bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted Delivery of Immunogen to Primate M Cells with Tetragalloyl Lysine Dendrimer
Authors: Misumi Shogo , Masuyama Mitsuaki , Takamune Nobutoki , Nakayama Daisuke , Mitsumata Ryotarou , Matsumoto Hirokazu , Urata Norimitsu , Takahashi Yoshihiro , Muneoka Atsunobu , Sukamoto Takayuki , Fukuzaki Koichiro , Shoji Shozo 
Published: May 2009

Abstract
Effective uptake of Ags by specialized M cells of gut-associated lymphoid tissues is an important step in inducing efficient immune responses after oral vaccination. Although stable nontoxic small molecule mimetics of lectins, such as synthetic multivalent polygalloyl derivatives, may have potential in murine M cell targeting, it remains unclear whether synthetic multivalent polygalloyl derivatives effectively target nonhuman and human M cells. In this study, we evaluated the ability of a tetragalloyl derivative, the tetragalloyl-d-lysine dendrimer (TGDK), to target M cells in both in vivo nonhuman primate and in vitro human M-like cell culture models. TGDK was efficiently transported from the lumen of the intestinal tract into rhesus Peyer’s patches by M cells and then accumulated in germinal centers. Oral administration of rhesus CCR5-derived cyclopeptide conjugated with TGDK in rhesus macaque resulted in a statistically significant increase in stool IgA response against rhesus CCR5-derived cyclopeptide and induced a neutralizing activity against SIV infection. Furthermore, TGDK was specifically bound to human M-like cells and efficiently transcytosed from the apical side to the basolateral side in the M-like cell model. Thus, the TGDK-mediated vaccine delivery system represents a potential approach for enabling M cell-targeted mucosal vaccines in primates.
Notch Activation Induces the Generation of Functional NK Cells from Human Cord Blood CD34-Positive Cells Devoid of IL-15
Authors: Haraguchi Kyoko , Suzuki Takahiro , Koyama Noriko , Kumano Keiki , Nakahara Fumio , Matsumoto Akihiko , Yokoyama Yasuhisa , Sakata-Yanagimoto Mamiko , Masuda Shigeo , Takahashi Tsuyoshi , Kamijo Aki , Takahashi Koki , Takanashi Minoko , Okuyama Yoshiki , Yasutomo Koji , Sakano Seiji , Yagita Hideo , Kurokawa Mineo , Ogawa Seishi , Chiba Shigeru 
Published: May 2009

Abstract
The development of NK cells from hematopoietic stem cells is thought to be dependent on IL-15. In this study, we demonstrate that stimulation of human cord blood CD34+ cells by a Notch ligand, Delta4, along with IL-7, stem cell factor, and Fms-like tyrosine kinase 3 ligand, but no IL-15, in a stroma-free culture induced the generation of cells with characteristics of functional NK cells, including CD56 and CD161 Ag expression, IFN-γ secretion, and cytotoxic activity against K562 and Jurkat cells. Addition of γ-secretase inhibitor and anti-human Notch1 Ab to the culture medium almost completely blocked NK cell emergence. Addition of anti-human IL-15-neutralizing Ab did not affect NK cell development in these culture conditions. The presence of IL-15, however, augmented cytotoxicity and was required for a more mature NK cell phenotype. CD56+ cells generated by culture with IL-15, but without Notch stimulation, were negative for CD7 and cytoplasmic CD3, whereas CD56+ cells generated by culture with both Delta4 and IL-15 were CD7+ and cytoplasmic CD3+ from the beginning and therefore more similar to in vivo human NK cell progenitors. Together, these results suggest that Notch signaling is important for the physiologic development of NK cells at differentiation stages beyond those previously postulated.
Trichothecene Mycotoxins Activate Inflammatory Response in Human Macrophages
Authors: Kankkunen Päivi , Rintahaka Johanna , Aalto Annika , Leino Marina , Majuri Marja-Leena , Alenius Harri , Wolff Henrik , Matikainen Sampsa 
Published: May 2009

