bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional Expression of Neurokinin 1 Receptors on Mast Cells Induced by IL-4 and Stem Cell Factor
Authors: van der Kleij Hanneke P. M. , Ma Donglai , Redegeld Frank A. M. , Kraneveld Aletta D. , Nijkamp Frans P. , Bienenstock John 
Published: April 2014

Abstract
It is widely accepted that neurokinin 1 (NK1) receptors are not generally expressed on mast cells but little is known about their expression in inflammation. The present study shows expression of NK1 receptors on bone marrow-derived mast cells (BMMC) under the influence of IL-4 or stem cell factor (SCF). Highest expression was found when both cytokines are present. Six days of coculture with the cytokines IL-4 and SCF showed significant expression of NK1 receptors (NK1 receptor+/c-kit+ BMMC; control: 7%, IL-4/SCF: 16%), while 12 days of cytokine coculture increased this expression to 37% positive cells. A longer coculture with IL-4 and SCF did not give an additional effect. Increased expression in IL-4/SCF-treated BMMC was further confirmed using Western blot analysis. Next, we demonstrated the functional relevance of NK1 receptor expression for mast cell activation, resulting in an enhanced degranulation upon stimulation by substance P. BMMC activation was significantly diminished by the NK1 receptor antagonist RP67580 (10 μM) when stimulated with low concentrations of substance P. The inactive enantiomer RP65681 had no effect. In addition, BMMC cultured from bone marrow of NK1 receptor knockout mice showed significantly decreased exocytosis to low concentrations of substance P. The present study clearly shows that NK1 receptor-induced activation contributes significantly at low physiological substance P concentrations (&lt;100 μM). In conclusion, BMMC were shown to express NK1 receptors upon IL-4/SCF coculture. This expression of NK1 receptors has been demonstrated to be of functional relevance and leads to an increase in the sensitivity of BMMC to substance P.
Airway IgG Counteracts Specific and Bystander Allergen-Triggered Pulmonary Inflammation by a Mechanism Dependent on FcγR and IFN-γ
Authors: Sehra Sarita , Pynaert Gwenda , Tournoy Kurt , Haegeman Anuschka , Matthys Patrick , Tagawa Yohichi , Pauwels Romain , Grooten Johan 
Published: April 2014

AbstractBesides IgE, the Ab isotype that gives rise to sensitization and allergic asthma, the immune response to common inhalant allergens also includes IgG. Increased serum titers of allergen-specific IgG, induced spontaneously or by allergen vaccination, have been implicated in protection against asthma. To verify the interference of topical IgG with the allergen-triggered eosinophilic airway inflammation that underlies asthma, sensitized mice were treated by intranasal instillation of specific IgG, followed by allergen challenge. This treatment strongly reduced eosinophilic inflammation and goblet cell metaplasia, and increased Th1 reactivity and IFN-γ levels in bronchoalveolar lavage fluid. In contrast, inflammatory responses were unaffected in IFN-γ-deficient mice or when applying F(ab′)2. Although dependent on specific allergen-IgG interaction, inflammation triggered by bystander allergens was similarly repressed. Perseverance of inflammation repression, apparent after secondary allergen challenge, and increased allergen capture by alveolar macrophages further characterized the consequences of topical IgG application. These results assign a novel protective function to anti-allergen IgG namely at the local level interference with the inflammatory cascade, resulting in repression of allergic inflammation through an FcγR- and IFN-γ-dependent mechanism. Furthermore, these results provide a basis for topical immunotherapy of asthma by direct delivery of anti-allergen IgG to the airways.
Synergism Between Platelet-Activating Factor-Like Phospholipids and Peroxisome Proliferator-Activated Receptor γ Agonists Generated During Low Density Lipoprotein Oxidation That Induces Lipid Body Formation in Leukocytes
Authors: de Assis Edson F. , Silva Adriana R. , Caiado Lara F. C. , Marathe Gopal K. , Zimmerman Guy A. , Prescott Stephen M. , McIntyre Thomas M. , Bozza Patricia T. , de Castro-Faria-Neto Hugo C. 
Published: April 2014

