bluuebunny/crossref_metadata_2025_split huggingface dataset:
Absence of Macrophage-Inflammatory Protein-1α Delays Central Nervous System Demyelination in the Presence of an Intact Blood-Brain Barrier
Authors: McMahon Eileen J. , Cook Don N. , Suzuki Kinuko , Matsushima Glenn K. 
Published: April 2014

AbstractChemokines are small chemotactic cytokines that modulate leukocyte recruitment and activation during inflammation. Here, we describe the role of macrophage inflammatory protein-1α (MIP-1α) during cuprizone intoxication, a model where demyelination of the CNS features a large accumulation of microglia/macrophage without T cell involvement or blood-brain barrier disruption. RNase protection assays showed that mRNA for numerous chemokines were up-regulated during cuprizone treatment in wild-type, C57BL/6 mice. RANTES, inflammatory protein-10, and monocyte chemoattractant protein-1 showed greatest expression with initiation of insult at 1–2 wk of treatment, whereas MIP-1α and β increased later at 4–5 wk, coincident with peak demyelination and cellular accumulation. The function of MIP-1α during demyelination was tested in vivo by exposing MIP-1α knockout mice (MIP-1α−/−) to cuprizone and comparing pathology to wild-type mice. Demyelination at 3.5 wk of treatment was significantly decreased in MIP-1α−/− mice (∼36% reduction), a result confirmed by morphology at the electron microscopic level. The delay in demyelination was correlated to apparent decreases in microglia/macrophage and astrocyte accumulation and in TNF-α protein levels. It was possible that larger effects of the MIP-1α deficiency were being masked by other redundant chemokines. Indeed, RNase protection assays revealed increased expression of several chemokine transcripts in both untreated and cuprizone-treated MIP-1α−/− mice. Nonetheless, despite this possible compensation, our studies show the importance of MIP-1α in demyelination in the CNS and highlight its effect, particularly on cellular recruitment and cytokine regulation.
Predominant Th2/Tc2 Polarity of Tumor-Infiltrating Lymphocytes in Human Cervical Cancer
Authors: Sheu Bor-Ching , Lin Rong-Hwa , Lien Huang-Chun , Ho Hong-Nerng , Hsu Su-Ming , Huang Su-Cheng 
Published: April 2014

AbstractCytotoxic T lymphocytes (Tc) play a central role in cellular immunity against cancers. The cytotoxic potential of freshly isolated tumor-infiltrating lymphocytes (TILs) is usually not expressed. This suggests the possible existence of as yet unspecified and perhaps complex immunosuppressive factors or cytokines that affect the anti-tumor capacity of these TILs in the tumor milieu. In the present study, we demonstrated for the first time that TILs derived from human cervical cancer tissue consist mainly of Th2/Tc2 phenotypes. In vitro kinetic assays further revealed that cancer cells could direct the tumor-encountered T cells toward the Th2/Tc2 polarity. Cancer cells promote the production of IL-4 and down-regulate the production of IFN-γ in cancer-encountered T cells. The regulatory effects of cervical cancer cells are mediated mainly by IL-10, and TGF-β plays only a synergistic role. The cancer-derived effects can be reversed by neutralizing anti-IL-10 and anti-TGF-β Abs. IL-10 and TGF-β are present in cancer tissue and weakly expressed in precancerous tissue, but not in normal cervical epithelial cells. Our study strongly suggests important regulatory roles of IL-10 and TGF-β in cancer-mediated immunosuppression.
Early Chemokine Cascades in Murine Cardiac Grafts Regulate T Cell Recruitment and Progression of Acute Allograft Rejection
Authors: Morita Ken , Miura Masayoshi , Paolone David R. , Engeman Tara M. , Kapoor Anil , Remick Daniel G. , Fairchild Robert L. 
Published: April 2014

