bluuebunny/crossref_metadata_2025_split huggingface dataset:
CC Chemokine Receptor 2 Expression in Donor Cells Serves an Essential Role in Graft-versus-Host-Disease
Authors: Rao Arun R. , Quinones Marlon P. , Garavito Edgar , Kalkonde Yogeshwar , Jimenez Fabio , Gibbons Caroline , Perez Jennifer , Melby Peter , Kuziel William , Reddick Robert L. , Ahuja Sunil K. , Ahuja Seema S. 
Published: April 2014

Abstract
The complete repertoire of cellular and molecular determinants that influence graft-vs-host disease (GVHD) is not known. Using a well-established murine model of GVHD (B6→bm12 mice), we sought to elucidate the role of the donor non-T cell compartment and molecular determinants therein in the pathogenesis of GVHD. In this model the acute GVHD-inducing effects of purified B6 wild-type (wt) CD4+ T cells was inhibited by wt non-T cells in a dose-dependent manner. Paradoxically, unlike the chronic GVHD phenotype observed in bm12 mice transplanted with B6wt unfractionated splenocytes, bm12 recipients of B6ccr2-null unfractionated splenocytes developed acute GVHD and died of IFN-γ-mediated bone marrow aplasia. This switch from chronic to acute GVHD was associated with increased target organ infiltration of activated CD4+ T cells as well as enhanced expression of Th1/Th2 cytokines, chemokines, and the antiapoptotic factor bfl1. In vitro, ccr2−/− CD4+ T cells in unfractionated splenocytes underwent significantly less activation-induced cell death than B6wt CD4+ T cells, providing another potential mechanistic basis along with enhanced expression of bfl1 for the increased numbers of activated T cells in target organs of B6ccr2−/− splenocyte→bm12 mice. Collectively, these findings have important clinical implications, as they implicate the donor non-T cell compartment as a critical regulator of GVHD and suggest that ccr2 expression in this cellular compartment may be an important molecular determinant of activation-induced cell death and GVHD pathogenesis.
Monoclonal Anti-MAGE-3 CTL Responses in Melanoma Patients Displaying Tumor Regression after Vaccination with a Recombinant Canarypox Virus
Authors: Karanikas Vaios , Lurquin Christophe , Colau Didier , van Baren Nicolas , De Smet Charles , Lethé Bernard , Connerotte Thierry , Corbière Véronique , Demoitié Marie-Ange , Liénard Danielle , Dréno Brigitte , Velu Thierry , Boon Thierry , Coulie Pierre G. 
Published: April 2014

Abstract
We have analyzed the T cell responses of HLA-A1 metastatic melanoma patients with detectable disease, following vaccination with a recombinant ALVAC virus, which bears short MAGE-1 and MAGE-3 sequences coding for antigenic peptides presented by HLA-A1. To evaluate the anti-MAGE CTL responses, we resorted to antigenic stimulation of blood lymphocytes under limiting dilution conditions, followed by tetramer analysis and cloning of the tetramer-positive cells. The clones were tested for their specific lytic ability and their TCR sequences were obtained. Four patients who showed tumor regression were analyzed, and an anti-MAGE-3.A1 CTL response was observed in three of these patients. Postvaccination frequencies of anti-MAGE-3.A1 CTL were 3 × 10−6, 3 × 10−3, and 3 × 10−7 of the blood CD8 T cells, respectively. These three responses were monoclonal. No anti-MAGE-1.A1 CTL response was observed. These results indicate that, like peptide immunization, ALVAC immunization produces monoclonal responses. They also suggest that low-level antivaccine CTL responses can initiate a tumor regression process. Taken together, our analysis of anti-MAGE-3.A1 T cell responses following peptide or ALVAC vaccination shows a degree of correlation between CTL response and tumor regression, but firm conclusions will require larger numbers.
Gene Transfer of a Cell Cycle Modulator Exerts Anti-Inflammatory Effects in the Treatment of Arthritis
Authors: Nonomura Yoshinori , Kohsaka Hitoshi , Nagasaka Kenji , Miyasaka Nobuyuki 
Published: April 2014

