggingface dataset:
GARP-TGFβ Axis on Activated Platelets Supports Tumor Progression
Authors: Metelli Alessandra , Wu Bill , Riesenberg Brian , Fugle Caroline Wallace , Sun Shaoli , Liu Bei , Li Zihai 
Published: January 2023

Abstract
Platelet-induced cancer progression is a well-known process driven by mitogenic factors released by activated platelets, among them the most pro-oncogenic is Latent Transforming Growth Factor Beta (LTGFβ). Glycoprotein-A Repetitions Predominant Protein (GARP), a receptor for LTGFβ that enhances its bioactivation, is expressed by regulatory T cells, platelets, and several human cancers. Upon activation platelets dramatically upregulate GARP, suggesting that GARP might play a role in activating LTGFβ released upon platelet degranulation and thus in platelet-induced cancer progression. To address this point we employed a novel mouse model based on the platelet-specific knock-out of the GARP gene. We show that in activated platelets GARP is critical for the expression of surface LTGFβ and for its conversion to the bioactive form. Lack of GARP on platelets, indeed, resulted in the complete absence of serum active TGFβ. To investigate whether GARP plays a role in platelet-induced cancer progression we tested multiple tumor models and observed that genetic deletion of GARP enhanced adoptive T cell therapy of B16 melanoma. We also found that in MC38 colon tumor model GARP on platelets contributes to cancer progression by increasing TGFβ bioavailability, promoting regulatory T lymphocytes and myeloid cells, and favoring the immune evasion of cancer cells. These results demonstrate that platelet-specific deletion of GARP blunted TGFβ activity in the tumor microenvironment and boosted protective immunity against pre-established cancers. We conclude that platelets constrain anti-tumor immunity via a GARP-TGFβ axis and we propose the combination of immunotherapy and platelet inhibitors as a novel treatment strategy against cancer.
Human cancer cells respond to cytosolic nucleic acids via RIG-I-MAVS-IRF3-mediated interferon-β production
Authors: Chen Jingtao , Qiao Yuan , Zhu Shan , Li Tete , Liu Yong-Jun 
Published: January 2023

Abstract
The innate immune system is the first line of defense against invading microbes via the action of pattern recognition receptors (PRR). Recently, human cancer cells were reported to express PRRs and respond to cytosolic nucleic acids by producing type I interferon. However, whether all nucleic acid-sensing pathways are intact and whether these pathways function in all types of cancer cells remain unclear. In this study, we investigated the effects of nucleic acids in eight types of cancer cells transfected with 5′ppp-dsRNA, poly(A:U), poly(I:C)-HMW, poly(I:C)-LMW, ISD, HSV60, VACV-70, poly(dG:dC), 3′-3′cGAMP, and poly(dA:dT). Interferon-β (IFN-β) secretion was increased following stimulation with 5′ppp-dsRNA, poly(I:C)-HMW, poly(I:C)-LMW, or poly(dA:dT) in most cells. Further, we evaluated the role of TLR3 and RIG-I/MDA-5 signaling in the pancreatic cancer cell line PANC-1. The expression of RIG-I, MDA5, and LGP2 was up-regulated by cytosolic poly(I:C) and poly(dA:dT). Knockdown experiments confirmed that IFN-β production was mediated by the RIG-I-IPS-1-IRF3 signaling pathway in response to cytosolic poly(I:C) and poly(dA:dT). Therefore, these potent adjuvant activities may be useful for drug and vaccine design for cancer immunotherapy.
Macrophage migration inhibitory factor promotes interplay between colorectal cancer, macrophages and T cells to regulate cancer progression.
Authors: Rodriguez-Sosa Miriam , Juarez-Avelar Imelda , Olguin Jonadab Efrain , Illescas Oscar , Terrazas Luis I , Cuellar María Sandra , Pacheco-Fernandez Thalia 
Published: January 2023

