bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lineage-specific IKKβ deficiency reveals a role for intestinal epithelial cells in lung immune response to ingested antigens (163.10)
Authors: Bonnegarde-Bernard Astrid , Jee Junbae , Steiner Haley , Fial Micheal , Davis Ian , Boyaka Prosper 
Published: January 2023

Abstract
The sites where immune responses are initiated are believed to play a key role at shaping subsequent responses at distant mucosal sites. However, little is known about the relative contribution of intestinal epithelial cells (IEC) to lung reactivity to foreign antigens and the development of allergic and non-allergic asthma. It has been demonstrated that nuclear factor κB (NF-κB) activation by IκB kinase (IKK)β deletion in macrophages increases pro-inflammatory cytokines responses. To address the potential regulatory effect of IEC for lung reactivity, control C57BL/6 mice and mice deficient in IKKβ in IEC (IKKβΔIEC) or in macrophage (IKKβΔMac) were orally sensitized by administration of ovalbumin and cholera toxin as adjuvant. All groups developed similar levels of antigen-specific IgE responses, but IgG2a responses were enhanced in IKKβΔIEC and, even more in IKKβΔMac. Subsequent nasal challenges of C57BL/6 mice with ovalbumin induced lung inflammation and increased lung resistance. Interestingly, both lung inflammation and lung resistance were lower in IKKβΔIEC mice and further reduced in IKKβΔMac mice. Taken together, these results show that localized alteration of NF-κB signaling in IECs have broader effects on immune responses to ingested antigen, which were similar, although of lower magnitude, than those seen when NF-κB signaling is altered on macrophages. They also reveal that IECs can shape immune responses at distant mucosal sites of the airways.
Mast cell-deficient mice show attenuated thermal pain responses (163.18)
Authors: Chatterjea Devavani , Wetzel Abigail , Mack Madison , Allen Juliann 
Published: January 2023

Abstract
Pain is a cardinal component of inflammation and a significant public health issue. Inflammatory cytokines such as TNF-alpha, IL-1beta, CXCL1/IL-8, as well as neutrophil influx have been implicated in the potentiation of peripheral inflammatory pain in models of thermal and mechanical hindpaw hypernociception in rodents.. Degranulation of mast cells has been shown to be important for phosphorylation of Erk in nociceptive neurons in a rat model of migraine-like stimulation. Mechanical bladder pain in a model of interstitial cystitis was abrogated in mast cell deficient mice. We show that degranulation of plantar mast cells caused by direct secretagogue treatment or passive antibody sensitization and challenge, causes reduction in paw withdrawal latencies as well as significant edema, neutrophil influx, and upregulation of local TNF-alpha and IL-1beta levels, as well as histamine release in the hindpaws of mice in a model of thermal pain. Mast cell-deficient C57BL/6 Wsh/Wsh mice show no edema, histamine release or pain response indicated by reduction in paw withdrawal latencies. This suggests that while pain is a complex and multifactorial physiology, tissue sentinel mast cells may be a critical initiator of inflammatory pain in both protective and allergic/pathological contexts.
Antibodies against GlcNAc modulate the immune response to Aspergillus fumigatus in the lung (163.19)
Authors: Stefanov Emily , Kin Nicholas , Kearney John 
Published: January 2023

Abstract
The incidence of childhood asthma has increased dramatically over the past few years. The hygiene hypothesis postulates that this increase is due in part to overly sanitized environments encountered during childhood. A lack of early microbial exposure is thought to facilitate allergic responses to normally innocuous antigens later in life. Chitin, a biopolymer of N-acetyl glucosamine (GlcNAc), is produced by many allergen-bearing organisms including: fungi, the exoskeleton of insects, crabs, shrimp and parasitic nematodes. Epidemiological studies have shown a negative correlation between Streptococcus pyogenes infection and the development of asthma later in life. S. pyogenes induces antibodies against GlcNAc moieties on its cell wall polysaccharide. We hypothesized that antibodies against GlcNAc, introduced passively, or induced by neonatal immunization of mice with Group A Streptococci, modulate the immune response in the lung to both chitin and Aspergillus fumigatus (AF), a chitin-bearing fungi and common asthma-associated allergen. We show that these antibodies reduce the influx of lymphocytes into the lung after intratracheal challenge with chitin or AF. We also find a dramatic decrease in pro-inflammatory cytokines in the lung when these antibodies are present. These findings are important in understanding allergic asthma and discovering potential ways to prevent its development.
Pathogenetic role of BATF in a murine model of allergic asthma (163.20)
Authors: Übel Caroline , Hildner Kai , Lehr Hans , Rieker Ralf , Murphy Kenneth , Finotto Susetta 
Published: January 2023