Abstract
Forced expression of a cyclin-dependent kinase inhibitor gene, p21Cip1 in the synovial tissues was effective in treating animal models of rheumatoid arthritis. Synovial hyperplasia in the treated joints was suppressed, reflecting the inhibitory effect of p21Cip1 on cell cycle progression. Additionally, lymphocyte infiltration, expression of inflammatory cytokines, and destruction of the bone and cartilage were inhibited. To determine why the cell cycle regulator gene exerted such anti-inflammatory effects, we investigated gene expression by rheumatoid synovial fibroblasts with or without the p21Cip1 gene transferred. We have found that p21Cip1 gene transfer down-regulates expression of various inflammatory mediators and tissue-degrading proteinases that are critically involved in the pathology of rheumatoid arthritis. These molecules included IL-6, -8, type I IL-1R (IL-1R1), monocyte chemoattractant protein-1, macrophage inflammatory protein-3α, cathepsins B and K, and matrix metalloproteinases-1 and -3. Down-regulation of IL-1R1 by p21Cip1 resulted in attenuated responsiveness to IL-1. Inhibition of the inflammatory gene expression by p21Cip1 was seen even when IL-1 is absent. This IL-1R1-independent suppression was accompanied by reduced activity of c-Jun N-terminal kinase, which was associated with p21Cip1, and inactivation of NF-κB and AP-1. These multiple regulatory effects should work in concert with the primary effect of inhibiting cell cycle in ameliorating the arthritis, and suggest a heretofore unexplored relationship between cyclin-dependent kinase inhibitor gene and inflammatory molecules.
Up-Regulation of Hlx in Immature Th Cells Induces IFN-γ Expression
Authors: Zheng Wei-ping , Zhao Qian , Zhao Xinyan , Li Baiyong , Hubank Mike , Schatz David G. , Flavell Richard A. 
Published: April 2014

Abstract
Differentiation of Th cells from naive precursors is a dynamic process that involves multiple transcription factors acting at specific time points to regulate gene expression. In this study we show that the homeobox transcription factor Hlx is up-regulated early in Th1 cell differentiation. Mice constitutively expressing an Hlx transgene driven by a CD4 promoter showed marked reduction in the CD4+CD8+ thymocyte population. The Hlx transgenic mice generated increased numbers of Th1 cells in response to keyhole limpet hemocyanin immunization. After differentiation under Th2-polarizing conditions in vitro, the transgenic CD4 T cells expressed high levels of IFN-γ. Intracellular cytokine staining revealed that in addition to Th2 cells, large numbers of Th0 and Th1 cells were generated from such in vitro differentiated transgenic CD4 T cells. Retrovirally overexpressed Hlx also induced the aberrant expression of IFN-γ in normal CD4 T cells differentiated under Th2-polarizing conditions. This effect was apparent only when Hlx was introduced into the cells by retroviral infection at an early time point that led to the expression of the retrovirally transferred Hlx gene at a time comparable to that of the up-regulation of the endogenous Hlx during Th1 cell differentiation. Later infection with Hlx-expressing retrovirus showed no effect. Thus, the induction of IFN-γ expression by Hlx depends on a permissive epigenetic state of the IFN-γ gene locus and/or the molecular context of the immature Th cells.
NK Cells Regulate CD8+ T Cell Effector Function in Response to an Intracellular Pathogen
Authors: Vankayalapati Ramakrishna , Klucar Peter , Wizel Benjamin , Weis Stephen E. , Samten Buka , Safi Hassan , Shams Homayoun , Barnes Peter F. 
Published: April 2014