Abstract
Colitis-Associated Colorectal Cancer (CAC) is triggered by chronic inflammation. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine promoting angiogenesis, metastasis, proliferation and survival in malignant cells. When MIF binds to CXCR2 and CXCR4 attracts macrophages and T cells, respectively. As MIF promotes inflammation and recruit immune cells, we investigated the role of MIF in murine model of CAC. Mif−/− and WT BALB/c mice received intraperitoneally azoxymethane and later were exposed to 3 cycles of Dextran Sodium Sulfate (DSS, 2%) in drinking water. After the first DSS cycle WT mice received a synthetic MIF’s inhibitor (CPSI-156). All mice were killed 68 days after CAC induction. Greater burden of tumors were observed in both Mif−/− (25.38±1.772) and CPSI-156-treated mice (18.83±2.43) compared to CAC-WT mice (13.00±1.862). Tumors from Mif−/− mice were histologically-identified as more aggressive. Lower percentages of tumor-associated macrophages were found in both, Mif−/− (0.6577 ± 0.117) and CPSI-156-treated mice (1.2 ± 0.14) compared to CAC-WT mice (2.044±0.39). Similar percentage of T-cells was observed in all groups. RT-PCR of tumors was performed, relative expression (RE) was compared to β-actin gene. CAC-WT mice increased T-regs (foxp3 RE= 0.49), M2 (arginase-1 RE=1.53) and IL-10 (il-10 RE=0.52) and reduces expression of IL-17 (il-17 RE=3.14). Conversely, CAC-Mif−/− mice developed higher IL-17 (il-17 RE=17.15) and lower foxp3 (RE=0.32), arginase-1 (RE=1.12) and il-10 (RE=0.47) expression. Our results suggest that MIF plays a role in regulating the tumor microenvironment attracting macrophages at the tumor site, condition that may favor antitumor responses.
Non-thermal atmospheric plasma ameliorates imiquimod-induced psoriasis-like skin inflammation in mice through inhibition of immune responses and up-regulation of PD-L1 expression.
Authors: Lee Yun Sang , Lee Myung-Hoon , Kim Hang-Jun , Won Ho-Ryun , Kim Chul-Ho 
Published: January 2023

Abstract
Plasma medicine is emerging as a novel therapeutic field. It has been reported that plasma can kill bacteria, promote wound healing and induce apoptosis of tumor cells. However, the effects of plasma on immune cells and immune related skin diseases have not been well studied. In this study, we demonstrated that non-thermal atmospheric plasma (NTP) treatment can inhibit psoriasis-like skin inflammation in mice. Psoriasis-like skin inflammation was induced through application of imiquimod for 5 days and NTP was treated on days 3 and 4. On day 5 mice were sacrificed for analysis. NTP treatment in imiquimod-applied mouse skin inhibited increases in epithelial cell thickness compared to imiquimod-applied mouse skin without NTP treatment and suppressed immune cell infiltration in the mouse skins. The expression of cytokines and chemokines and NF-κB activation in the skin were also suppressed by the NTP treatment. In addition, differentiation of Th17 cells, an important cell type for the pathogenesis of psoriasis, was inhibited in the NTP-treated mouse lymph nodes. It was also demonstrated that liquid type plasma (LTP), which is also known as indirect plasma, inhibited Th17 cell differentiation in vitro. Other in vitro experiments showed that LTP inhibits bone marrow-derived dendritic cell (BMDC) activation, and inflammation of HaCaT cells. Interestingly, LTP enhanced PD-L1 expression in BMDC and HaCaT cells, suggesting that NTP may inhibit unwanted over-activation of T cells through increased PD-L1 expression in dendritic cells or epithelial cells. Taken together, these results suggest that NTP can be used to treat CD4+ T cell-mediated autoimmune diseases such as psoriasis.
Identification of a novel tolerogenic cell subset in the treatment of autoimmune diseases
Authors: Marinelarena Alejandra , Bhattacharya Palash , Alharshawi Haled , El-Sayed Osaka , Kumar Prabhakaran , Prabhakar Bellur S. 
Published: January 2023

Abstract
We previously reported granulocyte macrophage colony-stimulating factor (GM-CSF) prevented type 1 diabetes in NOD mice through CD11c+CD8− dendritic cell (DCs) mobilization, precipitating regulatory T-cell (Treg) expansion. Furthermore, we found GM-CSF derived bone-marrow dendritic cells (G-BMDCs) can drive Treg expansion in ex-vivo CD4+splenic T-cell co-cultures through surface-bound molecule OX40L. To determine whether GM-CSF may lead to the formation of a distinct, novel CD11c+OX40L+ expressing DC subset, we generated OX40L+G-BMDCs (CD11c+OX40L+) and analyzed these cells through flow cytometry for various cell lineage markers. We determined OX40L+G-BMDCs expressed increased levels of co-stimulatory molecules CD80, CD86, PD-L1 and MHC-II in comparison to the OX40L− counterpart. Additionally, OX40L+G-BMDCs lacked expression of Ly6G, Ly6C, FceR1, surface markers indicative of granulocyte and mast cell lineage, but to our surprise, highly expressed macrophage markers F4/80, MerTK, and CD200R. To elucidate an in vivo physiological component of these OX40L+ G-BMDCs, we performed an unsupervised hierarchical clustering comparing the transcriptome of OX40L+G-BMDCs to that of all myeloid and lymphoid lineages from the Immgen database. We found that OX40L+G-BMDCs clustered most closely with macrophages and dendritic cells. Furthermore, a principal component analysis with the transcriptome of OX40L+G-BMDCs and that of macrophages and dendritic cells from the Immgen database revealed OX40L+G-BMDCs most closely clustered with macrophages. Collectively, these results suggest OX40L+ G-BMDCs may represent a distinct GM-CSF dependent, macrophage-like cell subset involved in physiological Treg homeostasis.
CD38+ cell depletion with TAK-079 reduces arthritis in a cynomolgus collagen-induced arthritis (CIA) model
Authors: Smithson Glennda , Zalevsky Jonathan , Korver Wouter , Roepcke Stefan , McLean Lachy 
Published: January 2023

