bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted chemotherapeutic delivery to disseminated lymphoma tumors via adoptive transfer of drug nanoparticle-carrying T cells (53.25)
Authors: Huang Bonnie , Irvine Darrell 
Published: January 2023

Abstract
Despite being sensitive to a wide variety of cytotoxic drugs, lymphomas often require high doses of systemically administered chemotherapy to eliminate disseminated tumors, causing toxicity. We hypothesized that the efficacy of chemotherapy could be enhanced while greatly reducing off-target toxicity if autologous lymphocytes were used as carriers to target drugs to the lymphoid tissue sites where lymphomas home. To test this concept, we prepared controlled release lipid nanoparticles (NPs) loaded with the potent topoisomerase I poison SN-38. These NPs were covalently conjugated to the plasma membrane of in vitro-activated primary T-cells that retained CD62L expression for lymph node homing. In vitro co-culture of T-cells and murine Eu-myc lymphoma cells with SN-38-releasing NPs showed that lymphoma cells were much more sensitive to SN-38 than T-cells. T-cells with plasma membrane-conjugated SN-38-releasing NPs were then used as live vectors to transport NPs systemically into lymphoid organs where lymphoma cells are enriched. NP-decorated T-cells retained and delivered NPs to Eu-myc lymphoma tumors in vivo as early as one day post-adoptive transfer. Therapy studies in a transplanted Eu-myc lymphoma model indicated that high numbers of SN-38 NP-functionalized T cells can rapidly reduce tumor burden in multiple anatomical sites. These results suggest that autologous lymphocytes may be useful as chaperones for targeted delivery of chemotherapy-loaded NPs to lymphoid tumors.
CϵmX peptide-carrying HBcAg virus-like particles induced antibodies that down-regulate mIgE-B cells (53.7)
Authors: Lin Chien-Jen , Nien-Yi Chen Nien-Yi , Chen Jiun-Bo , Lu Chien-Sheng , Hung Alfur Fu-Hsin , Shiung Yu-Yu , Wu Pheidias C. , Pan Rong-Long , Chang Tse Wen 
Published: January 2023

Abstract
Type-I hypersensitivity reactions play a critical role in the pathogenesis of various allergic diseases. The successful development of the anti-IgE antibody, omalizumab, has validated IgE as an effective therapeutic target for the treatment of various IgE-mediated allergic diseases. Two research groups have reported that mAbs specific for certain parts of CϵmX, a domain of 52 aa residues in human membrane-bound IgE (mIgE), can cause the lysis of mIgE-B cells by apoptosis and antibody-dependent cellular cytotoxicity (ADCC). Herein, we explore the virus-like particles (VLPs) formed by hepatitis B virus core antigen (HBcAg) that harbors the entire CϵmX peptide or its fragments as immunogens for inducing anti-CϵmX antibodies. Mice immunized subcutaneously with some of these immunogens produce antibodies that bind to recombinant CϵmX-containing human IgE.Fc in ELISA and Western blot analysis and to genetically engineered human mIgE-expressing Ramos B cell line in fluorescence flow cytometric assays. The IgG antibodies purified from the sera of immunized mice could cause the apoptosis of mIgE-expressing Ramos cells through a BCR-dependent caspase pathway. Furthermore, the IgG mediated ADCC on human mIgE-expressing murine B cell lymphoma A20. These results suggest that HBcAg-CϵmX peptide immunogens warrant further investigation as a therapeutic modality for modulating IgE in patients with IgE-mediated allergic diseases.
Engineering an RNA virus as a vector for targeted cellular immunity (53.8)
Authors: Pavelko Kevin , Bell Michael , Allen Kathleen , Hansen Michael , Pease Larry 
Published: January 2023

Abstract
One limitation to the development of targeted tumor immunity is the availability of safe vectors that can drive strong T-cell responses capable of eradicating tumors. We have designed viral vectors using Theiler’s murine encephalomyelitis virus (TMEV) that effectively inhibit melanoma outgrowth. By cloning the TMEV genome into a eukaryotic expression vector that can easily be manipulated we were able to generate several novel tumor specific virus vaccines. We find that incorporation of defined MHC class I epitopes into sites within the leader protein of the virus can drive strong CD8+ T-cell responses against these target peptides. Further, we find that the site of incorporation can change the elicited cytokine profile and the virulence of the virus. Incorporation of the ovalbumen peptide after the third amino acid of the L protein (p3) generates a strong IFNβ response, whereas insertion within the downstream XhoI restriction site elicits a strong IL6 response similar to wild-type TMEV. Further, the p3 virus is not lethal to RAG-deficient mice, where the XhoI and wild-type TMEV virus are. However, p3 virus persists and kills IFNα/β receptor-deficient mice, suggesting that innate immune responses are responsible for viral clearance. In spite of these differences the p3 and XhoI viruses can stimulate antigen specific T-cell responses and inhibit tumor outgrowth equivalently, demonstrating the efficacy of TMEV and its potential as a therapeutic intervention.
Platelet-associated CD40/CD154 mediates remote tissue damage after mesenteric ischemia/reperfusion injury (54.1)
Authors: Kannan Lakshmi , Lapchak Peter , Ioannou Antonis , Rani Poonam , Dalle Lucca Jurandir , Tsokos George 
Published: January 2023