AbstractWe studied the role of NK cells in regulating human CD8+ T cell effector function against mononuclear phagocytes infected with the intracellular pathogen Mycobacterium tuberculosis. Depletion of NK cells from PBMC of healthy tuberculin reactors reduced the frequency of M. tuberculosis-responsive CD8+IFN-γ+ cells and decreased their capacity to lyse M. tuberculosis-infected monocytes. The frequency of CD8+IFN-γ+cells was restored by soluble factors produced by activated NK cells and was dependent on IFN-γ, IL-15, and IL-18. M. tuberculosis-activated NK cells produced IFN-γ, activated NK cells stimulated infected monocytes to produce IL-15 and IL-18, and production of IL-15 and IL-18 were inhibited by anti-IFN-γ. These findings suggest that NK cells maintain the frequency of M. tuberculosis-responsive CD8+IFN-γ+ T cells by producing IFN-γ, which elicits secretion of IL-15 and IL-18 by monocytes. These monokines in turn favor expansion of Tc1 CD8+ T cells. The capacity of NK cells to prime CD8+ T cells to lyse M. tuberculosis-infected target cells required cell-cell contact between NK cells and infected monocytes and depended on interactions between the CD40 ligand on NK cells and CD40 on infected monocytes. NK cells link the innate and the adaptive immune responses by optimizing the capacity of CD8+ T cells to produce IFN-γ and to lyse infected cells, functions that are critical for protective immunity against M. tuberculosis and other intracellular pathogens.
APC-Independent Activation of NK Cells by the Toll-Like Receptor 3 Agonist Double-Stranded RNA
Authors: Schmidt Kerstin N. , Leung Beatrice , Kwong Mandy , Zarember Kol A. , Satyal Sanjeev , Navas Tony A. , Wang Fay , Godowski Paul J. 
Published: April 2014

Abstract
Toll-like receptors (TLRs) play a fundamental role in the recognition of bacteria and viruses. TLR3 is activated by viral dsRNA and polyinosinic-polycytidylic acid (poly(I:C)), a synthetic mimetic of viral RNA. We show that NK cells, known for their capacity to eliminate virally infected cells, express TLR3 and up-regulate TLR3 mRNA upon poly(I:C) stimulation. Treatment of highly purified NK cells with poly(I:C) significantly augments NK cell-mediated cytotoxicity. Poly(I:C) stimulation also leads to up-regulation of activation marker CD69 on NK cells. Furthermore, NK cells respond to poly(I:C) by producing proinflammatory cytokines like IL-6 and IL-8, as well as the antiviral cytokine IFN-γ. The induction of cytokine production by NK cells was preceded by activation of NF-κB. We conclude that the ability of NK cells to directly recognize and respond to viral products is important in mounting effective antiviral responses.
Cognate B Cell Signaling via MHC Class II: Differential Regulation of B Cell Antigen Receptor and MHC Class II/Ig-αβ Signaling by CD22
Authors: Mills David M. , Stolpa John C. , Cambier John C. 
Published: April 2014

AbstractRecent studies demonstrate that MHC class II molecules can signal via associated Ig-αβ dimers, signal transducers previously thought to function only in B cell Ag receptor (BCR) signaling. Surprisingly, the biologic outputs of MHC class II and BCR ligation (by thymus-dependent Ags) differ, e.g., MHC class II signaling leads to robust proliferation and extension of pseudopods. It seemed possible that these differences might be due, at least in part, to differential use of inhibitory coreceptors thought to modulate membrane Ig signals. In this study, we demonstrate that CD22, an inhibitory BCR coreceptor, neither associates with nor functions in MHC class II/Ig-αβ signaling. Interestingly, CD22 is actively excluded from cell surface MHC class II aggregates.
Cutting Edge: An Endogenous Pathway to Systemic Inflammatory Response Syndrome (SIRS)-Like Reactions through Toll-Like Receptor 4
Authors: Johnson Geoffrey B. , Brunn Gregory J. , Platt Jeffrey L. 
Published: April 2014