Abstract
Oxidized low density lipoprotein (LDL) has an important proinflammatory role in atherogenesis. In this study, we investigated the ability of oxidized LDL (oxLDL) and its phospholipid components to induce lipid body formation in leukocytes. Incubation of mouse peritoneal macrophages with oxidized, but not with native LDL led to lipid body formation within 1 h. This was blocked by platelet-activating factor (PAF) receptor antagonists or by preincubation of oxLDL with rPAF acetylhydrolase. HPLC fractions of phospholipids purified from oxLDL induced calcium flux in neutrophils as well as lipid body formation in macrophages. Injection of the bioactive phospholipid fractions or butanoyl and butenoyl PAF, a phospholipid previously shown to be present in oxLDL, into the pleural cavity of mice induced lipid body formation in leukocytes recovered after 3 h. The 5-lipoxygenase and cyclooxygenase-2 colocalized within lipid bodies formed after stimulation with oxLDL, bioactive phospholipid fractions, or butanoyl and butenoyl PAF. Lipid body formation was inhibited by 5-lipoxygenase antagonists, but not by cyclooxygenase-2 inhibitors. Azelaoyl-phosphatidylcholine, a peroxisome proliferator-activated receptor-γ agonist in oxLDL phospholipid fractions, induced formation of lipid bodies at late time points (6 h) and synergized with suboptimal concentrations of oxLDL. We conclude that lipid body formation is an important proinflammatory effect of oxLDL and that PAF-like phospholipids and peroxisome proliferator-activated receptor-γ agonists generated during LDL oxidation are important mediators in this phenomenon.
Intracellular Domain of Brain Endothelial Intercellular Adhesion Molecule-1 Is Essential for T Lymphocyte-Mediated Signaling and Migration
Authors: Greenwood John , Amos Claire L. , Walters Claire E. , Couraud Pierre-Olivier , Lyck Ruth , Engelhardt Britta , Adamson Peter 
Published: April 2014

AbstractTo examine the role of the ICAM-1 C-terminal domain in transendothelial T lymphocyte migration and ICAM-1-mediated signal transduction, mutant human (h)ICAM-1 molecules were expressed in rat brain microvascular endothelial cells. The expression of wild-type hICAM-1 resulted in a significant increase over basal levels in both adhesion and transendothelial migration of T lymphocytes. Endothelial cells (EC) expressing ICAM-1 in which the tyrosine residue at codon 512 was substituted with phenylalanine (hICAM-1Y512F) also exhibited increased lymphocyte migration, albeit less than that with wild-type hICAM-1. Conversely, the expression of truncated hICAM-1 proteins, in which either the intracellular domain was deleted (hICAM-1ΔC) or both the intracellular and transmembrane domains were deleted through construction of a GPI anchor (GPI-hICAM-1), did not result in an increase in lymphocyte adhesion, and their ability to increase transendothelial migration was attenuated. Truncated hICAM-1 proteins were also unable to induce ICAM-1-mediated Rho GTPase activation. EC treated with cell-permeant penetratin-ICAM-1 peptides comprising human or rat ICAM-1 intracellular domain sequences inhibited transendothelial lymphocyte migration, but not adhesion. Peptides containing a phosphotyrosine residue were equipotent in inhibiting lymphocyte migration. These data demonstrate that the intracellular domain of ICAM-1 is essential for transendothelial migration of lymphocytes, and that peptidomimetics of the ICAM-1 intracellular domain can also inhibit this process. Such competitive inhibition of transendothelial lymphocyte migration in the absence of an affect on adhesion further implicates ICAM-1-mediated signaling events in the facilitation of T lymphocyte migration across brain EC. Thus, agents that mimic the ICAM-1 intracellular domain may be attractive targets for novel anti-inflammatory therapeutics.
Prevention of Collagen-Induced Arthritis in Mice Transgenic for the Complement Inhibitor Complement Receptor 1-Related Gene/Protein y
Authors: Banda Nirmal K. , Kraus Damian M. , Muggli Michele , Bendele Alison , Holers V. Michael , Arend William P. 
Published: April 2014

