bluuebunny/crossref_metadata_2025_split huggingface dataset:
A recombinant adenovirus for targeted gene therapy of pulmonary inflammation (155.23)
Authors: Alberti Michael , Deshane Jessy , Pereboeva Larisa , Tsuruta Yuko , Abraham Ed , Chaplin David , Gerson Stanton , Curiel David , Roth Justin 
Published: January 2023

Abstract
Inflammation is a pathological component of many debilitating lung diseases. Thus, therapeutics that suppress the inflammatory response should also minimize inflammation-induced airway destruction. In this regard, Adenovirus type 5 (Ad5) vectors have a long history as therapeutic agents, due to their in vivo stability and amenability to genetic manipulation. Since circulating leukocytes infiltrate and mediate damage to the sites of pathology, we proposed to modulate Ad5 tropism to the dense leukocyte pool in the lung microvasculature for localized therapeutic intervention of inflammation. However, leukocytes do not express the coxsackie and adenovirus receptor (CAR) and are thus resistant to Ad5 infection. Therefore, we utilized phage display to identify a myeloid-binding peptide (MBP) and then genetically incorporated this sequence into an Ad5 fiber lacking the native CAR-binding domain (knob). Non-replicative Ad reporter vectors containing these MBP-fibers (Ad.MBP) maintained myeloid-binding specificity, and upon intravenous delivery the altered tropism enhanced lung gene transfer by five orders of magnitude over that obtained with unmodified Ad5. Disparity between cell types bound and those transduced suggest Ad.MBP is first sequestered by circulating leukocytes and subsequently “handed-off” to transduce pulmonary endothelium. These studies highlight the importance of pulmonary leukocytes as a target for therapeutic delivery in inflammatory lung disease.
Reversing the suppressive effects of regulatory T cells by targeting toll-like receptors and OX40 in human follicular lymphoma (156.11)
Authors: Voo Kui , Foglietta Myriam , Harlin Megan , Bover Laura , Kwak Larry , Liu Yong-Jun , Neelapu Sattva 
Published: January 2023

Abstract
Active immunotherapy is a promising approach for the treatment of follicular lymphoma (FL), an incurable B-cell lymphoma that accounts for 22% of all non-Hodgkin’s lymphomas worldwide. However, the clinical response rates following therapeutic cancer vaccination have been low in FL. We and others have shown that CD4+Foxp3+ regulatory T cells (Tregs) are increased in the peripheral blood and at the tumor site and are induced by tumor cells in FL. More importantly, Tregs potently suppressed the proliferation and cytokine production by FL tumor-specific effectors T cells. We previously reported that OX40 signaling shuts down the generation of IL-10-producing Tr1 cells. In this study, we showed that OX40 signaling blocks the suppressive function of Tregs and promotes tumor-specific effector T-cell proliferation in FL. We also showed that TLR ligands Pam3CSK4, flagellin, and CpG-B potently blocked the suppressive function of Tregs and restored the function of FL-specific effector T cells. However, agonists of TLR2/6, TLR3, TLR4, TLR7/8, and TLR8 were ineffective. These results suggest the potential usefulness of these agents as adjuvants to enhance the efficacy of therapeutic vaccines and other immunotherapeutic strategies in FL patients. Furthermore, they support the development of combinatorial strategies to promote effector T cell function and survival and block Treg function in FL and other malignancies.
Inflammation, apoptosis, and necrosis induced by neoadjuvant Fas ligand gene therapy improves survival of dogs with spontaneous bone cancer (156.18)
Authors: Modiano Jaime , Bellgrau Donald , Cutter Gary , Lana Susan , Ehrhart Nicole , Ehrhart Eugene , Wilke Vicki , Charles J. , Scott Milcah , Pozniak John , Schaack Jerome , Duke Richard 
Published: January 2023