AbstractThe identification of early inflammatory events after transplant in solid tissue organ grafts that may direct T cell recruitment and promote acute allograft rejection remain largely unknown. To better understand temporal aspects of early inflammatory events in vascularized organ grafts, we tested the intragraft expression of four different chemokines in heterotopically transplanted A/J (H-2a) and syngeneic heart grafts in C57BL/6 (H-2b) recipient mice from 1.5 to 48 h after transplant. Similar temporal expression patterns and equivalent levels of chemokine expression were observed in both syngeneic and allogeneic cardiac allografts during this time period. Expression of the neutrophil chemoattractant growth-related oncogene α (KC) was observed first and reached peak levels by 6 h after transplant and was followed by the monocyte/macrophage chemoattractant protein-1 (JE) and then macrophage inflammatory proteins 1β and 1α. Administration of rabbit KC antiserum to allograft recipients within 30 min of cardiac transplantation attenuated downstream events including intra-allograft expression of the T cell chemoattractants IFN-γ-inducible protein-10 and monokine induced by IFN-γ, cellular infiltration into the allograft, and graft rejection. Similarly, depletion of recipient neutrophils at the time of transplantation significantly extended allograft survival from day 8 to 10 in control-treated recipients up to day 21 after transplant. These results indicate the induction of highly organized cascades of neutrophil and macrophage chemoattractants in cardiac grafts and support the proposal that early inflammatory events are required for optimal recruitment of T cells into allografts during the progression of acute rejection of cardiac allografts.
Deficiency in β2-Microglobulin, But Not CD1, Accelerates Spontaneous Lupus Skin Disease While Inhibiting Nephritis in MRL-FaslprMice: An Example of Disease Regulation at the Organ Level
Authors: Chan Owen T. M. , Paliwal Vipin , McNiff Jennifer M. , Park Se-Ho , Bendelac Albert , Shlomchik Mark J. 
Published: April 2014

AbstractWhen mutations that inactivate molecules that function in the immune system have been crossed to murine lupus strains, the result has generally been a uniform up-regulation or down-regulation of autoimmune disease in the end organs. In the current work we report an interesting dissociation of target organ disease in β2-microglobulin (β2m)-deficient MRL-Faslpr (MRL/lpr) mice: lupus skin lesions are accelerated, whereas nephritis is ameliorated. β2m deficiency affects the expression of classical and nonclassical MHC molecules and thus prevents the normal development of CD8- as well as CD1-dependent NK1+ T cells. To further define the mechanism by which β2m deficiency accelerates skin disease, we studied CD1-deficient MRL/lpr mice. These mice do not have accelerated skin disease, excluding a CD1 or NK1+ T cell-dependent mechanism of β2m deficiency. The data indicate that the regulation of systemic disease is not solely governed by regulation of initial activation of autoreactive lymphocytes in secondary lymphoid tissue, as this is equally relevant to renal and skin diseases. Rather, regulation of autoimmunity can also occur at the target organ level, explaining the divergence of disease in skin and kidney in β2m-deficient mice.
Critical Involvement of OX40 Ligand Signals in the T Cell Priming Events During Experimental Autoimmune Encephalomyelitis
Authors: Ndhlovu Lishomwa C. , Ishii Naoto , Murata Kazuko , Sato Takayuki , Sugamura Kazuo 
Published: April 2014

AbstractOX40 ligand (OX40L) expressed on APCs, and its receptor, OX40 present on activated T cells, are members of the TNF/TNFR family, respectively, and have been located at the sites of inflammatory conditions. We have observed in OX40L-deficient mice (OX40L−/−) an impaired APC capacity and in our recently constructed transgenic mice expressing OX40L (OX40L-Tg), a markedly enhanced T cell response to protein Ags. Using these mice, we demonstrate here the critical involvement of the OX40L-OX40 interaction during the T cell priming events in the occurrence of experimental autoimmune encephalomyelitis (EAE). In OX40L−/− mice, abortive T cell priming greatly reduced the clinical manifestations of actively induced EAE, coupled with a reduction in IFN-γ, IL-2, and IL-6 production in vitro. Adoptive transfer experiments however revealed an efficient transfer of disease to OX40L−/− mice using wild-type donor T cells, indicating an intact capacity of OX40L−/− mice to initiate effector responses. On the other hand, OX40L−/− donor T cells failed to transfer disease to wild-type recipient mice. Furthermore, OX40L-Tg mice developed a greater severity of EAE despite a delayed onset, while both OX40L-Tg/CD28−/− and OX40L-Tg/CD40−/− mice failed to develop EAE demonstrating a requisite for these molecules. These findings indicate a pivotal role played by OX40L in the pathogenesis of EAE.
Control of the Autoimmune Response by Type 2 Nitric Oxide Synthase
Authors: Shi Fu-Dong , Flodström Malin , Kim Soon Ha , Pakala Shyam , Cleary Mary , Ljunggren Hans-Gustaf , Sarvetnick Nora 
Published: April 2014