AbstractThe objective of these studies was to examine collagen-induced arthritis (CIA) in C57BL/6 mice transgenic for the rodent complement regulatory protein complement receptor 1-related gene/protein y (Crry) (Crry-Tg), a C3 convertase inhibitor. The scores for clinical disease activity and for histological damage in the joints were both significantly decreased in Crry-Tg mice in comparison to wild-type (WT) littermates. The production of both IgG1 and IgG2a anti-collagen Abs was reduced in the Crry-Tg mice, although spleen cell proliferation in response to collagen type II was not altered. The production of IFN-γ, TNF-α, and IL-1β by LPS-stimulated spleen cells was decreased, and IL-10 was increased, in cells from Crry-Tg mice in comparison to WT. The steady-state mRNA levels for IFN-γ, TNF-α, and IL-1β were all decreased in the joints of Crry-Tg mice in comparison to WT. The synovium from Crry-Tg mice without CIA contained the mRNA for the Crry transgene, by RT-PCR, and the synovium from transgenic mice with CIA exhibited little deposition of C3 protein by immunohistological analysis. These results suggest that suppression of CIA in Crry-Tg mice may be due to enhanced synthesis of Crry locally in the joint with decreased production of proinflammatory cytokines.
A Plant-Based Allergy Vaccine Suppresses Experimental Asthma Via an IFN-γ and CD4+CD45RBlow T Cell-Dependent Mechanism
Authors: Smart Vanessa , Foster Paul S. , Rothenberg Marc E. , Higgins T. J. V. , Hogan S. P. 
Published: April 2014

AbstractAllergic asthma is currently considered a chronic airway inflammatory disorder associated with the presence of activated CD4+ Th2-type lymphocytes, eosinophils, and mast cells. Interestingly, therapeutic strategies based on immune deviation and suppression have been shown to successfully attenuate the development of the asthma phenotype. In this investigation, we have for the first time used a genetically modified (GM) plant, narrow leaf lupin (Lupinus angustifolius L.), expressing a gene for a potential allergen (sunflower seed albumin) (SSA-lupin) to examine whether a GM plant/food-based vaccine strategy can be used to suppress the development of experimental asthma. We show that oral consumption of SSA-lupin promoted the induction of an Ag-specific IgG2a Ab response. Furthermore, we demonstrate that the plant-based vaccine attenuated the induction of delayed-type hypersensitivity responses and pathological features of experimental asthma (mucus hypersecretion, eosinophilic inflammation, and enhanced bronchial reactivity (airways hyperreactivity). The suppression of experimental asthma by SSA-lupin was associated with the production of CD4+ T cell-derived IFN-γ and IL-10. Furthermore, we show that the specific inhibition of experimental asthma was mediated via CD4+CD45RBlow regulatory T cells and IFN-γ. Thus, our data demonstrate that a GM plant-based vaccine can promote a protective immune response and attenuate experimental asthma, suggesting that plant-based vaccines may be potentially therapeutic for the protection against allergic diseases.
A Novel Therapeutic Approach Targeting Articular Inflammation Using the Filarial Nematode-Derived Phosphorylcholine-Containing Glycoprotein ES-62
Authors: McInnes Iain B. , Leung Bernard P. , Harnett Margaret , Gracie J. Alastair , Liew Foo Y. , Harnett William 
Published: April 2014