Abstract
The use of Fas ligand (FasL) gene therapy for cancer has shown promise in laboratory animals. The mechanism by which this treatment works appears to be through induction of tumor inflammation and anti-tumor immunity. However, the efficacy of FasL to treat spontaneous tumors is unknown. To investigate this, we used the intratumoral FasL gene delivered in an adenovirus vector as neoadjuvant to standard of care in 56 dogs with naturally occurring appendicular osteosarcoma. Tumors from dogs treated with FasL had greater inflammation, necrosis, apoptosis, and fibrosis at day-10 (amputation) than tumors from controls dogs that did not receive FasL. These parameters also were increased when compared to pre-treatment biopsy samples (day-0). Survival improvement was apparent in dogs with greater inflammation or lymphocyte infiltration scores and in the top 50th percentile of apoptosis, whereas it was no different than standard of care alone in dogs with lower inflammation scores and the bottom 50th percentile of apoptosis. Reduced Fas expression in tumor cells was the only variable associated with prognostically advantageous inflammation; this relationship was not seen in dogs that did not receive FasL therapy. Together, the data suggest that FasL gene therapy can improve survival in naturally occurring tumors of large animals, and may be most effective when tumors fail to express Fas receptor, thus allowing FasL to exert its pro-inflammatory effects on the tumor microenvironment.
Functional and structural characterization of potent Th1 biasing 6′-derivatised α-GalCer iNKT cell agonists, and their superior role in tumor protection. (156.4)
Authors: Aspeslagh Sandrine , Li Yali , Yu Esther , Decruy Tine , Van Beneden Katrien , Girardi Enrico , Pauwels Nora , Trappeniers Matthias , Venken Koen , Drennan Michael , Leybaert Luc , Wang Jing , Van Calenbergh Serge , Zajonc Dirk , Elewaut Dirk 
Published: January 2023

Abstract
Invariant natural killer T cells are known to have marked immunomodulatory capacity due to their ability to produce copious amounts of effector cytokines. In this study, we report the first crystal structures of a novel class of strong Th1 biasing structural analogues of α-galactosylceramide by addition of aromatic structures on the 6-OH position of galactose. They are characterized by marked Th1 polarized cytokine patterns that are highly conserved between mice and men, and marked tumour protection in vivo. The strength of the Th1 response correlates well with enhanced lipid binding to CD1d as a result of an induced fit mechanism that binds the aromatic substitution as a third anchor, in addition to the two lipid chains. This induced fit is in contrast to another Th1 biasing glycolipid, α-C-GalCer, whose CD1d binding follows a conventional key-lock principle. These findings highlight the previously unexploited flexibility of CD1d in accommodating galactose-modified glycolipids and broaden the range of glycolipids that can stimulate iNKT cells. We speculate that glycolipids can be designed that induce a similar fit, thereby leading to superior and more sustained iNKT cell responses in vivo.
Antitumor effects of anti-CD137 mAb are influenced by Fc: Fcγ receptor interactions (156.5)
Authors: Sallin Michelle , Lin Wei , Chapoval Andrei , Schulze Dan , Strome Scott 
Published: January 2023

Abstract
In various preclinical models, agonist antibodies directed against CD137 (4-1BB) enhance the antitumor immunity. However, the contribution of the Fc:Fc receptor interactions to the process of anti-CD137 mediated tumor rejection is unknown. In this study, we provide early evidence that treatment of tumor bearing mice lacking all activating Fcγ receptors (Fcγ chain deficient mice) with the anti-CD137 mAb, 4-1BB2A, improves the survival compared to wild type mice. When Fcγ chain deficient mice and wild type are challenged with EL4E7 tumor cells, tumors were allowed to grow to an approximate size of 10mm by day 7 or 12mm by day 10. When the mice are treated with anti-CD137 mAb, the Fcγ chain deficient mice had increased survival compared to wild type mice even bearing ten day established tumors. Similarly, improved survival is seen in FcγRIII deficient mice bearing ten day established tumors after treatment with anti-CD137 mAb. While still preliminary, our observations suggest that strategies to modify Fc:FcR interactions may improve the therapeutic efficacy of anti-CD137 based cancer immunotherapy.
Muramyl dipeptide potentiates the ability of lipoteichoic acid to induce cyclooxygenase-2 expression in murine macrophages (157.11)
Authors: Ahn Kibum , Jeon Jun Ho , Park Ok-Jin , Yun Cheol-Heui , Han Seung-Hyun 
Published: January 2023

Abstract
Gram-positive bacterial cell wall contains lipoteichoic acid (LTA) and thick peptidoglycan (PGN) layers, both of which are the major virulence factors containing proinflammatory potential. In order to examine if LTA together with PGN synergistically induces inflammatory responses, we investigated the ability of staphylococcal LTA to induce cyclooxygenase-2 (COX-2) expression in the presence of muramyl dipeptide (MDP), the minimal structural unit of PGN with inflammatory potential, in murine macrophages. Although MDP failed to induce COX-2 expression, LTA alone was able to induce COX-2 expression and MDP remarkably enhanced LTA-induced COX-2 expression at both protein and mRNA levels. Up-regulation was also observed in the production of prostaglandin E2, which is mediated by COX-2. Notably, COX-2 expression, induced by LTA plus MDP treatment, was down-regulated by inhibitors for MAP kinases (ERK, p38 and JNK/SAPK), PI3 kinases, and reactive oxygen species, but not by inhibitors for PKC or PKA. Transient transfection and luciferase reporter gene assays demonstrated that MDP also enhanced the LTA-induced activation of transcription factors, NF-κB, CRE and AP-1, all of which are involved in the transcriptional activity of COX-2. Conclusively, these results suggest that MDP potentiates LTA-induced inflammatory responses by enhancing the expression of COX-2 in macrophages.
A novel mechanism for inhibition of IRF-3-dependent gene expression by Human Respiratory Syncytial Virus NS1 protein (158.19)
Authors: Bao Xiaoyong , Ren Junping , Liu Tianshuang , Garofalo Roberto , Casola Antonella 
Published: January 2023