Abstract
Immune defense against pathogens often requires NO, synthesized by type 2 NO synthase (NOS2). To discern whether this axis could participate in an autoimmune response, we immunized NOS2-deficient mice with the autoantigen acetylcholine receptor, inducing muscle weakness characteristic of myasthenia gravis, a T cell-dependent Ab-mediated autoimmune disease. We found that the acetylcholine receptor-immunized NOS2-deficient mice developed an exacerbated form of myasthenia gravis, and demonstrated that NOS2 expression limits autoreactive T cell determinant spreading and diversification of the autoantibody repertoire, a process driven by macrophages. Thus, NOS2/NO is important for silencing autoreactive T cells and may restrict bystander autoimmune reactions following the innate immune response.
Cutting Edge: Altered Pulmonary Eosinophilic Inflammation in Mice Deficient for Clara Cell Secretory 10-kDa Protein
Authors: Chen Li-Chen , Zhang Zhongjian , Myers Allen C. , Huang Shau-Ku 
Published: April 2014

AbstractClara cell secretory protein (CC10) is a steroid-inducible protein, and its in vivo function is currently unclear. The role of CC10 in modulation of pulmonary allergic inflammation was examined in mice deficient for the CC10 gene. Wild-type and homozygous CC10-deficient mice were sensitized with an Ag, OVA, and challenged with either OVA or saline. When compared with that seen in wild-type mice, a significantly higher level of pulmonary eosinophilia was found in Ag-sensitized and challenged CC10-deficient mice. Significantly increased levels of Th2 cytokines IL-4, IL-5, IL-9, and IL-13 were also found in CC10-deficient mice. In addition, an increased level of eotaxin, but not RANTES, was also seen in CC10-deficient mice. No significant difference was observed in the level of a Th1 cytokine, IFN-γ, between different groups of mice. These results provided the first in vivo evidence that CC10 plays a role in the modulation of pulmonary allergic inflammation.
Cutting Edge: The Spirochetemia of Murine Relapsing Fever Is Cleared by Complement-Independent Bactericidal Antibodies
Authors: Connolly Sean E. , Benach Jorge L. 
Published: April 2014

Abstract
Abs are the major effectors of host defense against infections with Borrelia. Bactericidal murine mAbs and their Fabs destroy B. burgdorferi, the agent of Lyme disease, and relapsing fever Borrelia in the absence of complement. These in vitro observations led to the expansion of a search for functionally similar Abs in vivo. In this study, we demonstrate that functionally unique IgM Abs develop in vivo and are responsible for the elimination of spirochetemia in murine models of relapsing fever, without the assistance of complement. Mice deficient in the fifth or third component of complement can clear the spirochetemia, whereas B cell-deficient mice cannot. The B cell-deficient mice developed spirochetemia that was an order of magnitude higher and persisted for a longer period of time in comparison to the wild-type mice. Additionally, B cell-deficient mice passively immunized with immune IgM and with immune serum were protected from challenge.
Relatively Normal Human Lymphopoiesis but Rapid Turnover of Newly Formed B Cells in Transplanted Nonobese Diabetic/SCID Mice
Authors: Rossi Maria Isabel D. , Medina Kay L. , Garrett Karla , Kolar Grant , Comp Phillip C. , Shultz Leonard D. , Capra J. Donald , Wilson Patrick , Schipul Arthur , Kincade Paul W. 
Published: April 2014

AbstractHuman B lineage lymphocyte precursors in chimeric nonobese diabetic/SCID mice transplanted with umbilical cord blood cells were directly compared with those present in normal bone marrow. All precursor subsets were represented and in nearly normal proportions. Cell cycle activity and population dynamics were investigated by staining for the Ki-67 nuclear Ag as well as by incorporation experiments using 5-bromo-2′-deoxyuridine. Again, this revealed that human B lymphopoiesis in chimeras parallels that in normal marrow with respect to replication and progression through the lineage. Moreover, sequencing of Ig gene rearrangement products showed that a diverse repertoire of VH genes was utilized by the newly formed lymphocytes but there was no evidence for somatic hypermutation. The newly formed B cells frequently acquired the CD5 Ag and had a short life span in the periphery. Thus, all molecular requirements for normal B lymphocyte formation are present in nonobese diabetic/SCID mice, but additional factors are needed for recruitment of B cells into a fully mature, long-lived pool. The model can now be exploited to learn about species restricted and conserved environmental cues for human B lymphocyte production.
Dissociation of Hemopoietic Chimerism and Allograft Tolerance After Allogeneic Bone Marrow Transplantation
Authors: Umemura Akihisa , Morita Hirofumi , Chang Li Xian , Tahan Steven , Monaco Anthony P. , Maki Takashi 
Published: April 2014