Abstract
The transcription factor Basic leucine zipper transcription factor (BATF) is a member of the AP-1 family of transcription factors which upregulate gene expression of genes containing the TPA-DNA response element. However, BATF is thought to inhibit AP-1 activity. BATF has recently been described to be crucial for Th17 differentiation. BATF deficient mice lack this subset of T helper cells which is known to play a key role in inducing airway hyperresponsiveness in allergic asthma. In our study, we analyzed BATF deficient mice in a murine model of allergic asthma. We could show for the first time that BATF deficient mice show decreased lung Th2 cytokine production, reduced airway hyperresponsiveness, serum IgE and IgG1 levels after allergen challenge compared to wild-type littermates. The number of eosinophils was also diminished in the airways of BATF(-/-) compared to wild-type mice. We consider this phenotype to be primarily caused by the lack of IL-17A-producing Th17 cells. These results underline the importance of Th17 and the respective IL-17 cytokines for inducing and maintaining allergic diseases such as asthma. As there is a high similarity between human and murine BATF molecules, targeting this transcription factor could lead to the development of new treatment strategies against human asthma.
Bee venom ameliorates lupus nephritis in New Zealand Black/White mice. (164.15)
Authors: Lee Hyojung , Shin Minkyu , Hong Moochang , Bae Hyunsu 
Published: January 2023

Abstract
Introduction: Bee venom (BV) therapy has been used to treat inflammatory diseases including rheumatoid arthritis in humans and in experimental animals. This study was conducted to examine the therapeutic effect of BV on established lupus nephritis in New Zealand Black/White (NZB/W) F1 female mice. Methods: Beginning at 18 weeks of age, mice were given a subcutaneous injection of either BV (3mg/kg body wt) or an equal volume of saline once a week until the end of the study. Results: The proteinuria level and the serum levels of total IgG, IgG2a and anti-dsDNA IgG antibodies in mice treated with BV were lower than those in the saline-treated mice. Concomitant with serum antibody levels, IgG2a immune complex deposition in the glomeruli was reduced in BV treated mice. Furthermore, renal proinflammatory cytokines were also decreased after BV treatment. Interestingly, CD4+CD25+ Regulatory T cells and CD4+Foxp3 positive T cells were significantly increased in the BV treated mice. Conclusions: Collectively, the administration of BV that has immune modulating effects represents an applicable treatment of lupus nephritis in NZB/W F1 mice.
TLR7 and TLR9 9 agonists enhance the exogenous IFNb-1a’s induction of immunomodulatory cytokine secretion via reconstituting a deficient IFNAR/TLR7 signaling in patients with relapsing remitting multiple sclerosis (164.16)
Authors: Tao Yazhong , Zhang Xin , Troiani Luigi , Markovic-Plese Silva 
Published: January 2023

Abstract
Objective: To explore possibilities to enhance IFNb’s therapeutic effects in RR MS patients. Results: B-cells derived from RR MS patients express a decreased IFNAR1, IFNAR2 and TLR7 gene expression, associated with increased IL-23 and decreased IL-27, IL-10 and IL-4 secretion, in comparison to healthy controls HCs. In-vitro administered IFNb-1a only partially reversed the B-cells’ pathogenic cytokine pattern. TLR9 ligand CpG enhanced exogenous IFNb-1a’s immuomodulatory effects on B-cells by significantly up-regulating IFNb-1, IRF7 and MyD88 gene expression, and IL-27, IL-10 secretion, while combination of TLR7 ligand Loxoribin (Lox) and IFNb-1a induced IL-4 production and endogenous IFN-b1 gene expression. In CD4+ T-cells, TLR7 and TLR9 ligand combinations with IFNb-1a induced a significantly higher IRF7 and MyD88 gene expression in comparison to the untreated CD4 cells. CpG and IFNb-1a combination induced TLR7 and TRAF6, and LOX and IFN-b1a inhibited SIGIRR gene expression. Both combinations with IFNb inhibited the secretion of IL-17A, IL-17F, IL-22 and IL-9, but induced IL-4, TGF-b1 and IL-10, while only CpG and IFNb-1a combination inhibited IL-21 secretion. Both combinations induced endogenous IFNb gene expression in CD4+ cells. Conclusion: TLR7 and TLR9 agonists enhance the in-vitro-mediated IFNb-1a immunomodulatory effects in B-cells and CD4 cells derived from RR MS patients, implicating their therapeutic potential in combination with IFNb-1a.
CD8+ T-cells are required for the action of glatiramer acetate therapy for autoimmune demyelinating disease (164.19)
Authors: Tyler Andrew , Mendoza Jason , Ortega Sterling , Firan Mihail , Karandikar Nitin 
Published: January 2023