Abstract
Several innate and adaptive immune cell types participate in ischemia/reperfusion induced tissue injury. Amongst them, platelets have received little attention as contributors in the process of tissue damage after ischemia reperfusion (I/R) injury. It is currently unknown whether platelets participate through the immunologically important molecules including, CD40 and when activated, CD154 (CD40L), in the pathogenesis of I/R injury. We hypothesized that constitutive expression of CD40 and activation-induced expression of CD154 on platelets mediate local mesenteric and remote lung tissue damage after I/R injury. Wild type (WT; C57BL/6J), CD40 and CD154 deficient mice underwent mesenteric ischemia for 30 minutes followed by reperfusion for 3 hours. WT mice subjected to mesenteric I/R injury displayed both local intestinal and remote lung damage. In contrast, there was significantly less intestinal damage and no remote lung injury in CD40 and CD154 deficient mice when compared to WT mice. Platelet-depleted WT mice transfused with platelets from CD40 or CD154 deficient mice failed to reconstitute remote lung damage. In contrast, when CD40 or CD154 deficient mice were transfused with WT platelets lung tissue damage was re-established. Together, these findings suggest that multiple mechanisms are involved in local and remote tissue injury and also identify platelet-expressed CD40 and/or CD154 as mediators of remote tissue damage.
Human astrocytes express a novel NLRP2 inflammasome complex activated by extracellular ATP (54.12)
Authors: Minkiewicz Julia , de Rivero Vaccari Juan , Keane Robert 
Published: January 2023

Abstract
Spinal cord injury/brain trauma involves extensive central nervous system loss due to the mechanical insult and to an innate inflammatory response that is, in part, in response to activation by extracellular ATP. The innate immune response is regulated by pattern recognition receptors (PRRs), which include NOD-like receptors (NLR). However, the PRR receptors and signaling cascades regulating innate glial responses to CNS injury remain largely undefined. Here we show for the first time that human astrocytes express NLRP2 inflammasome proteins and these proteins form an inflammasome complex. Treatment of human astrocytes with ATP resulted in a dose-dependent activation of the NLRP2 inflammasome leading to inflammatory caspase-1 cleavage and interleukin-1β (IL-1β) production. ATP induction of the NLRP2 inflammasome was blocked by the pannexin 1 inhibitor, probenecid and by treatment with the P2X7 receptor antagonist, brilliant blue G (BBG). siRNA knockdown of NLRP2 significantly decreased NLRP2 inflammasome activation and caspase-1 activation in response to ATP treatment. Our findings suggest that the NLRP2 inflammasome in astrocytes is an important component of the CNS inflammatory response and may be a therapeutic target to inhibit inflammation induced by CNS injury.
The receptor tyrosine kinase Ron attenuates obesity-induced atherosclerosis progression and liver injury by down-regulating inflammation in ApoE-/- mice (54.16)
Authors: Yu Shan , Xia Mingcan , Xiong Na , Hankey Pamela 
Published: January 2023

Abstract
Obesity and its associated metabolic diseases are leading causes of death worldwide. Obesity increases the likelihood of atherosclerosis, diabetes and hepatic steatosis, which are caused largely by macrophage activation at aorta, adipose tissue and liver, respectively. Macrophages are classified as classical activated macrophages(M1), which are associated with increased inflammatory mediators, and alternative activated macrophages(M2), which are associated with decreased inflammation and tissue repair. Recent studies suggest M2 predominate in non-inflamed tissue in lean animals, while either a switch from M2 to M1 or direct recruitment of M1 in aorta and adipose tissue promotes atherosclerosis and insulin resistance progression. Our previous studies show that the Ron receptor tyrosine kinase, expressed primarily on tissue-resident macrophages, inhibits hallmarks of M1 activation and skews populations towards an M2 phenotype both in vitro and in vivo. Here, we show that the absence of Ron results in increased severity of atherosclerosis and liver injury, which is accompanied by elevated expression of inflammatory markers in aortas and livers in ApoE-/- X Ron-/- mice on a high cholesterol diet. However, we failed to detect significant differences in glucose tolerance or fatty acid metabolism. Our results indicate Ron plays a central role in limiting obesity-induced inflammation and plays a protective role in the progression of atherosclerosis and hepatic steatosis.
Fibrocytes contribute to the increased levels of fibrosis observed in Th2 pulmonary granulomas in TLR9-/- mice (54.18)
Authors: Saito Fumitake , Ito Toshihiro , Burdick Marie , Allen Ronald , Hogaboam Cory , Lukacs Nicholas , Strieter Robert , Kunkel Steven 
Published: January 2023