Abstract
Systemic inflammatory response syndrome (SIRS) is typically associated with trauma, surgery, or acute pancreatitis. SIRS resembles sepsis, triggered by exogenous macromolecules such as LPS acting on Toll-like receptors. What triggers SIRS in the absence of infection, however, is unknown. In this study, we report that a SIRS-like response can be induced in mice by administration of soluble heparan sulfate, a glycosaminoglycan associated with nucleated cells and extracellular matrices, and by elastase, which cleaves and releases heparan sulfate proteoglycans. The ability of heparan sulfate and elastase to induce SIRS depends on functional Toll-like receptor 4, because mutant mice lacking that receptor or its function do not respond. These results provide a molecular explanation for the initiation of SIRS.
Inducible Heat Shock Protein 70 Promotes Myelin Autoantigen Presentation by the HLA Class II
Authors: Mycko Marcin P. , Cwiklinska Hanna , Szymanski Jacek , Szymanska Bozena , Kudla Grzegorz , Kilianek Lukasz , Odyniec Artur , Brosnan Celia F. , Selmaj Krzysztof W. 
Published: April 2014

AbstractIn this study, we investigated the role of the inducible form of heat shock protein 70 (hsp70) in the presentation of the major putative autoantigen in multiple sclerosis, myelin basic protein (MBP), in the context of appropriate MHC class II. By coimmunoprecipitation, we found that MBP is associated with hsp70 in APC in an ATP/ADP-dependent manner. Additionally, using confocal microscopy, hsp70 was detected in the endocytic pathway of APC, where it colocalized with MBP and HLA-DR. The immunodominant epitopes of MBP 85–99 and 80–99 were shown to bind selectively and specifically to hsp70 by surface plasmon resonance. The functional significance of MBP interaction with hsp70 was demonstrated by the detection of enhanced responses of an MBP-specific T cell hybridoma to MBP and MBP 80–99 with increasing levels of hsp70 and reduced responses when hsp70 expression was diminished within APC-expressing DRA*0101, DRB1*1501 (DR1501). However, when MBP 85–99 was used as the stimulus, T cell hybridoma responses were not enhanced by hsp70 overexpression within APC, suggesting that hsp70 contributes to Ag processing rather than Ag presentation. The importance of a direct association between MBP and hsp70 in the presentation pathways was demonstrated by enhanced efficacy of MBP presentation by APC transfected with a plasmid vector encoding a fusion hsp70-MBP protein. This is the first report on the involvement of self-inducible hsp70 in MHC class II-dependent autoantigen processing by APC. It implicates that aberrant self hsp expression may lead to the enhancement/modulation of autoimmune responses.
Effects of T Cell Frequency and Graft Size on Transplant Outcome in Mice
Authors: He Chunshui , Schenk Soren , Zhang Qiwei , Valujskikh Anna , Bayer Jörg , Fairchild Robert L. , Heeger Peter S. 
Published: April 2014

Abstract
The features that determine whether graft-reactive T lymphocytes develop into effector cells capable of mediating organ destruction are not well understood. To investigate potential factors involved in this process, we first confirmed that female recipient mice acutely rejected minor Ag-disparate male skin, but not heart transplants. Despite this difference in outcome, heart and skin transplantation induced antidonor T cell responses of similar magnitude, specificity, and cytokine profile. The heart-graft-primed T cells transiently infiltrated the graft and ultimately induced the development of chronic transplant vasculopathy. Increasing the frequency of donor-reactive T cells by presensitization or by using TCR (CD8+ antimale)-transgenic recipients did not mediate acute rejection but accelerated the pace and severity of the vasculopathy. Surprisingly, decreasing the tissue mass of the donor heart by 50% resulted in acute rejection of these smaller grafts without increasing the frequency of antidonor effector T cells in the recipients. In complementary studies, placement of one or two male skin grafts on a single recipient did not affect the frequency or cytokine profile of the induced antimale T cell repertoire. Nonetheless, the recipients of single grafts acutely rejected the transplanted skin while the recipients of two skin grafts did not. These results provide new insight into the pathogenesis of transplant vasculopathy and provide an explanation for the difference in outcome between murine skin and heart transplants by highlighting the novel concept that the efficiency of transplant-reactive T cell immunity is heavily influenced by the tissue burden it encounters at the effector stage.
Colorectal Cancer Cells Induce Lymphocyte Apoptosis by an Endothelial Monocyte-Activating Polypeptide-II-Dependent Mechanism
Authors: Murray J. Clifford , Symonds Peter , Ward Wynne , Huggins Mary , Tiga Anna , Rice Katherine , Heng Yee M. , Todd Ian , Robins R. Adrian 
Published: April 2014