Abstract
Damp building-related illnesses have caused concern for years in many countries. Although the problem is extensive, the knowledge of the immunological reactions behind damp building-related illnesses is still quite limited. Trichothecene mycotoxins form one major group of toxins, which possibly contribute to the illnesses. Stachybotrys chartarum is a well-known, but also controversial damp building mold and many strains of this mold are capable of producing trichothecenes. In this report, we have examined the effect of S. chartarum and trichothecene mycotoxins on the proinflammatory cytokine response in human macrophages. As a result, satratoxin-positive S. chartarum activated inflammasome-associated caspase-1, which is needed for proteolytic processing of IL-1β and IL-18. Furthermore, purified trichothecene mycotoxins, roridin A, verrucarin A, and T-2 toxin activated caspase-1, and these mycotoxins also strongly enhanced LPS-dependent secretion of IL-1β and IL-18. The satratoxin-positive strain of S. chartarum and the trichothecenes also triggered the activation of caspase-3, which is an effector caspase of apoptosis. Satratoxin-negative S. chartarum was not able to activate either caspase-1 or caspase-3. In conclusion, our results indicate that human macrophages sense trichothecene mycotoxins as a danger signal, which activates caspase-1, and further enables the secretion of IL-1β and IL-18 from the LPS-primed cells.
Potent Phagocytic Activity with Impaired Antigen Presentation Identifying Lipopolysaccharide-Tolerant Human Monocytes: Demonstration in Isolated Monocytes from Cystic Fibrosis Patients
Authors: del Fresno Carlos , García-Rio Francisco , Gómez-Piña Vanesa , Soares-Schanoski Alessandra , Fernández-Ruíz Irene , Jurado Teresa , Kajiji Tasneem , Shu Chen , Marín Elvira , Gutierrez del Arroyo Ana , Prados Concepción , Arnalich Francisco , Fuentes-Prior Pablo , Biswas Subrha K. , López-Collazo Eduardo 
Published: May 2009

Abstract
Monocyte exposure to LPS induces a transient state in which these cells are refractory to further endotoxin stimulation. This phenomenon, termed endotoxin tolerance (ET), is characterized by a decreased production of cytokines in response to the proinflammatory stimulus. We have established a robust model of ET and have determined the time frame and features of LPS unresponsiveness in cultured human monocytes. A large number of genes transcribed in tolerant monocytes were classified as either “tolerizable” or “nontolerizable” depending on their expression levels during the ET phase. Tolerant monocytes exhibit rapid IL-1R-associated kinase-M (IRAK-M) overexpression, high levels of triggering receptor expressed on myeloid cells-1 (TREM-1) and CD64, and a marked down-regulation of MHC molecules and NF-κB2. These cells combine potent phagocytic activity with impaired capability for Ag presentation. We also show that circulating monocytes isolated from cystic fibrosis patients share all the determinants that characterize cells locked in an ET state. These findings identify a new mechanism that contributes to impaired inflammation in cystic fibrosis patients despite a high frequency of infections. Our results indicate that a tolerant phenotype interferes with timing, efficiency, and outcome of the innate immune responses against bacterial infections.
Adiponectin Promotes Endotoxin Tolerance in Macrophages by Inducing IRAK-M Expression
Authors: Zacharioudaki Vassiliki , Androulidaki Ariadne , Arranz Alicia , Vrentzos George , Margioris Andrew N. , Tsatsanis Christos 
Published: May 2009

