bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative evaluation of biomarkers to assess efficacy of immunotherapy in inflammatory diseases (52.7)
Authors: Meno-Tetang Guy , Berges Alienor , Gisbert Sophie , Austin Daren 
Published: January 2023

Abstract
Background and aims: Clinical endpoints of disease activity, such as the Crohn’s disease activity index or the ulcerative colitis activity index are highly subjective and variable scales. To our knowledge, no systematic analysis of the quantitative relationship between degrees of alteration of biomarkers and the likelihood of relapse and remission following drug treatment is available in the literature. The objective of this work was to identify biomarkers that are predictors of drug efficacy and that could be used to optimize combination therapies. This work focused on immunomodulatory agents that target T-lymphocytes and cytokines. Methods and outcome: Several databases were searched up to early 2011. We limited our search to randomized clinical trials lasting as least 8 weeks for induction of remission and 52 weeks for prevention of relapse. Time-course of biomarkers in serum or urine and clinical endpoints were digitized in order to retrieve data. A quantitative analysis was performed only for drug that affected biomarkers and clinical endpoints. We investigated the correlation between the level of modulation of biomarkers and clinical scores. Techniques such as principal component analysis, multiple regression, linear and nonlinear regression were applied. In this systematic review of more than 150 articles, we present information relating to the quantitative predictability of biomarkers for relapse and remission of treatment with small molecules and biologics.
Naturally occurring MHC class I restricted TCRs effectively redirect human T regulatory cells to suppress high affinity, polyfunctional CD8 T cell responses (52.8)
Authors: Riley James , Plesa Gabriela , Lingjie Zheng , Zhao Yangbing , Jakobsen Bent 
Published: January 2023

Abstract
Because most autoimmune diseases exist in the periphery, we investigated whether MHC class I restricted TCRs could be used to re-direct expanded human Tregs in order to better target engineered Tregs to the site of the aberrant immune response. By taking advantage of a series of HLA-A2 restricted TCRs that recognize the same peptide-MHC class I (pMHC) with varying affinities, we observed augmenting TCR affinity had no effect on the ability of Tregs to function. In fact, MHC class I restricted TCRs that had limited activity in CD4+ T effector cells (Teff) were fully able to suppress the expansion of highly functional CD8 T cells expressing a high affinity TCR. These studies demonstrate that Tregs expressing naturally occurring, introduced MHC class I restricted TCRs have potent suppressive activity and further highlight the fundamental differences that exist between effector and regulatory T cells.
Novel antigen discovery by proteome-wide screening of CD4 and CD8 T cell epitopes using P. falciparum as a model (53.14)
Authors: Doolan Denise , Douradinha Bruno , Roddick Joanne , Robinson Leanne , Taraika Jack , Mark Danga , Rarau Patricia , Mueller Ivo , Peters Bjoern , Sidney John , Sette Alessandro 
Published: January 2023

Abstract
For many complex pathogens, the targets of cellular immunity are largely unknown and correlates of protection after exposure or immunization are unclear. A major challenge for rational vaccine development is to identify the key antigens and epitopes targeted by protective immune responses. Using malaria as a model, we are addressing this problem using an integrated approach that incorporates bioinformatic predictions, HLA supertype considerations, high-throughput MHC peptide binding assays, and cellular assays. Antigens and epitopes can be prioritized on the basis of frequency and magnitude of immune responses, and responses to novel proteins ranked against characterized antigens already in clinical development. This strategy has allowed us to identify a number of novel immunoprevalent target antigens from P. falciparum that are recognized frequently and in the context of multiple genetic restrictions. Many of these antigens are more immunogenic than antigens identified historically, and at least one has been confirmed as a target of cross-species protection. These antigens and their epitopes represent promising candidates for next generation vaccine development. Additionally, data provide important information on the patterns of immunodominance following exposure to a complex pathogen.
Heterologous immunization induces potent anti-SIV immunity with qualitative and quantitative improvements (53.22)
Authors: Tang Xian , Chen Zhiwei 
Published: January 2023