Abstract
TAK-079 is a fully human, cytolytic IgG1 mAb against human CD38. We tested the ability of TAK-079 to treat arthritis using a monkey CIA model with features of symmetrical small joint polyarthritis resembling human RA. Monkeys were injected with bovine collagen type II in complete Freund’s adjuvant on Day 0 and Day 21 to induce arthritis. 1 monkey was used as a disease-free, age-matched control (naïve). In monkeys with CIA, the prophylactic group (n=8; 3 mg/kg, QW, iv) started treatment on Day 7 and continued for 8 weeks. The therapeutic treatment groups were randomized, after progression to overt disease, to 1 of 3 treatments: Vehicle (n=5; QW, iv), TAK-079 (n=7; 3 mg/kg, QW, iv), or dexamethasone (Dex; n=4; 0.1 mg/kg QD, po) and treated for 5 weeks.
Prophylactic treatment with TAK-079 inhibited arthritis induction and therapeutic treatment reduced arthritic disease to a similar extent as Dex. TAK-079 treatment reduced CD38+ cells in the blood and spleen vs. naïve animal. After the first dose, blood monocytes, B and T cells were each reduced ≤ 55%, but reduction of monocyte and T cell counts were transient despite continued dosing. NK cells showed almost complete depletion. Neutrophil and platelet counts, elevated due to active arthritis, appeared normalized by TAK-079 vs. the naïve animal. TAK-079 treatment reduced systemic and local inflammation. Treated animals suffered less weight loss, and had reduced CRP and ALP levels and increased albumin levels. TAK-079 treatment reduced cartilage degradation and bone resorption in the IP and MCP joints based on radiology findings and confirmed by qualitative histological grading. TAK-079 was effective in treating CIA, supporting its continued investigation for the treatment of autoimmune disease.
Molecular mechanisms promoting progression of autoimmune myocarditis to dilated cardiomyopathy.
Authors: Nalawade Saisha Abhay , Bloom Joshua , Sunsong Robin , Rauhut Anja , Thomas Dominic , Al-Abed Yousef , Forsthuber Thomas 
Published: January 2023

Abstract
Myocarditis is an inflammatory disease of the myocardium, described by infiltration of immune cells and cardiomyocyte necrosis. It is a major cause of sudden death in young adults. Patients often progress to a more severe form of the disease termed dilated cardiomyopathy (DCM). It is characterized by extensive fibrosis leading to impaired cardiac function. Immunosuppressive treatments with corticosteroids (CSs) have not been effective in preventing the disease. We hypothesized that macrophage migration inhibitory factor (MIF), being the only known pro-inflammatory cytokine induced by CSs may play a role in resistance to CSs. Also, MIF counter-regulates CS-mediated immunosuppression. Using the experimental autoimmune myocarditis (EAM) animal model, we observed that MIF−/− mice treated with Dexamethasone (Dex) were highly resistant to EAM and progression to DCM. Furthermore, from a translational approach, treatment using small molecule inhibitors of MIF combined with Dex recapitulated this phenotype in wild type mice. We observed that treated mice showed decreased expression of key chemokines and extracellular matrix molecules compared with controls, implicating these molecules in disease progression. Currently, we are investigating these molecules by selectively inhibiting them in order to understand their contribution to disease pathogenesis. We observed that inhibition of CCL2 after, although not prior to establishment of EAM attenuated progression to DCM. Thereby, suggesting that CCL2 is predominantly involved during the fibrotic phase aiding in progression as opposed to the induction phase of the disease. Besides a novel approach to prevent DCM, our studies may provide new insights into the mechanisms driving DCM.
Therapeutic effects of erythroid differentiation regulator 1 (Erdr1) on atopic dermatitis-like skin inflammation in NC/Nga mice
Authors: Kim Kyung Eun , Cho Daeho 
Published: January 2023