Abstract
Despite many recent advances in the field, the underlying mechanisms governing pulmonary fibrosis remain poorly understood. We have used an experimental system of fibrotic granuloma development via the embolization of Schistosoma mansoni eggs to the lungs. Egg embolization results in the release of highly antigenic glycoproteins (Schistosoma egg antigen,SEA) that promote a dominant Th2 immune response. We previously demonstrated that in comparison to wild-type mice, TLR9-/- mice showed increased granuloma size and augmented collagen deposition. In the present study, we investigated the mechanisms underlying the fibrotic change of this Th2-driven pulmonary granuloma system, and the contribution of TLR9 signals to this phenomenon. The chemokine receptor/ligand pair CXCR4/CXCL12 has been shown to play an important role in the homing of fibrocytes; these cells express CXCR4 and migrate in response to CXCL12 in a model of bleomycin-induced pulmonary fibrosis. Levels of CXCL12 were higher in the lungs of mice treated with S. mansoni eggs, but there were no difference between wild-type and TLR9-/- mice. Flow cytometry data indicated that TLR9-/- mice showed increased number of CD45+Col I+CXCR4+ fibrocytes in the lungs of TLR9-/- mice treated with S. mansoni eggs in comparison to wild-type mice. Thus, our results suggested that increased fibrocytes may contribute to the increased levels of fibrosis observed in TLR9-/- mice.
TRAF-6 dependent signaling pathway is essential for TNF-related apoptosis-inducing ligand (TRAIL) induces osteoclast differentiation (54.21)
Authors: Hsu Ping-Ning , Liao Hsiu-Jung , Tsai Hwei-Fang 
Published: January 2023

Abstract
Human osteoclast formation from mononuclear phagocyte precursors involves interactions between tumor necrosis factor (TNF) ligand superfamily members and their receptors. Recent evidence indicates that in addition to triggering apoptosis, the TNF-related apoptosis-inducing ligand (TRAIL) induces osteoclast differentiation. To understand TRAIL-mediated signal transduction mechanism in osteoclastogenesis, we demonstrated that TRAIL induces osteoclast differentiation via a Tumor necrosis factor receptor-associated factor 6 (TRAF-6)-dependent signaling pathway. TRAIL-induced osteoclast differentiation was significantly inhibited by treatment with TRAF-6 siRNA and TRAF6 decoy peptides in both human monocytes and murine RAW264.7 macrophage cell lines, as evaluated in terms of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and bone resorption activity. Moreover, TRAIL-induced osteoclast differentiation was also abolished in TRAF6 knockout bone marrow macrophages. In addition to induction of NFATc1, treatment of TRAIL also induced ubiquitination of TRAF6 in osteoclast differentiation. Thus, our data demonstrate that TRAIL induces osteoclastic differentiation via a TRAF-6 dependent signaling pathway. This study suggests TRAF6-dependent signaling may be a central pathway in osteoclast differentiation, and that TNF superfamily molecules other than RANKL may modify RANK signaling by interaction with TRAF6-associated signaling.
Glycogen synthase kinase-3 facilitates Con A-induced IFN-γ-mediated immune hepatic injury (54.24)
Authors: Tsai Cheng-Chieh , Huang Wei-Ching , Chen Chia-Ling , Hsieh Chia-Yuan , Lin Yee-Shin , Chen Shun-Hua , Yang Kao-Chi , Lin Chiou-Feng 
Published: January 2023