AbstractCreation of stable hemopoietic chimerism has been considered to be a prerequisite for allograft tolerance after bone marrow transplantation (BMT). In this study, we demonstrated that allogeneic BMT with bone marrow cells (BMC) prepared from either knockout mice deficient in both CD4 and CD8 T cells or CD3E-transgenic mice lacking both T cells and NK cells maintained a high degree of chimerism, but failed to induce tolerance to donor-specific wild-type skin grafts. Lymphocytes from mice reconstituted with T cell-deficient BMC proliferated when they were injected into irradiated donor strain mice, whereas lymphocytes from mice reconstituted with wild-type BMC were unresponsive to donor alloantigens. Donor-specific allograft tolerance was restored when donor-type T cells were adoptively transferred to recipient mice given T cell-deficient BMC. These results show that donor T cell engraftment is required for induction of allograft tolerance, but not for creation of continuous hemopoietic chimerism after allogeneic BMT, and that a high degree of chimerism is not necessarily associated with specific allograft tolerance.
Regulation of Fas Ligand-Induced Apoptosis by TNF
Authors: Elzey Bennett D. , Griffith Thomas S. , Herndon John M. , Barreiro Ramon , Tschopp Jurg , Ferguson Thomas A. 
Published: April 2014

AbstractFas ligand (FasL, CD95L) expression helps control inflammatory reactions in immune privileged sites such as the eye. Cellular activation is normally required to render lymphoid cells sensitive to FasL-induced death; however, both activated and freshly isolated Fas+ lymphoid cells are efficiently killed in the eye. Thus, we examined factors that might regulate cell death in the eye. TNF levels rapidly increased in the eye after the injection of lymphoid cells, and these cells underwent apoptosis within 24 h. Coinjection of anti-TNF Ab with the lymphoid cells blocked this cell death. Furthermore, TNFR2−/− T cells did not undergo apoptosis in the eyes of normal mice, while normal and TNFR1−/− T cells were killed by apoptosis. In vitro, TNF enhanced the Fas-mediated apoptosis of unactivated T cells through decreased intracellular levels of FLIP and increased production of the pro-apoptotic molecule Bax. This effect was mediated through the TNFR2 receptor. In vivo, intracameral injection of normal or TNFR1−/− 2,4,6-trinitrophenyl-coupled T cells into normal mice induced immune deviation, but TNFR2−/− 2,4,6-trinitrophenyl-coupled T cells were ineffective. Collectively, our results provide evidence of a role for the p75 TNFR in cell death in that TNF signaling through TNFR2 sensitizes lymphoid cells for Fas-mediated apoptosis. We conclude that there is complicity between apoptosis and elements of the inflammatory response in controlling lymphocyte function in immune privileged sites.
Gene Microarrays Reveal Extensive Differential Gene Expression in Both CD4+ and CD8+ Type 1 and Type 2 T Cells
Authors: Chtanova Tatyana , Kemp Roslyn A. , Sutherland Andrew P. R. , Ronchese Franca , Mackay Charles R. 
Published: April 2014

AbstractAn important subdivision of effector T cells can be made based on patterns of cytokine production and functional programs. Type 1 T cells produce IFN-γ and protect against viral pathogens, whereas type 2 cells produce cytokines such as IL-4 and IL-5 and protect against large extracellular parasites. Both CD4+ and CD8+ T cells can be polarized into type 1 or type 2 cytokine-secreting cells, suggesting that both populations play a regulatory role in immune responses. In this study, we used high-density oligonucleotide arrays to produce a comprehensive picture of gene expression in murine CD4+ Th1 and Th2 cells, as well as CD8+ type 1 and type 2 T cells. Polarized type 1 and 2 cells transcribed mRNA for an unexpectedly large number of genes, most of which were expressed in a similar fashion between type 1 and type 2 cells. However, &gt;100 differentially expressed genes were identified for both the CD4+ and CD8+ type 1 and 2 subsets, many of which have not been associated with T cell polarization. These genes included cytokines, transcription factors, molecules involved in cell migration, as well as genes with unknown function. The program for type 1 or type 2 polarization was similar for CD4+ and CD8+ cells, since gene expression patterns were roughly the same. The expression of select genes was confirmed using real-time PCR. The identification of genes associated with T cell polarization may give important insights into functional and phenotypic differences between effector T cell subsets and their role in normal responses and inflammatory disease.
Diverse Transcriptional Response of CD4+ T Cells to Stromal Cell-Derived Factor (SDF)-1: Cell Survival Promotion and Priming Effects of SDF-1 on CD4+ T Cells
Authors: Suzuki Yasuhiro , Rahman Monzur , Mitsuya Hiroaki 
Published: April 2014