Abstract
Background: The live replication-competent modified vaccinia virus Tiantan (MVTT) is an attractive vaccine vector. In this study, we constructed a recombinant MVTT expressing SIV Gag-Pol and Env (MVTT-SIV) and compared its efficacy for inducing antigen-specific immunity when administrated in different routes with or without rAd5-based vaccine encoding the same antigens (rAd5-SIV). Methods: MVTT-SIV was tested for its immunogenicity in mice administered homologously by a prime-boost strategy or heterologously in combination with rAd5-SIV. The prime routes included intranasal (IN), sublingual (SL), oral, mixed (mix of the previous three musocal routes) or intramuscular (IM) injection. All groups received IM boost. Result: Mice given heterologous boost produced significantly greater SIV specific T cell and Gag-specific antibody responses than homologous boost groups. Besides, heterologous immunization generated much higher level of neutralizing antibodies, despite of the lower titers of Env-specific binding antibodies according to Elisa assay. Moreover, the immunogenicity of MVTT-SIV given by mixed route followed by rAd5-SIV intramuscular boost was unique in terms of anti-SIV cellular and humoral immunity. Conclusion: Heterologous immunization induces potent anti-SIV Immunity with improvements in quality and quantity. The combination of MVTT-SIV mixed prime and rAd5-SIV intramuscular boost may be an effective and protective vaccination strategy in further studies.
Generation of human CD154 BAC transgenic mice to explore therapy for X-linked Hyper-IgM syndrome (53.6)
Authors: Cron Randy , Genin Anna 
Published: January 2023

Abstract
XHIM is a congenital immunodeficiency from inadequate CD154 expression on activated CD4 T cells. The only curative therapy is bone marrow transplantation. Recently, lentiviral gene therapy approaches for XHIM have been explored. However, beyond the CD154 transcriptional promoter, the regulatory cis-elements required for cell type-specific, activation dependent, and time-limited expression of CD154 are unclear. We generated a hCD154 BAC transgenic mouse spanning ~143 kb upstream, ~11 kb of the intact hCD154 gene, and ~20 kb of downstream DNA sequence. This BAC contains all known CD154 regulatory elements (promoter, enhancers, 3’ UTR). Confirmation of the intact BAC sequence was determined by DNA sequencing at intervals throughout the BAC. hCD154 transgene expression was detected by flow cytometry. After polyclonal activation of splenocytes, hCD154 is restricted to CD4 T cells (absent on B and CD8 T cells). Activated CD4 T cells co-express mCD154 and hCD154. Like mCD154, hCD154 expression is activation dependent but displays a slightly delayed and prolonged expression. Human CD4 T cells activated for 6 hours and irradiated to prevent division stimulate mCD40 expressing B cells (EdU incorporation), and this is inhibited by anti-hCD154 antibody. By deletion or mutation of known cis-regulatory elements in the hCD154 BAC construct, we will test the minimal requirements for optimal hCD154 expression to stimulate CD40+ cells. This will help design gene therapy vectors for XHIM.
In vivo molecular imaging for a nasal botulism vaccine in mice and nonhuman primates (53.8)
Authors: Yuki Yoshikazu , Nochi Tomonori , Harada Norihiro , Katakai Yuko , Mejima Mio , Tokuhara Daisuke , Kurokawa Shiho , Takahashi Yuko , Shibata Hiroaki , Kohda Tomoko , Kozaki Shunji , Tsukada Hideo , Kiyono Hiroshi 
Published: January 2023

Abstract
Nasal administration is an effective route for a needle-free vaccine. However, safety concerns were raised by the potential of nasally administered antigens to reach the central nervous system. We tested the real-time quantitative tracking of a nasal vaccine candidate for botulism, which is a recombinant nontoxic fragment of botulinus toxin A (BoHc/A), by using a newly established in vivo imaging method, [18F]-labeled BoHc/A-positron emission tomography (PET). This method provides results that are consistent with direct counting of [18F] radioactivity or the traditional [111In]-radiolabel method in dissected tissues of mice and non-human primates. In addition, no deposition of BoHc/A in the cerebrum and olfactory bulb was found after nasal administration of [18F]-BoHc/A in mice and non-human primates. We also established a real-time quantitative profile of elimination of this nasal vaccine candidate and demonstrated that it induces highly protective immunity against botulism in non-human primates. These results demonstrate a new way to use in vivo imaging for safety evaluation of nasal vaccines.
Effect of chronic ingestion of a histamine H1 receptor antagonist on the progression of atherosclerosis in the apolipoprotein-E null mouse (54.1)
Authors: Vimala Raveendran Vineesh , Tan Xiaoyu , Sweeney Matthew , Stechschulte Daniel , Dileepan Kottarapat 
Published: January 2023