Abstract
Multiple sclerosis (MS) is a chronic disabling disease characterized by immune-mediated destruction of central nervous system (CNS) myelin. Murine experimental autoimmune encephalomyelitis (EAE) is a well characterized animal model of MS. The FDA-approved drug glatiramer acetate (GA, Copaxone®), discovered through EAE studies, ameliorates the symptoms of MS without immunosuppression, although its mechanism is still poorly understood. Our studies have suggested that CD8+ T-cells may be involved in exerting the therapeutic effects of the drug. We have shown that in response to drug treatment, the GA-specific subset of CD8+ T-cells greatly expands in MS patients and possesses the ability to suppress/kill CD4+ T-cells in vitro. We now demonstrate that GA also induces a robust CD8+ T-cell response in the mouse model. Importantly, GA treatment is ineffective in ameliorating EAE in mice deficient in CD8+ T-cells or MHC Class I, indicating that pathways involving only CD4+ T-cells and APCs bearing MHC Class II are insufficient to mediate protection. GA-induced CD8+ T-cells transferred into wild-type or CD8-deficient mice restore disease suppression. Induction of GA-induced regulatory CD8+ T-cells requires indoleamine 2,3-dioxygenase (IDO) and their function is dependent on IFNγ, perforin, and MHC Class I. These studies demonstrate an essential in vivo role for cytotoxic/suppressor CD8+ T-cells during GA therapy and identify their potential use as adoptive immunotherapeutic agents.
Baicalein promotes PPAR-β-mediated alternative activation of microglia in alleviating experimental autoimmune encephalomyelitis (164.4)
Authors: Xu Jingwei , Zhang Yanyun 
Published: January 2023

Abstract
Microglia, when induced to an alternatively activated state, play important roles in cellular immunity and tissue repair. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), alternatively activated microglia (aaMG) exhibit a reduced inflammatory response, confined phagocytosis, and promoted functional recovery of myelin, which together can alleviate EAE. Here we investigated the effect of baicalein (BA), a potent neuroprotective compound, on EAE. BA administration significantly attenuated EAE severity by reducing both inflammatory infiltration and demyelination in the central nervous system. The inhibitory effect of BA was not caused by impaired T cell responses in the periphery. Interestingly, we observed that BA significantly increased the expression of alternative activation-associated genes in microglia. Furthermore, we showed that induction of aaMG by BA is attributable to increased peroxisome proliferator-activated receptor (PPAR)-β transcriptional activity through activation of the PI3K signal. Importantly, BA-induced aaMG showed significant preventive effects in EAE mice. Taken together, these data demonstrate that BA has a potent inductive effect on aaMG through PPAR-β expression in microglia that mediated by PI3K activation, which led to reduced disease severity during EAE disease process. This provides novel insights into a therapeutic modality in MS.
Inhibition of activated protein C dramatically attenuated experimental autoimmune encephalomyelitis (164.9)
Authors: Alabanza Leah , Bynoe Margaret 
Published: January 2023

Abstract
Activated Protein C (APC) is an anticoagulant that is involved in the complex two-way interactions between the coagulation and immune systems. APC is widely known to be anti-inflammatory; most notably it has been clinically developed for treatment of severe sepsis. The anti-inflammatory properties of APC include conferring endothelial barrier protection, thus limiting the extravasation of immune cells into tissues. Given that the major pathological component of multiple sclerosis and its mouse model, experimental autoimmune encephalomyelitis (EAE), is the extravasation of autoreactive immune cells in the central nervous system (CNS) due to blood brain barrier (BBB) dysfunction, we investigated whether APC can affect the progression of EAE. We saw that blocking endogenous APC during EAE resulted in considerable immune cell infiltration in the CNS. Interestingly, however, these mice exhibited mild to no outward signs of EAE as assessed by paralysis severity. The anti-APC treated mice also had significantly higher percentage of CD4+Foxp3+ cells both in the CNS and in the periphery compared to controls. Moreover, the cytokine profile of leukocytes from the anti-APC mice was skewed to T helper-2, which is known to be protective in EAE. These data show that lowered APC levels during EAE can lead to divergent effects on EAE pathogenesis, specifically leading to increased BBB dysfunction while simultaneously inducing immunological conditions that are non-pathogenic in EAE.
Administration of a vaccine composed of dendritic cells pulsed with premalignant oral lesion lysate stimulates Th1 and Th17 immunity in mice bearing carcinogen-induced premalignant oral lesions. (165.13)
Authors: De Costa Anna-Maria , Walker David , Schuyler Corinne , Young Rita 
Published: January 2023