AbstractStromal cell-derived factor (SDF)-1 is a ligand for the chemokine receptor CXCR4 which is broadly expressed in lymphocytes, but the effects of SDF-1 on T cells are largely unknown. When examined using complementary DNA microarray, up-regulation of genes which are associated with DNA repair, detoxification, apoptosis, cell morphology, cell adhesion, and signal transduction was seen in CD4+ T cells upon SDF-1 exposure. SDF-1 was shown to promote CD4+ T cell survival through the phosphatidylinositol 3-kinase (PI3K)- and mitogen-activated protein kinase (MAPK)-cascades without cell cycle progression. The proapoptotic Bcl-2 antagonistic of cell death protein was also seen inactivated by the SDF-1-mediated activation of MAPK-extracellular signal-regulated kinases (MEK)-extracellular signal-regulated kinase-ribosomal S6 kinases- and PI3K-pathways. Moreover, the genes known to be associated with cell survival were up-regulated upon SDF-1 exposure and were linked to the MAPK-MEK and PI3K-pathways. Thus, SDF-1 promotes cell survival by two mechanisms: posttranslational inactivation of the cell death machinery and an increased transcription of cell survival-related genes. SDF-1 also primed resting CD4+ T cells for cytokine- and TCR-mediated stimuli. These data suggest that the SDF-1-mediated cell survival combined with its priming function would set T cells to respond to immunologic challenges.
The Role of IFN-γ in the Production of Th2 Subpopulations: Implications for Variable Th2-Mediated Pathologies in Autoimmunity
Authors: Wensky Allen , Garibaldi Marcondes Maria Cecília , Lafaille Juan J. 
Published: April 2014

AbstractIt has become increasingly apparent in studies of mutant mice and observations of disease that cytokine production by fully committed effector T cells within the Th1 and Th2 phenotype can vary within each group. This can potentially influence the type and effectiveness of a given immune response. The factors responsible for inducing variable Th1 and Th2 subtype responses have not been well established. Using transgenic mice expressing the myelin basic protein-specific TCR, we demonstrate here that two distinct populations of Th2 cells that are characterized primarily by differential IL-4 and IL-5 expression levels can be generated depending upon the levels of IFN-γ present at the time of priming. We also demonstrate that populations expressing high levels of IL-4 relative to IL-5 vs those with intermediate levels of IL-4 relative to IL-5 are stable and possess distinct effector functions in an experimental autoimmune encephalomyelitis model.
Direct Recognition of Foreign MHC Determinants by Naive T Cells Mobilizes Specific Vβ Families Without Skewing of the Complementarity-Determining Region 3 Length Distribution
Authors: Sebille Fabien , Gagne Katia , Guillet Marina , Degauque Nicolas , Pallier Annaïck , Brouard Sophie , Vanhove Bernard , Delsuc Marc-André , Soulillou Jean-Paul 
Published: April 2014

AbstractThe capacity of T cells to interact with nonself-APC, also referred to as direct allorecognition, is an essential feature of the cellular response involved in graft rejection. However, there is no study on TCR repertoire biases associated with direct restricted T cell activation. In this paper, we have addressed the impact of direct recognition on the whole naive T cell repertoire, using a new approach that provides, for the first time, an integrated depiction of the quantitative and qualitative alterations in the TCR Vβ transcriptome. This method can differentiate resting patterns from polyclonally activated ones, as evidenced by superantigen usage. According to this new readout, we show that direct recognition of nonself-MHC molecules triggers mRNA accumulation of several TCR Vβ families, specific to the combination studied. Moreover, in marked contrast to the situation that prevails in indirect allorecognition, T cell activation through the direct presentation pathway was not associated with skewing of the complementarity determining region (CDR) 3 length distribution. Altogether, these data argue for the significance of TCR contacts with the MHC framework in direct allorecognition. In addition, the TCR diversity mobilized by this interaction and the massive TCRβ mRNA accumulation observed after a few days of culture suggest that a significant proportion of naive T cells receive a signal leading to TCRβ transcriptional activation even though only a few of them engage in mitosis.