AbstractUnderstanding modulation of the host immune system by pathogens offers rich therapeutic potential. Parasitic filarial nematodes are often tolerated in human hosts for decades with little evidence of pathology and this appears to reflect parasite-induced suppression of host proinflammatory immune responses. Consistent with this, we have previously described a filarial nematode-derived, secreted phosphorylcholine-containing glycoprotein, ES-62, with immunomodulatory activities that are broadly anti-inflammatory in nature. We sought to evaluate the therapeutic potential of ES-62 in vitro and in vivo in an autoimmune disease model, namely, collagen-induced arthritis in DBA/1 mice. ES-62 given during collagen priming significantly reduced initiation of inflammatory arthritis. Crucially, ES-62 was also found to suppress collagen-induced arthritis severity and progression when administration was delayed until after clinically evident disease onset. Ex vivo analyses revealed that in both cases, the effects were associated with inhibition of collagen-specific pro-inflammatory/Th1 cytokine (TNF-α, IL-6, and IFN-γ) release. In parallel in vitro human tissue studies, ES-62 was found to significantly suppress macrophage activation via cognate interaction with activated T cells. Finally, ES-62 suppressed LPS-induced rheumatoid arthritis synovial TNF-α and IL-6 production. Evolutionary pressure has promoted the generation by pathogens of diverse mechanisms enabling host immune system evasion and induction of “tolerance.” ES-62 represents one such mechanism. We now provide proof of concept that parasite-derived immunomodulatory strategies offer a novel therapeutic opportunity in inflammatory arthritis.
Differentiation of CD8+ T Cells from Tumor-Invaded and Tumor-Free Lymph Nodes of Melanoma Patients: Role of Common γ-Chain Cytokines
Authors: Anichini Andrea , Scarito Alessia , Molla Alessandra , Parmiani Giorgio , Mortarini Roberta 
Published: April 2014

AbstractDifferentiation of CD8+ T cells at the tumor site toward effector and memory stages may represent a key step for the efficacy of antitumor response developing naturally or induced through immunotherapy. To address this issue, CD8+ T lymphocytes from tumor-invaded (n = 142) and tumor-free (n = 42) lymph nodes removed from the same nodal basin of melanoma patients were analyzed for the expression of CCR7, CD45RA, perforin, and granzyme B. By hierarchical cluster analysis, CD8+ T cells from all tumor-free lymph nodes and from 56% of the tumor-invaded lymph node samples fell in the same cluster, characterized mainly by CCR7+ CD45RA+/− cytotoxic factor− cells. The remaining three clusters contained only samples from tumor-invaded lymph nodes and showed a progressive shift of the CD8+ T cell population toward CCR7− CD45RA−/+ perforin+ granzyme B+ differentiation stages. Distinct CD8+ T cell maturation stages, as defined by CCR7 vs CD45RA and by functional assays, were identified even in melanoma- or viral Ag-specific T cells from invaded lymph nodes by HLA tetramer analysis. Culture for 7 days of CCR7+ perforin− CD8+ T cells from tumor-invaded lymph nodes with IL-2 or IL-15, but not IL-7, promoted, mainly in CCR7+CD45RA− cells, proliferation coupled to differentiation to the CCR7− perforin+ stage and acquisition of melanoma Ag-specific effector functions. Taken together, these results indicate that CD8+ T cells differentiated toward CCR7− cytotoxic factor+ stages are present in tumor-invaded, but not in tumor-free, lymph nodes of a relevant fraction of melanoma patients and suggest that cytokines such as IL-2 and IL-15 may be exploited to promote Ag-independent maturation of anti-tumor CD8+ T cells.
Immunoregulatory Role of CD1d in the Hydrocarbon Oil-Induced Model of Lupus Nephritis
Authors: Yang Jun-Qi , Singh Avneesh K. , Wilson Michael T. , Satoh Minoru , Stanic Aleksandar K. , Park Jang-June , Hong Seokmann , Gadola Stephan D. , Mizutani Akiei , Kakumanu Srinivasa R. , Reeves Westley H. , Cerundolo Vincenzo , Joyce Sebastian , Van Kaer Luc , Singh Ram Raj 
Published: April 2014