Abstract
The use of dendritic cell (DC) vaccines as treatment for malignancy is complicated by the immune suppression often exhibited in the presence of solid carcinomas such as head and neck squamous cell carcinoma (HNSCC). The goal of this study is to determine if an immune response can be elicited by administering a DC vaccine during the premalignant stages of HNSCC, prior to development of immune suppression. Mice treated with the carcinogen 4NQO in drinking water develop premalignant oral lesions which progress to HNSCC. As previous studies demonstrated that premalignant lesions and HNSCC overexpress common tumor antigens, BM-derived DCs were pulsed with premalignant lesion lysate (DCpm) and administered to 4NQO-treated mice exhibiting premalignant lesions. Lymphocytes were then isolated and tested for response to antigenic challenge. The levels of Th1, Th17, and to a lesser extent, Th2 cytokines, were increased in supernatant of unchallenged lymphocytes from DCpm-vaccinated mice compared to controls. In response to premalignant and HNSCC challenge, lymphocytes from DCpm-vaccinated mice released greatly increased levels of Th1 cytokines than control lymphocytes, while levels of Th2 cytokines released by control lymphocytes increased to, or near to, levels released from DCpm-vaccinated mouse lymphocytes. This suggests that DCpm vaccination of 4NQO-treated mice stimulates the development of Th1 immunity that may be specific to premalignant and HNSCC antigens.
Exposure to abnormal self antigens during non-malignant events may provide immunological defense against tumors (165.15)
Authors: Iheagwara Uzoma , Beatty P. , Chan Su-Wan B. , Finn O. 
Published: January 2023

Abstract
Antibodies and T cells specific for several tumor associated antigens exist not only in cancer patients but also in healthy individuals. We hypothesize that non-malignant events such as viral infections elicit abnormal expression of self antigens on infected cells and specific immune memory for those antigens. Abnormal expression of the same antigens on tumor cells triggers specific immune responses and provides anti-tumor immunosurveillance. We are testing this hypothesis by examining changes in expression of known tumor associated antigens MUC1 and cyclin B1 during influenza virus infection of MUC1 transgenic mice. We found increased MUC1 and cyclin B1 expression in acutely infected lung tissue collected three days post infection. Furthermore, MUC1 became hypoglycosylated, the form found on cancer cells. Importantly, we found increased MUC1-specific and cyclin B1-specific antibodies in serum from mice post-infection compared to pre-infection. These antigens are likely to be representative of a much larger number of normal cell molecules that undergo changes in expression and induce an immune response important for cancer immunosurveillance. To address this, post-infection serum was blotted against tumor lysate separated by SDS-PAGE and compared to serum from uninfected mice. We found a marked increase in reactivity with several tumor proteins. In future experiments we will correlate immunity to specific antigens with cancer immunosurveillance.
Regulatory mechanism of Axl-mediated lymphotoxin expression in cancer cells (165.24)
Authors: Song Min-Ji , Lee Eun-Hee , Kang Hyung-Sik 
Published: January 2023

Abstract
We investigated the regulatory mechanism of Axl receptor tyrosine kinase-mediated lymphotoxin (LT) expression. LT expression was markedly downregulated in various cancer cells that over-expressed Axl, but it was increased by siRNA of Axl. Axl-/- mice showed upregulated LT expression in different tissues compared to wild type mice. Blockade of LT signaling resulted in the suppression of apoptosis in these cancer cells, which was further promoted by Axl silencing. Upon triggering of Axl signaling, the activation of PI3K/AKT signaling was induced, but the transcriptional activation of NF-κB was inhibited. These data suggested that Axl suppressed LT expression through NF-κB transcriptional inactivation via PI3K/AKT signaling pathway in cancer cells.
Progressive abrogation of early anti-tumor immunity by dendritic cells provides opportunities for novel diagnostic interventions (165.25)
Authors: Scarlett Uciane , Rauwerdink Adam , Rutkowski Melanie , Martinez Diana , Fields Jennifer , Gonzales Jorge , Fiering Steve , Conejo-Garcia Jose 
Published: January 2023