Abstract
IFN-γ-mediated inflammation followed by hepatic cell death determines Con A-induced immune hepatic injury. Glycogen synthase kinase (GSK)-3, which acts proapoptotically and is proinflammatory, is also important for facilitating IFN-γ signaling. We hypothesized a pathogenic role for GSK-3 in Con A hepatic injury. Con A stimulation caused GSK-3 activation in the livers of C57BL/6 mice. Inhibiting GSK-3 reduced Con A hepatic injury, including hepatic necrosis and apoptosis, inflammation, infiltration of T cells and granulocytes, and deregulated expression of adhesion molecule CD54. Con A induced hepatic injury in an IFN-γ receptor 1-dependent manner. Con A/IFN-γ induced activation and expression of STAT1 in a GSK-3-dependent manner. GSK-3 facilitated IFN-γ-induced inducible NO synthase, but had limited effects on CD95 upregulation and CD95-mediated hepatocyte apoptosis in vitro. Notably, inhibiting GSK-3 decreased Con A-induced IFN-γ production in both wild-type and IFN-γ receptor 1-deficient C57BL/6 mice. In Con A-activated NKT cells, GSK-3 was also activated and was required for nuclear translocation of T-box transcription factor Tbx21, a transcription factor of IFN-γ, but it was not required for CD95 ligand expression or activation-induced cell death. These results demonstrate the dual and indispensable role of GSK-3 in Con A hepatic injury by facilitating IFN-γ-induced hepatopathy.
The role of macrophages and neutrophils in pulmonary Francisella infection (55.24)
Authors: Steiner Donald , Metzger Dennis 
Published: January 2023

Abstract
Francisella tularensis is the causative agent of tularemia. Due to its ease of dissemination, high lethality, and low infectious dose required for respiratory infection, this bacterium poses a risk as an agent of bioterrorism. Though F. tularensis is believed to be an intracellular pathogen that requires replication within macrophages during respiratory infection, we have found that depletion of alveolar macrophages by intranasal treatment with liposomal Clodronate reduced mean time to death and total survival rates of infected mice. Furthermore, mice with a macrophage-specific insensitivity to interferon-γ (MIIG mice) similarly show heightened sensitivity to pulmonary Francisella infection. Such mice exhibited reduced expression of tumor necrosis factor-α, a potent neutrophil chemoattractant, in lung tissue, and systemic neutrophil depletion resulted in reduced mean time to death and total survival rates. Exogenous interleukin-12 promoted survival and bacterial clearance in mice, but this effect was lost upon neutrophil depletion and in IFN-γ-/- mice. The results suggest that rather than being a required reservoir for bacterial replication, alveolar macrophages are necessary for defense against F. tularensis infection by recruiting neutrophils to the lung, which are the primary cells responsible for clearing the bacterium.
High M-CSF and IL-13 levels are associated with foamy cell expansion in experimental actinomycetoma by Nocardia brasiliensis. (55.27)
Authors: Meester Irene , Rosas-Taraco Adrian , Salinas-Carmona Mario 
Published: January 2023

Abstract
Foamy cells (FC) have been described in various infectious diseases, and can be usurped by intracellular pathogens for survival. In a mouse model of experimental actinomycetoma induced by Nocardia brasiliensis, FC have been observed at day 3 after inoculation, remaining constant during acute inflammation, and expanding in surface area during chronic disease. These FC seem to be monocytes/macrophages and/or dendritic cells (DC) that accumulate lipid droplets upon infection. Our aim was to elucidate the levels of cytokines known to be involved in the differentiation of macrophages or DC (IL-4, IL-13, M-CSF, and GM-CSF). Female BALB/c mice (8-12 wk) were infected with N. brasiliensis in the left hind foot pad and sacrificed at 0, 0.5, 1, 3, 7, 15, 30 and 60 days of infection (n=5). Biopsies of the left foot pads were homogenized in PBS or Trizol to determine the cytokine concentrations at both the protein and the transcript level by means of ELISA and RT-PCR. We found the highest M-CSF and IL-13 levels during chronic inflammation, when the major expansion of CF occurs. M-CSF and IL-13 have been related with the alternative activation of macrophages. In conclusion: high M-CSF and IL-13 levels coincide with the expansion of CF in an experimental model of actinomycetoma.
CXCR3 ligand blockade ameliorates the experimental autoimmune cystitis (EAC) in mice (56.3)
Authors: Singh Udai , Singh Narendra , Singh Balwan , Price Robert , Nagarkatti Mitzi , Nagarkatti Prakash 
Published: January 2023