Abstract
Histamine (HIS) is a known modulator of vascular functions and its levels are elevated in coronary arteries in ischemic heart disease and variant angina. We have shown that HIS, acting via H1 receptors (H1R), stimulates the expression of IL-6, COX2, TLR2 and TLR4 in human endothelial cells. The study tested the effect of chronic ingestion of cetirizine (CET), an H1R antagonist, on atherosclerosis progression in ApoE-/- mice. CET containing water (5 mg/L) or plain water was supplied ad libitum to male ApoE-/- mice for 3 and 5 months, after which 24h urine, blood, and aorta were collected. The lesion coverage in the descending aorta and intima/media thickness at aortic root were quantified. The aortic tissue was also analyzed for COX1, COX2, H1R, IL10, Egr1 and MCP2 mRNA expression and for macrophages (MAC3+), T lymphocytes (CD3+) and mast cells (CD117+). A significant increase in plaque thickness was noted in CET-treated mice at 3 months but not at 5 months. Aortic lesion coverage between control and CET groups remained unchanged at 3 and 5 months. PGI2 and TXA2 indices in urine at 3 months showed reduction in PGI2/TXA2 ratio. RT- PCR data showed significantly decreased expression of COX1 and H1R but no changes in other genes. The lesion coverage, urinary prostanoid levels, gene expression, serum lipids, and MAC3+, CD3+ and CD117+ cell numbers were unchanged at 5 months. The results suggest that long-term use of CET does not alter atherosclerosis progression in ApoE-/- mice.
Identification of novel small molecule inducers of endothelium-driven innate immunity (54.10)
Authors: Kibbie Jon , Whang Zhiming , Kwon Ohyun , Modlin Robert , Cruz Daniel 
Published: January 2023

Abstract
The endothelium plays a critical role in promoting inflammation in cardiovascular disease and other chronic inflammatory conditions. Conversely, an augmented immune response can be protective against microbial pathogens and in cancer immunotherapy. Many small molecule screens have sought to identify agents that prevent endothelial cell activation. Yet, small molecule screens to identify agents that induce endothelial cell activation have not been reported. In this regard, a bioassay was developed which identifies activated endothelium by its capacity to trigger MIP1 beta from primary monocytes. Subsequently, a 642 compound library of 39 distinctive scaffolds generated by diversity oriented synthesis was screened for small molecules that activated the endothelium. From the identified inflammatory compounds, 96 analogs of one particular class of compounds were efficiently prepared by solid phase split-and-pool synthesis. Structure-function analysis combined with transcriptional profiling of active and inactive analogues identified inflammatory gene networks induced exclusively by the active compound. The identification of a family of chemical probes that augment innate immunity through endothelial cell activation provides a framework for understanding gene networks involved in endothelial inflammation as well as the development of novel endothelium-driven immunotherapeutic agents.
Liver sinusoidal endothelial cells undergo apoptosis during sepsis, leading to organ dysfunction. (54.13)
Authors: Hutchins Noelle , Borgerding Joshua , Chung Chun-Shiang , Ayala Alfred 
Published: January 2023

Abstract
Sepsis is the leading cause of death in critically ill patients, and treatment options are limited. Our laboratory studies polymicrobial sepsis in murine models, and uses the liver as a model organ to investigate the disease’s pathophysiology. The liver, characterized as an immune tolerant organ, is susceptible to septic induced inflammation. We have previously reported that there is a twofold increase in the number of liver CD8+ T cells, 24 hours following cecal ligation and puncture (CLP—a surgical procedure that generates sepsis in mice). Since activated T lymphocytes must transverse the endothelium to reach the site of infection, it is possible that they directly interact with LSECs, and mediate liver injury through Fas-mediated apoptosis. This led us to hypothesize that as CD8+ T cells directly interact with LSECs, endothelial cell dysfunction occurs. Our preliminary results indicate that septic liver CD8+ T cells have cytotoxic effects on endothelial monolayer integrity, and release pro-inflammatory cytokines when directly co-cultured with CRL-2167, a murine endothelial cell line. We have also observed through flow cytometry that LSECs (CD146+/CD45- and CD31+/CD45- populations) have an increased expression of CD54 (ICAM-1), Fas, and Annexin V staining in vivo. These data suggest that CD8+ T cells directly interact with LSECs, alter the tolerance capacity of LSECs, and potentially kill LSECs through the Fas-FasL system, ultimately leading to liver organ injury in sepsis.
CD11b+/Gr-1int monocytic myeloid derived suppressor cells contribute to high-fat induced inflammation and delayed tolerance in mouse liver (54.15)
Authors: Xie Qifa , Zhang Jingwen , Ghare Smita , Barve Shirish , McClain Craig 
Published: January 2023