Abstract
We have generated an inducible genetic model of ovarian carcinoma that leads to terminal disease and recapitulates the immune microenvironment of human tumors. Our model progresses through a phase of dynamic equilibrium that keeps tumor expansion in check for the first 4 weeks, followed by a phase of exponential growth from ~D40-D60 (evasion phase). Our inducible system reveals that dendritic cells, with enhanced endocytic pathways, accumulate at primordial ovarian cancer lesions and drive early anti-tumor immune responses. The immunostimulatory phenotype of tumor-associated dendritic cells is progressively impaired as the disease advances, so that the evasion phase coincides with the exponential accumulation of immunosuppressive dendritic cells. Taking advantage of the spontaneous homing of dendritic cells (with enhanced endocytic activity) to solid tumor masses, we have been able to detect magnetic nanoparticle-derived signals specifically at tumor locations before they become macroscopically visible. We have shown that inflammatory leukocytes function is progressively impaired at tumor locations, which unveils a strategy for early diagnosis.
The effects of 1,25-dihydroxy vitamin D3 on tumor-associated immunosuppression in squamous cell carcinoma of the head and neck. (165.29)
Authors: Walker David , Reeves Travis , De Costa Anna-Maria , Schuyler Corinne , Young M. Rita 
Published: January 2023

Abstract
Head and neck squamous cell carcinoma (HNSCC) evades the host immune system via several mechanisms. In HNSCC patients, 1,25-dihydroxy vitamin D3 (vitamin D3) promotes differentiation of CD34+ progenitor cells into antigen-presenting cells. However, the downstream immune effects of vitamin D3 have not been well-characterized. This is particularly true with respect to systemic versus intra-tumoral effects. The objective of this study is to evaluate the role vitamin D3 in modulating tumor-associated immunosuppression. To compare the peripheral and local immune status of vitamin D3 treatment, we analyzed immune mediator levels in plasma and tissue samples from normal controls, HNSCC patients, and HNSCC patients treated with vitamin D3. Vitamin D3 treatment results in a systemic increase in Th2-associated cytokines, IL-6 (p-value = 0.005), IL-8 (p-value = 0.01), and IL-10 (p-value = 0.005) as compared to untreated HNSCC patients. However, this trend is reversed in tumor homogenates, suggesting systemic markers may not accurately reflect the immunologic status of the tumor environment. Furthermore, inflammatory systemic cytokines IL-2 (p-value = 0.04) and IFN-γ (p-value = 0.05) are increased compared to tumor controls, with a concomitant increase in the pro-tumor mediators GM-CSF (p-value = 0.02 ) and VEGF (p-value = 0.02). These findings are surprising, as treatment with vitamin D3 fails to induce a systemic Th1 response thought to be responsible for anti-tumor activity.
Antigen immunoselection as a mechanism of cancer immunoediting (165.3)
Authors: Matsushita Hirokazu , Vesely Matthew , Uppaluri Ravindra , Schreiber Robert 
Published: January 2023

Abstract
Cancer immunoediting is the process wherein the immune system not only protects against tumor development but also promotes outgrowth of tumors with reduced immunogenicity. Although we and others identified several key immune components that participate in this process, we know very little about the targets of cancer immunoediting. In this study we used a highly immunogenic methylcholanthrene induced sarcoma cell line (d42m1) to ask whether tumor antigens can be immunoediting targets. Like most unedited MCA sarcomas, d42m1 cells form tumors when transplanted into immunodeficient mice but are rejected in naive syngeneic wild type (WT) mice. We identified two antigens of d42m1 by expression cloning: a point mutant of spectrin-β2 and a point mutant of M-phase phosphoprotein 8 (MPP8). In WT mice, d42m1 occasionally produces escape variants lacking mutant spectrin-β2 but maintaining expression of mutant MPP8 that can form tumors in naive WT mice. Enforced expression of mutant but not WT spectin-β2 into escape variant cell lines converted them into regressors. Analysis of the parental d42m1 cell line revealed that only 80% of d42m1 clones expressed mutant spectrin-β2 whereas 100% expressed mutant MPP8. Only spectrin-β2 expressing d42m1 clones were rejected in WT mice. Thus, mutant spectrin-β2 is not only the major rejection antigen of d42m1 sarcoma cells but is the target of a cancer immunoediting immunoselection process that facilitates tumor escape from immune control.