Abstract
Interstitial cystitis (IC) is a complex disease associated with chronic bladder inflammation that primarily affects women. The symptoms of IC include frequent urinary urgency accompanied by discomfort or pain in the bladder and lower abdomen. The autoimmune mechanisms have an important role in IC pathogenesis and triggered lots of attention after development of autoimmune phenotype experimental autoimmune cystitis (EAC) model, similar to IC with functional and histological alterations confined to the urinary bladder. We report that the serum levels of CXCR3 ligand and local T helper type 1 (Th1) cytokines are elevated in patients with IC as well as in the murine EAC model of IC. We also show that CXCL10 blockade can attenuate the overall clinical score, reverse the development of IC-associated pathogenesis, decrease the local as well as systemic cytokines and CXCR3 and its ligands level. Urinary bladder CD4+ T cell, mast cell, and neutrophil infiltrates are also reduced following anti-CXCL10 antibody (Ab) treatment to mice with IC. We demonstrate that anti-CXCL10 Ab treatment reversed the up-regulated level of CXCR3 ligand mRNA at sites in the urinary bladder. Moreover, the decreased number and percentage of systemic CD4+ T cells in mice with IC reversed back to normal after anti-CXCL10 Ab treatment. Taken together, the present study provides new and important information on a useful animal model for IC and cellular mechanism of CXCR3 ligand mediated amelioration of IC.
Tolerance induction by monoclonal CD3 antibodies is dependent on indoleamine 2,3 dioxygenase (IDO) (56.5)
Authors: Kuhn Chantal , You Sylvaine , Valette Fabrice , Bach Jean-François , Waldmann Herman , Chatenoud Lucienne , Grohmann Ursula 
Published: January 2023

Abstract
Experimental data demonstrated that a short treatment with CD3 antibodies (CD3 Ab) promotes immune tolerance in primed hosts. Successful clinical transfer of this strategy has been achieved in autoimmune diabetes, and on this basis, CD3 Abs are currently under pharmaceutical development. The tolerogenic effect of CD3 Ab evolves in two consecutive phases: a first phase of “induction” during Ab treatment, involving transient T cell depletion as well as antigenic modulation and a second phase of “maintenance” that persists after CD3 Ab clearance and that correlates with the presence of active and transferable tolerance involving TGF-β dependent Tregs. We focused on the causal links relating the “induction” and “maintenance” phases of tolerance using spontaneously diabetic NOD mice and human CD3ϵ transgenic NOD mice, a novel preclinical model that we established. It is well known that abnormalities in dendritic cells (DCs) contribute to autoimmune diabetes in NOD mice, e.g. indoleamine 2,3 dioxygenase (IDO) induction in CD8+ DCs of NOD mice by IFN-γ is defective. Our results show that depletion of DCs or inhibition of IDO during CD3 Ab therapy abrogates the tolerogenic effect. TGF-β has been shown to induce IDO and we reported that remission from diabetes after CD3 Ab therapy is TGF-β-dependent. We propose that CD3 Ab mediated tolerance ensues from a local immune privilege in the pancreas driven by induction of TGF-β and tolerogenic DCs expressing IDO.
Asthma-associated IL13 single nucleotide polymorphisms (SNPs) upregulate human IL4 expression in mice carrying a human Th2 locus BAC transgene (57.10)
Authors: Pivniouk Vadim , Bailey Tom , Pivniouk Oksana , Rosenbaum David , Mobley Sara , Stern Debra , Halonen Marilyn , Vercelli Donata 
Published: January 2023

Abstract
A block of 9 SNPs in human (h) IL13 is strongly associated with increased susceptibility to allergy and asthma in multiple human populations. To study the functional significance of these SNPs in vivo, we generated mice that carry a 160 kb BAC5 transgene (TG) encompassing a non-polymorphic hTh2 cytokine locus (HapI). A HapII TG was engineered by introducing the asthma-associated IL13 SNPs into BAC5. hTh2 cytokine expression was faithfully regulated in HapI and HapII mice. To evaluate the effects of asthma-associated SNPs, we compared Th2 cytokine expression by polarized Th2 cells from Hap I and Hap II mice. Mouse Th2 cytokine expression was unaffected. hIL13 secretion was marginally upregulated in Hap II mice but, surprisingly, hIL4 protein and mRNA levels were dramatically increased. Increased hIL4 expression in carriers of IL13 SNPs was confirmed in humans. To elucidate the mechanisms underlying the effects of hIL13 SNPs on hIL4 expression, we performed a high-resolution analysis of DNA methylation at the Th2 cytokine locus in HapI and HapII Th2 cells. Several differentially methylated regions were identified. Notably, the HSIV element that is located ~25 kb 3’ of the IL13 SNPs and acts as an IL4 silencer in mice, was significantly hypermethylated at three consecutive CpG sites in HapII Th2 cells. Collectively, our results point to novel long-range effects of the IL13 SNPs on HSIV-dependent IL4 silencing, which may increase susceptibility to Th2-dependent allergic disease.