Abstract
High levels of plasma adiponectin are associated with low levels of inflammatory markers and cardioprotection. The mechanism via which adiponectin exerts its anti-inflammatory effect is yet unknown. In the present study, we demonstrate that globular adiponectin (gAd) induces the expression of the inactive isoform of IL-1R-associated kinases (IRAK), IRAK-M. Homologous deletion of IRAK-M in IRAK-M−/− mice abolished the tolerogenic properties of gAd because pretreatment of IRAK-M−/− macrophages with gAd did not suppress LPS-induced proinflammatory cytokine production. GAd activated the MAPKs MEK1/2 and ERK1/2 in macrophages via their upstream regulator Tpl2. Activation of ERK1/2 via Tpl2 appeared necessary for the induction of IRAK-M because gAd did not induce IRAK-M in Tpl2−/− macrophages or in macrophages pretreated with the MEK1/2 inhibitor UO126. In addition, activation of PI3K and Akt1 also appeared necessary for the induction of IRAK-M by gAd, because treatment of Akt1−/− macrophages or pretreatment of macrophages with the PI3K inhibitor wortmannin abolished gAd-induced IRAK-M expression. Analysis of IRAK-M expression in human peripheral blood cells confirmed that serum adiponectin was negatively associated with IRAK-M and responsiveness to LPS. In conclusion, our data demonstrate that IRAK-M is a major mediator of gAd-induced endotoxin tolerance in primary macrophages, expression of which depends on the activation of Tpl2/ERK and PI3K/Akt1 signaling pathways.
Presence of Membrane-Bound TGF-β1 and Its Regulation by IL-2-Activated Immune Cell-Derived IFN-γ in Head and Neck Squamous Cell Carcinoma Cell Lines
Authors: Ahn Yong-Oon , Lee June-Chul , Sung Myung-Whun , Heo Dae Seog 
Published: May 2009

Abstract
The presence of membrane-bound TGF-β1 (mTGF-β1) has been recently observed in regulatory T cells, but only a few studies have reported the same phenomenon in cancer cells. In this study, we investigate the regulation of mTGF-β1 expression in five head and neck squamous cell carcinoma cell lines using FACS analysis. Through blocking Ab and exogenous cytokine treatment experiments, we found that expression of mTGF-β1 is significantly induced by the activated immune cell-derived factor IFN-γ. In addition, IFN-γ and TNF-α are shown to have a synergistic effect on mTGF-β1 expression. Moreover, we found that exogenous TNF-α induces endogenous TNF-α mRNA expression in an autocrine loop. In contrast to previous reports, we confirm that, in this model, mTGF-β1 is neither a rebound form of once-secreted TGF-β1 nor an activated form of its precursor membrane latency-associated peptide. Inhibitors of transcription (actinomycin D), translation (cycloheximide), or membrane translocation (brefeldin A) effectively block the induction of mTGF-β1, which suggests that induction of mTGF-β1 by IFN-γ and/or TNF-α occurs through de novo synthesis. These findings suggest that some cancer cells can detect immune activating cytokines, such as IFN-γ and TNF-α, and actively block antitumor immunity by induction of mTGF-β1.
T-bet Inhibits the In Vivo Differentiation of Parasite-Specific CD4+ Th17 Cells in a T Cell-Intrinsic Manner
Authors: Guo Siqi , Cobb Dustin , Smeltz Ronald B. 
Published: May 2009

Abstract
CD4+ Th17 cells have emerged as a new T cell subset in the Th1/Th2 paradigm, and efforts have shifted toward understanding the factors that regulate their development in vivo. To analyze the role of the transcription factor T-bet in regulation of Th17 cells, we used a murine model of Trypanosoma cruzi infection, a protozoan parasite that causes Chagas disease in humans. Infection of Tbx21−/− mice led to normal, unimpaired development of Ag-specific CD4+ T cells producing IFN-γ. However, a robust Th17 response developed concomitant with Th1 responses. Despite significant IFN-γ production, the physiological effects of Th17 responses prevailed as there was a sharp increase in Gr-1+Ly6G+ neutrophils. Adoptive transfer of T cells from infected Tbx21−/− mice into Rag-2−/− mice (Tbx21+/+) revealed that CD4+ T cells maintained their IL-17-producing phenotype, including those cells capable of producing both IFN-γ and IL-17. Furthermore, and in contrast to the effects of IL-2 on Th17 development, IL-2 had no effect on IL-17 production by primed T cells. Importantly, adoptive transfer of T cells from naive Tbx21−/− mice into infected Rag-2−/− mice recapitulated the differentiation of T. cruzi-specific Th17 cells observed in infected Tbx21−/− mice. Conversely, transfer of wild-type T cells into infected Tbx21−/− mice did not reveal an increase in Th17 development. These results demonstrate that T-bet regulates the differentiation of T. cruzi-specific Th17 cells in vivo in a T cell-intrinsic manner. These data provide important insight into the role of T-bet in regulation of parasite-specific Th17 responses.
TLR Signals Promote IL-6/IL-17-Dependent Transplant Rejection
Authors: Chen Luqiu , Ahmed Emily , Wang Tongmin , Wang Ying , Ochando Jordi , Chong Anita S. , Alegre Maria-Luisa 
Published: May 2009