Abstract
Endothelial monocyte-activating polypeptide-II (EMAP-II) was first isolated from cell growth medium conditioned by tumor cells, and is closely related or identical with the p43 component of the mammalian multisynthase complex. In its secreted form, EMAP-II has multiple cytokine-like activities in vitro, inducing procoagulant activity on the surface of endothelial cells, increasing expression of E- and P-selectins and TNF-R1, and directing migration of monocytes and neutrophils. EMAP-II has also been shown to induce apoptosis in endothelial cells, leading to the suggestion that it is a proinflammatory polypeptide with antiangiogenic activity. The role of secreted EMAP-II in tumors remains poorly understood, and we hypothesized that EMAP-II may play a role in immune evasion by tumor cells. We investigated its effects on lymphocytes, using recombinant protein, or colorectal cancer cell lines, as a source of native EMAP-II. Recombinant EMAP-II inhibits DNA synthesis and cell division, and induces apoptosis in mitogen-activated lymphocytes in PBMC preparations, and in Jurkat T cells. Native EMAP-II, released by or expressed on the surface of colorectal carcinoma cells, also induces activation of caspase 8 and apoptosis of PBLs and Jurkat cells, which are partially blocked by addition of Abs against EMAP-II. Thus, activated lymphocytes, along with proliferating endothelial cells, are targets for the cytotoxic activity of EMAP-II. Membrane-bound and soluble EMAP-II appear to play multiple roles in the tumor microenvironment, one of which is to assist in immune evasion.
The α1β1 and αEβ7 Integrins Define a Subset of Dendritic Cells in Peripheral Lymph Nodes with Unique Adhesive and Antigen Uptake Properties
Authors: Pribila Jonathan T. , Itano Andrea A. , Mueller Kristen L. , Shimizu Yoji 
Published: April 2014

AbstractDendritic cells (DCs) are a heterogeneous population of APCs with critical roles in T cell activation and immune regulation. We report in this study the identification and characterization of a novel subset of DCs resident in skin-draining peripheral lymph nodes of normal mice. This subset of CD11chighCD40highCD8αintermediate (int) DCs expresses the collagen-binding integrin, α1β1, and the E-cadherin-binding integrin, αEβ7. Although α1β1 and αEβ7 are also expressed on CD11chighCD40intCD8αhigh lymphoid DCs, CD11chighCD40highCD8αint DCs demonstrate preferential integrin-mediated adhesion to collagen and fibronectin. This DC subset most likely acquires expression of these integrins in peripheral lymph node, as this subset is not found in the spleen or mesenteric lymph node, and recent DC migrants from the skin lack expression of α1β1 and αEβ7 integrins. Resident CD40high DCs express α1β1 integrin and colocalize with collagen in lymph nodes. When compared with CD11chighCD40highCD8αint DCs lacking expression of these integrins, the α1β1+αEβ7+ DC subset exhibits more efficient formation of Ag-independent conjugates with T cells, and a decreased ability to acquire soluble Ag. Thus, the α1β1 and αEβ7 integrins define a unique population of peripheral lymph node-derived DCs with altered functional properties and adhesive potential that localizes these cells to sites in lymph nodes where Ag presentation to T cells occurs.
Dermal Enhancement: Bacterial Products on Intact Skin Induce and Augment Organ-Specific Autoimmune Disease
Authors: Riminton D. Sean , Kandasamy Rama , Dravec Danijela , Basten Antony , Baxter Alan G. 
Published: April 2014