Abstract
Atopic Dermatitis (AD) is a representative chronic inflammatory skin disease. It is characterized by a defective skin barrier and dysregulation of the immune system as result of excessive Th2 immune response. IL-18, a well-known pro-inflammatory cytokine, is particularly closely associated with AD severity and IgE level in AD patients. Recent studies have been reported that erythroid differentiation regulator (Erdr1) has a negative correlation with IL-18 and exerts anti-inflammatory effects on inflammatory skin diseases, such as psoriasis, rosacea, and melanoma. In this study, to investigate whether Erdr1 has a preventive effect on AD, NC/Nga mice were used to induce AD-like skin inflammation. Then, recombinant Erdr1 (rErdr1) was administered by intraperitoneal (i.p.) injection. As results, rErdr1 administration significantly decreased the severity of AD including redness, edema, scaling, and excoriation. In addition, IgE and IL-4 production were suppressed by rErdr1 in the AD mouse model. To elucidate the related mechanisms, the expression of Th2 chemoattractants and angiogenic factor was determined. The expression of CCL17 and CCL22 was significantly lower in rErdr1-treated mice than in vehicle control-treated mice. Also, a representative angiogenic factor, VEGF expression was inhibited by rErdr1 administration. To our knowledge, this is the first evidence that rErdr1 has a preventive effect on AD based on its ability to reduce Th2 chemoattractants and angiogenesis in an AD-like mouse model. Therefore, we suggest that supplementation with rErdr1 might be an effective and improved therapeutic strategy for the treatment of AD.
FVIII BAR-CD8 T cells to target antigen-specific antibody secreting cells
Authors: parvathaneni kalpana , Scott David W 
Published: January 2023

Abstract
Hemophilia A (HA) is an autoimmune bleeding disorder due to a variety of mutations in coagulation factor (FVIII). HA is currently treated by administering clotting factor VIII (FVIII) prophylactically or on demand after bleeds. Due to the lack of tolerance to FVIII, many of these patients make an antibody response (called “inhibitor formation”) to the therapeutic FVIII, thus neutralizing the circulating plasma FVIII levels. The current treatment for inhibitor formation is frequent high dose administration of FVIII, which is expensive and often fails. An alternative immune tolerance protocol is an unmet need. Understanding and applying the CAR therapy has been one of the major notable discoveries in the last decade in both oncology and hematology research areas. Modifying this approach to target the antibody secreting cells, we engineered a B cell antibody receptor (BAR), consisting of antigen domains (FVIII A2 or C2, OVA) fused to lymphocyte signaling domains. BAR-CD8 T cells provide the antigen on their surfaces to be recognized by specific-antibody secreting B cells (ASCs) and can target to kill the cells in a non-MHC dependent manner. The BAR-CD8 T cells in the presence of the respective targets FVIII-C2 or OVA specific hybridoma cells are activated and secrete INF-γ. In vitro, FVIII-C2 BAR-CD8 T cells (both human and mouse origin) specifically kill target cells, including FVIII domain specific hybridomas. We suggest that BAR T cells offer a novel approach for the treatment of autoimmune diseases where formation of autoantibodies is life threatening.
Suppression of acute uveitis following treatment with repository corticotropin injection
Authors: Wright Albion D , Sharma Prabha , Zweifel Ben , Oh Luke 
Published: January 2023

Abstract
Repository corticotropin injection (RCI: H.P. Acthar® gel) contains a purified porcine pituitary ACTH-analogue, and is an FDA-approved treatment for several inflammatory eye diseases. ACTH binds to all 5 known melanocortin receptors and may suppress inflammation by steroid-dependent and independent pathways. Endotoxin-induced uveitis (EIU) in rodents is a useful experimental model to investigate mechanism of action and pharmacological efficacy of potential treatments. This study was conducted to investigate the potential anti-inflammatory benefit of RCI in an acute rat model of EIU. EIU is characterized by clinically relevant signs of inflammation, including inflammatory cytokines and cells in the anterior and vitreous chambers. Rats (n=16 group) were treated with dexamethasone (Dex), placebo, or RCI at 160 IU/kg, 400 IU/kg or 800 IU/kg following EIU induction. Eyes were clinically examined at pre-challenge, 6–8, 24, and 48 hours post LPS challenge using the Combined Draize and McDonald – Shadduck Scoring System.
Treatment GroupOcular Clinical Score (mean ± sem)IL-1a (pg/ml) (mean ± sem)MIP2a (pg/ml) (mean ± sem)Placebo15.5 ± 1.2207.1 ± 68.9240 ± 47Acthar 160 IU/kg9.4 ± 1.0130.3 ± 34.6158 ± 43Acthar 400IU/kg2.0 ± 0.3*95.7 ± 20.3114 ± 18*Acthar 800 IU/kg0.9 ± 0.2*50.9 ± 8.3*126 ± 32*Dex2.6 ± 0.5*54.4 ± 10.5*92 ± 10**= p ≤ 0.01
We show that RCI treatment significantly reduced ocular inflammation and inflammatory cytokines in an EIU model of acute uveitis. RCI has the potential opportunity to be therapeutic for a wide range of inflammatory and autoimmune diseases, including uveitis. The mechanism of action of RCI may involve more than the induction of corticosteroids, and will be explored further in future studies.
Easy ways to increase immunology content engagement in and out of the classroom
Authors: Lukin Kara R 
Published: January 2023