Abstract
Human respiratory syncytial virus (RSV), a leading cause of respiratory tract infections in infants, inhibits type I interferon (IFN)-dependent signaling, as well as IFN synthesis. RSV nonstructural protein NS1 plays a significant role in this inhibition, however the mechanism(s) responsible are not fully known. The transcription factor interferon regulatory factor (IRF)-3 is essential for viral-induced IFN-β synthesis. In this study, we found that NS1 protein inhibits IRF-3-dependent gene transcription in constitutively active IRF-3 overexpressing cells, demonstrating that NS1 directly targets IRF-3. NS1 associates with IRF-3 and inhibits IFN-β transcription by blocking IRF-3 binding to the IFN-β promoter, without affecting viral-induced IRF-3 phosphorylation and nuclear translocation, thereby identifying a novel molecular mechanism by which RSV inhibits IFN-β synthesis.
Regulation of human paramyxovirus pathogenesis by pulmonary dendritic cells (158.4)
Authors: Guerrero-Plata Antonieta , Wakamatsu Nobuko , Lancelin Wallissa 
Published: January 2023

Abstract
Human metapneumovirus (hMPV), is an important paramyxovirus that is associated with clinical syndromes ranging from mild illnesses, such as common cold, to more devastating conditions, such as bronchiolitis and pneumonia. hMPV has worldwide distribution and high incidence in children, elderly and immunocopromised patients. Understanding the immune mechanisms that regulate hMPV pathogenesis is important clinically for the development of new treatment strategies or novel vaccines for hMPV infection. Respiratory tract dendritic cells (DC) play a fundamental role in the immune system by bridging both innate and adaptive immunity. Therefore, we examined the role of plasmacytoid DC (pDC) in hMPV pathogenesis in an experimental mouse model of infection. Depletion of pDC resulted in an increased viral replication in the lungs from 4.3±1.3×104 to 1.7±6.1×105. However, no change in IFN-α/β production was observed. In addition, pDC-depleted mice demonstrated an exacerbated mucus production and pulmonary inflammation (&gt;60%). Interestingly, the balance of lung DC was altered by the depletion of pDC as the recruitment of classical DC (cDC) into the lungs of infected mice was significantly incremented from 9.9±1.2×105 to 1.7±1.6×106. Finally, the production of CCL20, a DC-attracting chemokine, was also increased after depletion of pDC (&gt;60%). In conclusion, these novel findings demonstrate that pDC play a protective role during hMPV infection by modulation of local immune responses.
Maintenance of peripheral naive T cells: a mouse-man divide (159.1)
Authors: Vrisekoop Nienke , Den Braber Ineke , Mugwagwa Tendai , Westera Liset , Mogling Ramona , De Boer Anne Bregje , Willems Neeltje , Schrijver Elise , Spierenburg Gerrit , Gaiser Koos , Mul Erik , Otto Sigrid , Ruiter An , Ackermans Mariette , Miedema Frank , Borghans Jose , De Boer Rob , Tesselaar Kiki 
Published: January 2023

Abstract
Insights from T-cell dynamic studies in mice are widely extrapolated to men and vice versa, while no formal proof exists that such extrapolations are justified. At the same time, there is a lot of controversy about the dynamic properties of T cells, including life span and the relative contributions of thymus output and peripheral proliferation to the maintenance of the naive T-cell pool during aging. We have investigated the hypothesis that part of this controversy is due to improper extrapolation of dynamic parameters of T cells from mice to men. By combining in vivo kinetic labeling using deuterated water, thymectomy experiments, analysis of TRECs, the expression of the thymic proximity marker CD31, and mathematical modeling, we have quantified the contributions of de novo T-cell production by the thymus and peripheral naive T-cell division to life-long maintenance of the naive T-cell pool in both mice and men under normal physiological conditions. Our results show that mice and men are incomparable with respect to naive T-cell maintenance. While in mice - throughout their life time - the naive T-cell pool is almost exclusively sustained by thymus output, the maintenance of the adult human naive T-cell pool occurs almost exclusively through peripheral T-cell division. These findings put serious constraints on the use of mouse experiments to understand immunological processes such as T-cell reconstitution in lymphopenic patients or the effects of aging in healthy humans.
B cell autonomous function of Bim in B cell apoptosis and tolerance (159.10)
Authors: Wright Jacqueline , Castro Iris , Zinkel Sandra , Khan Wasif 
Published: January 2023