Abstract
Myeloid derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells with universal expansion in nearly all inflammatory conditions. This study investigated the accumulation of MDSC in chronic inflammation and tolerance of obesity-related fatty liver disease. We found that the expansion of MDSC, specifically associated with the monocytic MDSC (M-MDSC): CD11b+Gr-1intLy6G-Ly6Chigh in the liver of B6 mice fed a high-fat diet contributes to liver inflammation and tolerance. M-MDSCs isolated from the liver of obese mice are more easily activated by way of Toll-like receptor (TLR4) stimulation resulting in inflammatory cytokine expression, and were functional MDSCs, readily inhibiting T cell proliferation in vitro dependent on cell-cell contact between MDSCs and T cells. The rapid accumulation of M-MDSC also contributed to delayed ConA tolerance in obesity-related fatty liver disease. M-MDSCs isolated from the liver of obese mice developed with ConA tolerance induce less liver regulatory T (Treg) cell expansion and less suppressing T cell proliferation in vitro. Experiments using mice depleted of Gr-1, or M- MDSC adoptive transfer demonstrated the important role of M-MDSC in liver inflammation and tolerance. These data unveil that M-MDSCs play an essential negative feedback function in liver immune homeostasis.
Role for NADPH oxidase in macrophage clearance of apoptotic cells (54.2)
Authors: Zeng Melody , Dinauer Mary 
Published: January 2023

Abstract
Ingestion of apoptotic neutrophils by macrophages (efferocytosis) is important for both neutrophil (PMN) homeostasis and resolution of tissue inflammation following infection or injury. In this study, we demonstrated that apoptotic PMN triggered activation of the NADPH oxidase in engulfing mouse macrophages, leading to oxidant production in phagosomes containing PMNs (also called efferosomes). Consistently, immunofluorescent staining revealed accumulation of gp91phox, a membrane-associated subunit of the oxidase, on the efferosome membrane. Examination of MyD88-/- macrophages illustrated a partial requirement for MyD88 in apoptotic PMN-mediated activation of the oxidase. To delineate the role of the NADPH oxidase in degradation of PMNs by macrophages, we observed that in macrophages from gp91 phox -/- mice, which do not generate oxidants during efferocytosis, lysosome-efferosome fusion occurred at a slower rate, thus implicating the importance of oxidants in efferosome maturation. Degradation of ingested PMNs within macrophages was further monitored by staining PMN myeloperoxidase (MPO), which was much more prominent in gp91phox-/- macrophages 6 hours after efferocytosis compared to WT macrophages, suggesting slower degradation in the absence of oxidants. Taken together, our data support that, in addition to its well-characterized anti-microbial function, macrophage NADPH oxidase may be an integral player in PMN clearance to facilitate the resolution of inflammation.
Recovery of wound healing in immunosuppressed mice by L-Arginine topical treatment (54.6)
Authors: Jeronimo Marcio , Nóbrega Yanna , Souza Ana Camila , Siqueira Isaque , Souza Nathalia , Amorim Rivadávio , Cavalcanti Neto Florencio , Borim Maria , Bocca Anamélia 
Published: January 2023