Abstract
Acute allograft rejection has often been correlated with Th1 differentiation, whereas transplantation tolerance is frequently associated with induction of regulation. The discovery of the Th17 phenotype has prompted its scrutiny in transplant rejection. Although IL-17 has recently been observed in settings of acute allograft rejection and drives rejection in T-bet-deficient mice that have impaired type 1 T cell responses, there is little evidence of its requirement during acute rejection in wild-type animals. We and others have previously shown that TLR9 signaling by exogenous CpG at the time of transplantation is sufficient to abrogate anti-CD154-mediated acceptance of fully mismatched cardiac allografts. In this study, we investigated the mechanism by which acute rejection occurs in this inflammatory context. Our results indicate that CpG targets recipient hemopoietic cells and that its pro-rejection effects correlate both with prevention of anti-CD154-mediated conversion of conventional CD4+ T cells into induced regulatory T cells and with the expression of IFN-γ and IL-17 by intragraft CD4+ T cells. Moreover, the combined elimination of IL-6 and IL-17 signaling abrogated the ability of CpG to promote acute cardiac allograft rejection. Thus, proinflammatory signals at the time of transplantation can change the quality of the effector immune response and reveal a pathogenic function for IL-6 and IL-17 in wild-type recipients.
RhoH/TTF Negatively Regulates Leukotriene Production in Neutrophils
Authors: Daryadel Arezoo , Yousefi Shida , Troi David , Schmid Inès , Schmidt-Mende Jan , Mordasini Carlo , Dahinden Clemens A. , Ziemiecki Andrew , Simon Hans-Uwe 
Published: May 2009

Abstract
Leukotriene B4 (LTB4) is an important proinflammatory lipid mediator generated by neutrophils upon activation. GM-CSF stimulation is known to enhance agonist-mediated LTB4 production of neutrophils within minutes, a process called “priming”. In this study, we demonstrate that GM-CSF also limits the production of LTB4 by neutrophils via a transcriptional mechanism at later time points. We identified hemopoietic-specific Ras homologous (RhoH)/translocation three four (TTF), which was induced following GM-CSF stimulation in neutrophils, as a key regulator in this process. Neutrophils derived from RhoH/TTF-deficient (Rhoh−/−) mice demonstrated increased LTB4 production upon activation compared with normal mouse neutrophils. Moreover, neutrophils from cystic fibrosis patients expressed enhanced levels of RhoH/TTF and generated less LTB4 upon activation compared with normal human neutrophils. Taken together, these data suggest that RhoH/TTF represents an inducible feedback inhibitor in neutrophils that is involved in the limitation of innate immune responses.
Human Pregnancy Up-Regulates Tim-3 in Innate Immune Cells for Systemic Immunity
Authors: Zhao Jie , Lei Zhang , Liu Yanyan , Li Bo , Zhang Liang , Fang Haoshu , Song Chuanwang , Wang Xiaomei , Zhang Gui-Mei , Feng Zuo-Hua , Huang Bo 
Published: May 2009