Abstract
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is accompanied by the emergence of autoreactive T cells and a reduction in regulatory T cells. Humans and mice with SLE have reduced numbers of CD1d-restricted NK T cells, suggesting a role for these cells in the regulation of SLE. In this study, we show that CD1d deficiency exacerbates lupus nephritis induced by the hydrocarbon oil pristane. This exacerbation in disease is associated with: 1) reduced TNF-α and IL-4 production by T cells, especially during the disease induction phase; and 2) expansion of marginal zone B cells. Strikingly, inoculation of pristane in wild-type mice resulted in reduced numbers and/or functions of NK T cells and CD1d-expressing dendritic cells. These findings suggest that CD1d may play an immunoregulatory role in the development of lupus in the pristane-induced model.
Reconstitution of CD8+ T Cells by Retroviral Transfer of the TCR αβ-Chain Genes Isolated from a Clonally Expanded P815-Infiltrating Lymphocyte
Authors: Tahara Hiroyuki , Fujio Keishi , Araki Yasuto , Setoguchi Keigo , Misaki Yoshikata , Kitamura Toshio , Yamamoto Kazuhiko 
Published: April 2014

AbstractGene transfer of TCR αβ-chains into T cells may be a promising strategy for providing valuable T lymphocytes in the treatment of tumors and other immune-mediated disorders. We report in this study the reconstitution of CD8+ T cells by transfer of TCR αβ-chain genes derived from an infiltrating T cell into P815. Analysis of the clonal expansion and Vβ subfamily usage of CD8+ TIL in the tumor sites demonstrated that T cells using Vβ10 efficiently infiltrated and expanded clonally. The TCR α- and β-chain sequences derived from a tumor-infiltrating CD8+/Vβ10+ single T cell clone (P09-2C clone) were simultaneously determined by the RT-PCR/single-strand conformational polymorphism method and the single-cell PCR method. When P09-2C TCR αβ-chain genes were retrovirally introduced into CD8+ T cells, the reconstituted T cells positively lysed the P815 tumor cells, but not the A20, EL4, or YAC-1 cells, in vitro. In addition, the CTL activity was blocked by the anti-H2Ld mAb. Furthermore, T cells containing both TCR α- and β-chains, but not TCR β-chain alone, accumulated at the tumor-inoculated site when the reconstituted CD8+ T cells were adoptively transferred to tumor-bearing nude mice. These findings suggest that it is possible to reconstitute functional tumor-specific CD8+ T cells by transfer of TCR αβ-chain genes derived from TIL, and that such T cells might be useful as cytotoxic effector cells or as a vehicle for delivering therapeutic agents.
HER-2/neu-Specific Monoclonal Antibodies Collaborate with HER-2/neu-Targeted Granulocyte Macrophage Colony-Stimulating Factor Secreting Whole Cell Vaccination to Augment CD8+ T Cell Effector Function and Tumor-Free Survival in Her-2/neu-Transgenic Mice
Authors: Wolpoe Matthew E. , Lutz Eric R. , Ercolini Anne M. , Murata Satoshi , Ivie Susan E. , Garrett Elizabeth S. , Emens Leisha A. , Jaffee Elizabeth M. , Reilly R. Todd 
Published: April 2014

Abstract
HER-2/neu is overexpressed in several cancers including 30% of breast carcinomas, and correlates with a poor outcome. HER-2/neu-transgenic (neu-N) mice that overexpress the non-transforming rat neu develop spontaneous mammary carcinomas and demonstrate immunotolerance to the neu protein similar to that observed in patients with neu-expressing cancers. In neu-N mice, neu-targeted vaccination induces weak T cell and negligible Ab responses sufficient to delay but not eradicate transplanted neu-expressing tumor. Here we demonstrate that passive infusion of neu-specific mAbs in sequence with whole cell vaccination significantly improves tumor-free survival over either modality alone. Importantly, treatment of neu-N mice with vaccine in combination with two distinct neu-specific Abs is particularly efficacious, preventing tumor in 70% and eradicating established tumor in 30% of neu-N mice. In vivo lymphocyte subpopulation depletion experiments demonstrate that the efficacy of Ab, alone or combined with vaccine, is dependent on both CD4+ and CD8+ T cells. Furthermore, the in vivo antitumor effects of vaccine and Ab are associated with a significant increase in the number and function of neu-specific CD8+ T cells. Collectively, these observations suggest that similarly increased efficacy could be obtained by combining neu-targeted vaccination and neu-specific Abs such as trastuzumab (Herceptin) in patients with neu-expressing cancers.
Cutting Edge: Requirement for Growth Hormone-Releasing Hormone in the Development of Experimental Autoimmune Encephalomyelitis
Authors: Ikushima Hideto , Kanaoka Masaharu , Kojima Shinichi 
Published: April 2014