Abstract
Splenic immature B cells traverse through the early transitional (T1) and late transitional (T2) stages to produce the mature B cell repertoire. BCR specificity-based selection ensures elimination of pathogenic B cells by apoptosis, receptor editing or anergy. These processes are tightly regulated by anti- and pro-apoptotic members of the Bcl-2 family. Conventional gene deletion of the pro-apoptotic member Bim lead to prolonged life-span of autoreactive B cells, defective anergy and production of autoantibodies. Whether these pathophysiological conditions arise as a result of B cell autonomous function of Bim remains unclear. We have found that T1 cells express higher levels of Bim and display increased susceptibility to BCR-induced apoptosis than more mature B cells. These properties are shared by BCR signaling defective Bruton’s tyrosine kinase (Btk) deficient B cells. We investigated the B cell-intrinsic role of Bim in the regulation of B cell maturation and survival in mice carrying floxed Bim and CD19-Cre in Btk-sufficient or deficient background. B lineage-specific deletion of Bim increased the B cell compartment through selective expansion of mature B cells and significantly restored mature B cells in Btk-mutant mice. These studies demonstrate a B cell autonomous role for Bim in BCR-dependent regulation of B cell homeostasis. Analysis of these mice in the context of BCR transgene will reveal the B cell autonomous function of Bim in tolerance and autoimmunity.
Role of antigen persistence and dose for CD4+ T-cell exhaustion and recovery (159.7)
Authors: Obst Reinhard , Han Shaobo , Asoyan Ayuna , Rabenstein Hannah , Nakano Naoko 
Published: January 2023

Abstract
It is currently not understood how some chronic infections exhaust antigen-specific T cells over time and how different pathogen components contribute to the exhausted state. Here, we dissected the behavior of primed CD4+ T cells exposed to persistent antigen using an inducible transgenic mouse system that allowed us to control antigen presentation as the only experimental variable independent of persistent inflammation and disease progression. In this system presentation of an MHC-II presented antigen is restricted to dendritic cells so that confounding B, CD8+ T, or innate cell responses are not triggered. When antigen presentation was extended beyond the expansion phase, primed CD4+ T cells survived, but exhibited reduced memory functionality in terms of their proliferative capacity and cytokine expression potential. The effect was antigen dose and time dependent, not associated with increased PD-1 expression or reduced calcium influx, but with impaired Jun phosphorylation in response to TCR engagement. Upon antigen removal, the cells regained the ability to proliferate, but remained unable to produce high levels of IL-2 and TNF-α. These data show that persistent antigen at a high dose rapidly induces a dysfunctional state in CD4+ T cells that is only partially reversible upon antigen removal. At a low dose, however, antigen has to persist longer before T cell impairment becomes detectable.
Oral L. monocytogenes infection preferentially imprints memory precursor CD8 T cells for gut retention (161.10)
Authors: Sheridan Brian , Pham Quynh-Mai , Lee Young-Tae , Cauley Linda , Lefrançois Leo 
Published: January 2023

Abstract
The intestinal mucosa contains unique sites designed for antigen presentation and promotion of primary and memory CD8 T cell responses. Thus, generation of adaptive immunity within distinct tissues likely results in T cell responses with specific cellular outcomes. Here, we utilized an oral Listeria monocytogenes (LM) infection model in which internalin A is modified to promote invasion of murine intestinal epithelial cells. Oral infection induced a robust CD8 T cell response. In peripheral nonmucosal tissues, the majority of LM-specific CD8 T cells are short-lived effector cells (CD127- KLRG1+). Surprisingly, the majority of effector CD8 T cells in the intestinal mucosa are memory precursor effector cells (MPEC; CD127+ KLRG1-) early following oral infection. This effect appears to be due to preferential infiltration and retention of MPECs in intestinal tissues. CD103 (integrin αE), which is thought to be vital for retention of intestinal epithelial lymphocytes within the epithelium, was almost exclusively expressed by MPECs. The generation of distinct CD8 T cell subsets uniquely tailored to respond to intestinal pathogens early following infection may be a hallmark of oral challenge. Indeed, CD8 T cells that infiltrate the intestinal mucosa following intranasal influenza virus infection are early effector cells (CD127- KLRG1-), but failed to be maintained long-term, demonstrating the importance of intestinal priming for generating robust mucosal memory CD8 T cells.
Global gene expression analysis of Act1’s effects in airway epithelial cells (161.17)
Authors: Velichko Sharlene , Anderson Johnathon , Ryan Stephanie , Wu Reen 
Published: January 2023