Abstract
Pregnant women have both the local immune tolerance at the maternal-fetal interface and the systemic immune defense against pathogens. To date, regardless of the extensive investigation on the maternal-fetal immune tolerance, the maintenance of systemic immune defense in pregnant women still remains poorly understood. In the present study, we demonstrate that the immunoregulatory molecule T cell Ig and mucin domain (Tim)-3 plays important roles in innate and adaptive immunity of human pregnancy. During pregnancy, Tim-3 is strikingly up-regulated in peripheral blood of pregnant women, most by monocytes but not by T or B cells. The increased IL-4/STAT6 signaling may contribute to such up-regulation of Tim-3. In turn, the increased Tim-3 enhances not only innate immunity but also Th1-associated immune responses of pregnant women against pathogens. In contrast, our clinical data show that abnormal Tim-3 expression level might be connected to the pregnancy loss. In conclusion, our data show in this study that an immune regulatory molecule Tim-3, by virtue of its up-regulation in innate immune cells in pregnant women, enhances both innate and adaptive immune responses. Nevertheless, the abnormality of Tim-3 in pregnant woman may be deleterious to normal pregnancy.
Differential Expression of Granzyme B and C in Murine Cytotoxic Lymphocytes
Authors: Cai Sheng F. , Fehniger Todd A. , Cao Xuefang , Mayer Joshua C. , Brune Joel D. , French Anthony R. , Ley Timothy J. 
Published: May 2009

Abstract
Cytotoxic lymphocytes use the granule exocytosis pathway to kill pathogen-infected cells and tumor cells. Although many genes in this pathway have been extensively characterized (e.g., perforin, granzymes A and B), the role of granzyme C is less clear. We therefore developed a granzyme C-specific mAb and used flow cytometry to examine the expression of granzyme B and C in the lymphocyte compartments of wild-type and mutant GzmB−/− cre mice, which have a small deletion in the granzyme B gene. We detected granzyme B and C expression in CD4+ and CD8+ T cells activated with CD3/CD28 beads or MLRs. Stimulation of NK cells in vitro with IL-15 also induced expression of both granzymes. Granzyme C up-regulation was delayed relative to granzyme B in wild-type lymphocytes, whereas GzmB−/− cre cells expressed granzyme C earlier and more abundantly on a per-cell basis, suggesting that the deleted 350-bp region in the granzyme B gene is important for the regulation of both granzymes B and C. Quantitative RT-PCR revealed that granzyme C protein levels were regulated by mRNA abundance. In vivo, a population of wild-type CD8αα+ intraepithelial lymphocytes constitutively expressed granzyme B and GzmB−/− cre intraepithelial lymphocytes likewise expressed granzyme C. Using a model of a persistent murine CMV infection, we detected delayed expression of granzyme C in NK cells from infected hosts. Taken together, these findings suggest that granzyme C is activated with persistent antigenic stimulation, providing nonredundant backup protection for the host when granzyme B fails.
IL-17A-Expressing T Cells Are Essential for Bacterial Clearance in a Murine Model of Hypersensitivity Pneumonitis
Authors: Simonian Philip L. , Roark Christina L. , Wehrmann Fabian , Lanham Allison M. , Born Willi K. , O'Brien Rebecca L. , Fontenot Andrew P. 
Published: May 2009

Abstract
Hypersensitivity pneumonitis (HP) is an inflammatory lung disease characterized by a diffuse mononuclear cell infiltrate in the lung that can progress to pulmonary fibrosis with chronic exposure to an inhaled Ag. We previously reported that C57BL/6 mice repeatedly exposed to the ubiquitous microorganism Bacillus subtilis develop mononuclear infiltrates in the lung that contain Vγ6/Vδ1+ γδ T cells. In the absence of this T cell subset, mice treated with B. subtilis had significantly increased collagen deposition in the lung, suggesting a regulatory role for Vγ6/Vδ1+ γδ T cells. To further investigate the role of Vγ6/Vδ1+ γδ T cells in B. subtilis-induced lung fibrosis, we exposed transgenic Vγ6/Vδ1 mice to this microorganism and found decreased collagen content in the lung compared with wild-type C57BL/6 mice. Cytokine analysis of lung homogenates from wild-type C57BL/6 mice demonstrated increased IL-17A concentrations with repeated exposure to B. subtilis. In the absence of IL-17 receptor signaling, IL-17ra−/− mice had delayed clearance of B. subtilis with increased lung inflammation and fibrosis. Although IL-17A was predominantly expressed by Vγ6/Vδ1+ T cells, a compensatory increase in IL-17A expression by CD4+ T cells was seen in the absence of γδ T cells that resulted in similar levels of IL-17A in the lungs of TCRδ−/− and wild-type C57BL/6 mice. In combination, our data suggest an important role for IL-17A-expressing T lymphocytes, both γδ and αβ T cells, in eliminating this microorganism that prevents excessive inflammation and eventual lung fibrosis in this murine model of B. subtilis-induced hypersensitivity pneumonitis.
A Backup Role of DNA Polymerase κ in Ig Gene Hypermutation Only Takes Place in the Complete Absence of DNA Polymerase η
Authors: Faili Ahmad , Stary Anne , Delbos Frédéric , Weller Sandra , Aoufouchi Said , Sarasin Alain , Weill Jean-Claude , Reynaud Claude-Agnès 
Published: May 2009