Abstract
The skin is both an essential barrier for host defense and an important organ of immunity. In this study, we show that the application of cholera toxin to intact mouse skin induces and enhances autoimmune diseases affecting organs at distant anatomic sites, whereas its administration by the mucosal route has been reported to have the opposite effect. First, the CNS autoantigen myelin oligodendrocyte glycoprotein 35–55, when applied repeatedly with cholera toxin to the intact skin of healthy C57BL/6 mice, induced relapsing paralysis with demyelinating immunopathologic features similar to multiple sclerosis. Second, the application of cholera toxin in the absence of autoantigen exacerbated the severity of conventional experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein in CFA. Third, the application of cholera toxin to the intact skin of NOD/Lt mice, with or without insulin B peptide 9–23, exacerbated insulitis and T lymphocyte-derived IFN-γ and IL-4 production in the islets of Langerhans, resulting in an increased incidence and rate of onset of autoimmune diabetes. The data presented in this study highlight the different outcomes of adjuvant administration by different routes. Because dermal application of cholera toxin, and other bacterial products with similar adjuvant activities, is being developed as a clinical vaccination strategy, these data raise the possibility that it could precipitate autoimmune disease in genetically susceptible humans.
Pulmonary Tumors Inefficiently Prime Tumor-Specific T Cells
Authors: O’Mara Leigh A. , Allen Paul M. 
Published: April 2014

Abstract
The lung is a common site of metastatic and primary tumor growth, and has been shown to be an immunosuppressive environment. We tested the impact of the lung environment on the development of tumor-specific T cell responses against the CMS5 fibrosarcoma, and found a deficit in the efficacy of naive tumor-specific DUC18 T cells against tumors established in the lung. One hundred-fold more naive tumor-specific T cells were required to protect against tumor development or reject established tumors in the lung than an identical tumor challenge delivered s.c. in the flank. Importantly, CMS5 growing in the flank facilitated the rejection of tumors present in the lungs. In the presence of flank tumors, transferred T cells were not phenotypically altered but were present in much greater numbers in the parabronchial lymph nodes, bronchoalveolar lavage, and lung parenchyma than in mice bearing lung tumors alone. We hypothesized that APC present in the lung and skin draining lymph nodes were differentially initiating T cell proliferation, leading to differences in the size of the final effector populations. A direct comparison of DUC18 T cell proliferation against APC from flank or lung draining lymph nodes showed profoundly greater proliferation to flank draining lymph node APC. The impaired stimulation of naive T cell proliferation by lung draining APC provides one mechanistic explanation for the lower overall immune response, and inability to effectively reject tumors, in the lung.
B7 Expression on T Cells Down-Regulates Immune Responses through CTLA-4 Ligation via R-T Interactions
Authors: Taylor Patricia A. , Lees Christopher J. , Fournier Sylvie , Allison James P. , Sharpe Arlene H. , Blazar Bruce R. 
Published: April 2014

AbstractAlthough B7 on APCs has a well-recognized role in T cell costimulation, little is known about the functional significance of constitutive and activation-induced B7 expression that also occurs on T cells. To analyze the role of B7 on T cells, B7-1/B7-2-deficient mice (B7 double knockout) and mice overexpressing B7-2 exclusively on T cells (B7-2 transgenic) were used as T cell donors for allogeneic transplant recipients, and graft-vs-host disease (GVHD) was assessed. B7 double-knockout T cells resulted in significant GVHD acceleration compared with wild-type T cells. Conversely, B7-2 transgenic donor T cells mediated reduced GVHD mortality compared with wild-type T cells. Data indicated that B7 expression on T cells down-regulated alloresponses through CTLA-4 ligation. This study is the first to provide definitive in vivo data illustrating the importance of T cell-associated B7 as a negative regulator of immune responses in a clinically relevant murine model of GVHD. The up-regulation of B7 on T cells may be an important component of normal immune homeostasis.