Abstract
The wound healing is a coordinated mechanism involving soluble and insoluble mediators and immune response activation. Some pathological conditions are related with this mechanism, like immunosuppression, which interferes with important mechanisms of tissue repair like healing phase. This study aims to evaluate the capacity of immunosuppressed mice to wound healing after L-arginine supplementation. Swiss mice received 25 mg/kg of hydrocortisone for two consecutive days intraperitoneally. To evaluate the wound healing, a lesion was made with a 5 mm diameter biopsy punch. The animals received daily topical 10% L-arginine in glycerin and were killed 7 days post lesion (dpl). Animals treated only with the vehicle were used as control. Fragments of the healing process area were collected for immunohistochemistry analysis for CD31, TGF-b and iNOS. It was also performed a qRT-PCR analysis of the healing tissue for IL-1α, TNF-α and CCR5 genes. We found an increased expression of CD31 molecule in the animals treated with L-arginine and decreased of iNOS expression compared with the control group. The transcriptions of CCR-5, IL-1 and TNF-α in treated animals were increased. These results indicate enhanced neovascularization and cell migration, promoting the inflammatory phase recoverment and improving the repair in the group receiving the treatment. Our work demonstrates the modulation by L-arginine in the wound healing process; it can be a new approach as an adjuvant treatments.
TNFRSF25 mediated in vivo expansion of regulatory T-cells reduces immunopathology in a chronic model of allergic lung inflammation (55.4)
Authors: Tsai Matthew , Schreiber Taylor , Wolfe Dietlinde , Podack Eckhard 
Published: January 2023

Abstract
TNF receptor super family member 25 (TNFR25, DR3) signaling by agonistic antibody (4C12) has been shown to effectively expand CD4+FoxP3+ regulatory T-cells (Treg) in vivo, and prevent acute allergic lung inflammation, a model for asthma. Here we investigate if Treg expansion by TNFR25 stimulation can reduce lung immunopathology associated with chronic allergic lung inflammation. After antigen priming (Ovalbumin/ALUM) and three weeks of antigen aerosol exposure (Ovalbumin in Saline), TNFR25 agonistic antibody given during an aerosol-free period is able to expand Tregs in the peripheral blood and in the lungs as previously reported. After two additional weeks of antigen aerosol exposure, and at a time when TNFR25-expanded Tregs have almost contracted to baseline levels, 4C12 treated animals remained protected from chronic lung immunopathology. Specifically, TNFR25 agonistic antibody treated mice, as compared to IgG treated controls, showed reduced eosinophils in the bronchoalveolar lavage fluid, reduced expression of Th2 cytokines (IL-4, IL-5, IL-13), CCL11 (eotaxin-1), and TNF-a, and reduced mucus production in the bronchial epithelium. These results indicate that TNFR25 mediated expansion of Tregs after established pulmonary inflammation, is able to generate a sustained suppression of chronic lung immunopathology, which may be mediated by antigen-specific Tregs.
Innate imprinting of resident alveolar macrophages by a preceding allergic bronchial inflammation increases the inflammatory TLR-reactivity through an enhanced MyD88-independent signaling and the type I interferon, IFN-β. (55.5)
Authors: Naessens Thomas , Vander Beken Seppe , De Koker Stefaan , Lienenklaus Stefan , Van Rooijen Nico , Grooten Johan 
Published: January 2023

Abstract
Resident alveolar macrophages (rAM) play an important regulatory role in limiting excessive inflammatory responses in the respiratory tract. In a mouse model of allergic asthma we identified a new autofluohigh CD11c+ CD11b+ DEC205+ F4/80+ rAM population residing in the airways following the clearance of a prior allergic bronchial inflammation. Compared to naïve rAM, post-inflammation rAM feature a reduced basal phagocytosis along with an increased in vitro inflammatory response to LPS. Especially genes dependent for expression on the MyD88-independent signaling pathway and the type I interferon, IFN-β, showed strongly increased expression levels compared to the naïve rAM. A preferential enhancement of MyD88-independent signaling in post-inflammation rAM was also observed after in vivo LPS-challenge and resulted in a differential response pattern to TLR-3 and TLR-7 ligands. Using CD45 chimeric mice and intratracheal instilled fluorescent microparticles to distinguish resident from elicited AM, we observed a rapid and near complete disappearance of naïve rAM during allergen challenges. Furthermore, we showed that this inflammation-induced rAM turnover is a crucial event in the development of the post-inflammation rAM phenotype. This novel mechanism of innate imprinting may contribute to the increased sensitivity of the post-inflammation lung to inflammatory insults.