Abstract
Patients with the variant form of xeroderma pigmentosum (XPV) syndrome have a genetic deficiency in DNA polymerase (Pol) η, and display accordingly an increased skin sensitivity to UV light, as well as an altered mutation pattern of their Ig V genes in memory B cells, alteration that consists in a reduced mutagenesis at A/T bases. We previously suggested that another polymerase with a different mutation signature, Pol κ, is used as backup for Ig gene hypermutation in both humans and mice in cases of complete Pol η deficiency, a proposition supported in this study by the analysis of Pol η × Pol κ double-deficient mice. We also describe a new XPV case, in which a splice site mutation of the first noncoding exon results in a decreased mRNA expression, a mRNA that otherwise encodes a normal Pol η protein. Whereas the Pol η mRNA level observed in patient’s fibroblasts is one-twentieth the value of healthy controls, it is only reduced to one-fourth of the normal level in activated B cells. Memory B cells from this patient showed a 50% reduction in A/T mutations, with a spectrum that still displays a strict Pol η signature. Pol η thus appears as a dominant enzyme in hypermutation, its presence precluding the use of a substitute enzyme even in conditions of reduced availability. Such a dominant behavior may explain the lack of Pol κ signature in Ig gene mutations of some XPV patients previously described, for whom residual Pol η activity might exist.
Regulation of Helminth-Induced Th2 Responses by Thymic Stromal Lymphopoietin
Authors: Ramalingam Thirumalai R. , Pesce John T. , Mentink-Kane Margaret M. , Madala Satish , Cheever Allen W. , Comeau Michael R. , Ziegler Steven F. , Wynn Thomas A. 
Published: May 2009

Abstract
Thymic stromal lymphopoietin was recently identified as a master switch for the development of allergen-driven Th2 responses. However, the role of thymic stromal lymphopoietin (TSLP) in the development of helminth-induced Th2 responses is unclear. Here, using TSLPR−/− mice, we show that while TSLPR signaling participates in the development of Schistosoma mansoni egg-induced CD4+ Th2 responses, it plays only a transient role in the development of Th2-dependent pathology in the lung, liver, and intestine. Studies conducted in a pulmonary granuloma model showed that while a reduction in IL-4/IL-13-dependent granulomatous inflammation and tissue eosinophilia was observed in TSLPR−/− mice undergoing a primary response, lesion formation was not affected during a secondary granulomatous response, even though IL-5 and IL-13 were modestly reduced in the knockout mice. To evaluate the importance of TSLPR signaling in the development of a chronic Th2-dependent response, TSLPR−/− mice were also infected with S. mansoni cercariae. Here, the only significant difference noted in TSLPR−/− mice was a modest decrease in liver fibrosis in acutely infected animals. The transient decrease in fibrosis was associated with increased production of the antifibrotic cytokine IFN-γ and decreased production of the profibrotic cytokine IL-13. Although the altered cytokine response persisted in chronically infected TSLPR−/− mice, it failed to reduce granuloma formation or fibrosis, confirming that TSLPR signaling plays a limited role in the development of chronic Th2-dependent pathology. Collectively, these findings suggest that while TSLPR signaling serves a key role in allergen-driven Th2 responses, it exerts minor regulatory activity during this chronic helminth infection.