Abstract
Most traditional science courses, especially large-format courses, are lecture-based. However, the literature clearly demonstrates that this is one of the least effective methods for teaching complex content and results in poor retention. Curricula that infuse a variety of discipline-specific active strategies as well as time for “brain dumps” are more enjoyable for students and result in better content integration and long-term retention. To create time for these activities, students can be required to view short videos of core concepts prior to class. Students can be held accountable with no, low or high stakes assessments or group peer-pressure. Interestingly, students report increased content contact time because they also view these resources after class and prior to assessments. Here, multiple low-risk, high-engagement activities are presented with classroom-ready resources. Various tools for short (&lt;2 min) self-assessments (with aggregate class data) and content engagement will be shared. In addition, demonstration of and directions for free, easy to use screen capture programs like Jing will be provided for making quick core content videos. All strategies are appropriate for high school, undergraduate and graduate courses of small and large sizes. Starting one session at a time and using their current teaching materials, educators can slowly integrate these engaging strategies into their syllabi to enhance students’ experiences and outcomes.
Implementation and student perceptions of the Just in Time Teaching (JiTT) strategy in an upper level immunology course
Authors: Brown Deborah M , Brazeal Kathleen R. , Couch Brian A. 
Published: January 2023

Abstract
Instructional pedagogy has undergone innovative changes to meet the demands of 21st century science education. One such teaching strategy, known as Just-in-Time Teaching or JiTT, is an inquiry based, active learning approach that evolved to meet those demands and has been shown to enhance student retention of complex concepts. Prior to class, students read assignments and answer specific conceptual questions that involve linking new material or ideas with previously learned concepts. Importantly, an open-ended, reflective question is also asked about what students found most interesting, confusing, or difficult about the particular assignment. Student responses to these conceptual and reflective questions help identify incoming misconceptions and are used during class to modify instruction and facilitate discussion. Students are graded based on effort, rather than complete correctness, as “low stakes” assessments have been shown to increase student participation and encourage inquiry. Some of the most successful JiTTs in my course are based on the Case Studies in Immunology companion book to Janeway’s ImmunoBiology. These case studies introduce topics such as the importance of MHC molecules in the development of specific CD8 or CD4 T cells. Additional examples will be given that demonstrate the breadth and scope of JiTT concepts and questions as well as student responses to JiTT assessments. Finally, results from a student survey will be presented to demonstrate how students perceive the JiTT strategy to support their learning. Overall, the JiTT approach has been well-received for upper level Immunology students and is beneficial to student and instructor to assess understanding of complex biological concepts.
Self-Directed Learning within Postgraduate Immunology Education
Authors: Sika-Paotonu Dianne 
Published: January 2023

Abstract
Immunology education is essential for the understanding of mechanistic and cellular events responsible for specific diseases. To support proper understanding by students, contemporary learning and teaching methods are becoming increasingly focused on student centered practices that include Self-Directed Learning (SDL). SDL is the process where a student determines their own learning aims and undertakes methods of their own choosing to achieve and assess their own learning outcomes. SDL has become an area of emphasis particularly within the nursing profession. Although the importance of SDL may be emphasized to students, they may not necessarily receive instruction or have SDL strategies to facilitate effective learning. This work sought to explore the impact of teaching and promoting SDL strategies for postgraduate nursing, midwifery and health students undertaking Immunology education by distance within a postgraduate Pathophysiology course. In-class Immunology teaching sessions for these students contained instruction that taught and promoted various SDL strategies. Favorable student outcomes were achieved for Immunology assessment components of the Pathophysiology course with in-class feedback related to specific instruction regarding SDL strategies, positive. Formal student evaluation of the Immunological course elements also highlighted favorable student satisfaction scores. These findings support SDL as an effective learning tool for postgraduate Immunology education.