Abstract
Act1/CIKS is an intracellular protein that has been shown to play an important role in mediating IL-17A and IL-25 signaling effects. Recently, defects in Act1 function and/or expression has been implicated in inflammatory disease, such as psoriatic arthritis and atopic dermatitis. We have found that the modulation of Act1 expression levels in human airway epithelial cells changes the expression levels of some genes, in the absence of cytokine stimulation. RNAseq is a powerful new technique to quantitatively measure changes at the transcriptome level. Here we describe the use of RNAseq to globally analyze the effects of modulating Act1 expression in human airway epithelial cells.
MyD88-dependent TLR signals are necessary and sufficient to confer dendritic cells with gut-specific imprinting properties. (161.2)
Authors: Wang Sen , Villablanca Eduardo , Gomes Daniel , Nguyen Deanna , Mizoguchi Emiko , Kagan Jonathan , Reinecker Hans-Christian , Hacohen Nir , Nagler Cathryn , Xavier Ramnik , Rossi-Bergmann Bartira , Chen Yi-Bin , Blomhoff Rune , Snapper Scott , Mora Rodrigo 
Published: January 2023

Abstract
Lymphocyte migration is at the heart of normal and pathological immune responses in the intestinal mucosa. We and others have shown that, in addition to activating lymphocytes, gut-associated dendritic cells (GALT-DC) can metabolize dietary vitamin A into all-trans retinoic acid (RA), which is required for inducing gut-tropic lymphocytes and IgA antibody-secreting cells (IgA-ASC). GALT-DC from mice deficient in the intracellular signaling adaptor MyD88, which lack most Toll-like receptor (TLR) signals, were significantly impaired in their capacity to induce gut-homing T cells and IgA-ASC and expressed low levels of retinal dehydrogenases (RALDH), which are critical enzymes for RA biosynthesis. MyD88-/- mice were also impaired in generating gut-tropic T cells upon immunization and exhibited low numbers of intestinal IgA-ASC. Pre-treatment of murine spleen-DC and human monocyte-derived DC with a TLR1/2 agonist was sufficient to induce RALDH and to confer these extra-intestinal DC with the capacity to induce gut-homing lymphocytes and IgA-ASC via a mechanism dependent on MyD88 and c-JNK/MAPK. Thus, MyD88-dependent TLR signals are both necessary and sufficient to educate DC with gut-specific imprinting properties.
Secretory IgA: coordinating the capture and sampling of enteric pathogens (161.20)
Authors: Mantis Nicholas , Forbes Stephen , Amarasinghe Jayaleka , Reid Richelle , Park Chae Gyu , Corthesy Blaise 
Published: January 2023

Abstract
Secretory IgA (SIgA) antibodies directed against the O-antigen (O-Ag) component of lipopolysaccharide are the primary determinants of mucosal immunity to enteric bacterial pathogens, such as Shigella flexneri and Salmonella enteric serovar Typhimurium. In this report, we demonstrate that monoclonal IgA Abs against the O-Ag are effective inhibitors of the bacterial type 3 secretion systems (T3SS) required for bacterial entry into intestinal epithelial cells. While these Abs did not affect bacterial viability, they did transiently de-energize both S. flexneri and S. Typhimurium, possibly accounting for the “paralysis” that has been observed in the case of S. Typhimurium, following Ab treatment. O-Ag specific IgA Abs also elicited long lasting ultrastructural changes in the bacterial outer membranes, suggesting that S. flexneri and S. Typhimurium made undergo specific adaptations in response to SIgA. These findings may have implications for understanding immune surveillance in the gut. We have shown that Peyer’s patch M cells transport SIgA and SIgA-antigen complexes from the intestinal lumen to underlying dendritic cells (DC), and that the uptake of SIgA-immune complexes by DCs may be mediated by the mannose receptor and/or DC-¬SIGN. The fact that SIgA may be capable of transiently rendering S. flexneri and S. Typhimurium avirulent suggests a mechanism by which the normally pathogenic bacteria can be sampled safely by the mucosal immune system.