Abstract
Growth hormone (GH)-releasing hormone (GHRH) is a neuropeptide that stimulates secretion of GH from the pituitary gland. Although GHRH and its receptor (GHRHR) are expressed in leukocytes, physiological function of GHRH in the immune system remains unclear. To study the influence of GHRH in autoimmunity, susceptibility to experimental autoimmune encephalomyelitis (EAE) was examined in C57BL/6J-Ghrhrlit/lit (lit/lit), mice deficient in the GHRHR gene. We found that lit/lit mice were resistant to myelin oligodendrocyte glycoprotein (MOG)-induced EAE. Splenocytes from MOG-immunized lit/lit mice proliferated normally in response to MOG peptide, suggesting that activation of MOG-specific T cells in GHRHR-deficient mice is not impaired. Our data strongly suggest that GHRH plays a crucial role in the development of EAE and may provide the basis for a novel therapeutic approach protecting from autoimmune diseases.
Cutting Edge: A Possible Role for CD4+ Thymic Macrophages as Professional Scavengers of Apoptotic Thymocytes
Authors: Esashi Eiji , Sekiguchi Takashi , Ito Hiroaki , Koyasu Shigeo , Miyajima Atsushi 
Published: April 2014

Abstract
A vast majority of thymocytes are eliminated during T cell development by apoptosis. However, apoptotic thymocytes are not usually found in the thymus, indicating that apoptotic thymocytes must be eliminated rapidly by scavengers. Although macrophages and dendritic cells are believed to play such role, little is known about scavengers in the thymus. We found that CD4+/CD11b+/CD11c− cells were present in the thymus and that they expressed costimulatory molecules for T cell selection and possessed Ag-presenting activity. Moreover, these CD4+/CD11b+ cells phagocytosed apoptotic thymocytes much more efficiently than thymic CD4−/CD11b+ cells as well as activated peritoneal macrophages. CD4+/CD11b+ cells became larger along with thymus development, while no such change was observed in CD4−/CD11b+ cells. Finally, engulfed nuclei were frequently found in CD4+/CD11b+ cells. These results strongly suggest that thymic CD4+/CD11b+ cells are major scavengers of apoptotic thymocytes.
Cutting Edge: Multiple Autoimmune Pathways in kd/kd Mice
Authors: Hancock Wayne W. , Tsai Tsai-Lung , Madaio Michael P. , Gasser David L. 
Published: April 2014

Abstract
The kidney disease (kd) mutation was transferred to a C57BL/6 (B6) background by selection for closely linked microsatellite markers. The resulting congenic strain, B6.kd, was mated with partners homozygous for targeted mutations of CD4, CD8, CD28, IL-2, recombinase-activating gene-1 (Rag-1), ICAM-1, or β2-microglobulin. In most of the resulting double mutants, kidney disease occurred as readily and as severely as in the B6.kd controls, although disease occurred somewhat less frequently in age-matched CD28−/− kd/kd mice. Immunohistology demonstrated a predominance of macrophages in the lesions of B6.kd and most of the double mutants, with the remaining cells consisting of T cells and variable numbers of NK cells. In Rag-1−/− kd/kd, ∼50% of infiltrating cells were macrophages, and ∼50% were NK cells. These results suggest that the initial lesion caused by the mutant gene is intrinsic to the kidney and that the immune response that subsequently occurs can involve any one of several different cellular compositions.