bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antibody Targeting of the CC Chemokine Ligand 5 Results in Diminished Leukocyte Infiltration into the Central Nervous System and Reduced Neurologic Disease in a Viral Model of Multiple Sclerosis
Authors: Glass William G. , Hickey Michelle J. , Hardison Jenny L. , Liu Michael T. , Manning Jerry E. , Lane Thomas E. 
Published: April 2014

Abstract
Intracerebral infection of mice with mouse hepatitis virus, a member of the Coronaviridae family, reproducibly results in an acute encephalomyelitis that progresses to a chronic demyelinating disease. The ensuing neuropathology during the chronic stage of disease is primarily immune mediated and similar to that of the human demyelinating disease multiple sclerosis. Secretion of chemokines within the CNS signals the infiltration of leukocytes, which results in destruction of white matter and neurological impairment. The CC chemokine ligand (CCL)5 is localized in white matter tracts undergoing demyelination, suggesting that this chemokine participates in the pathogenesis of disease by attracting inflammatory cells into the CNS. In this study, we administer a mAb directed against CCL5 to mice with established mouse hepatitis virus-induced demyelination and impaired motor skills. Anti-CCL5 treatment decreased T cell accumulation within the CNS based, in part, on viral Ag specificity, indicating the ability to differentially target select populations of T cells. In addition, administration of anti-CCL5 improved neurological function and significantly (p ≤ 0.005) reduced the severity of demyelination and macrophage accumulation within the CNS. These results demonstrate that the severity of CNS disease can be reduced through the use of a neutralizing mAb directed against CCL5 in a viral model of demyelination.
Intralesional Injection of Adenovirus Encoding CC Chemokine Ligand 16 Inhibits Mammary Tumor Growth and Prevents Metastatic-Induced Death after Surgical Removal of the Treated Primary Tumor
Authors: Guiducci Cristiana , Di Carlo Emma , Parenza Mariella , Hitt Mary , Giovarelli Mirella , Musiani Piero , Colombo Mario P. 
Published: April 2014

Abstract
The CC chemokine ligand (CCL)16 exerts chemotactic activity on human monocytes and lymphocytes. Although no murine homologous has been defined, the TSA mouse adenocarcinoma cells engineered to express human CCL16 are rapidly rejected by syngenic mice. An adenovirus encoding CCL16 (AdCCL16) was generated using a Cre-Lox-based system and was used to determine whether this chemokine might also block pre-existing tumors. Both recombinant and viral CCL16 showed in vitro chemotactic activity for murine CD4+ and CD8+ lymphocytes and dendritic cells (DC). AdCCL16, but not the control empty vector, when injected in established nodules significantly delayed tumor growth. Immunohistochemistry revealed accumulation of CD4+ and CD8+ T cells and DC in the treated tumors as well as in draining lymph nodes. DC from such lymph nodes stimulated IFN-γ by a T cell clone specific for the known TSA tumor-associated Ag (TAA), suggesting the tumor origin of these cells. Lymphocytes from the same nodes showed specific CTL activity against TSA tumor cells and their immunodominant TAA peptide. Antitumor activity required CD4, CD8, and IFN-γ production, as shown using subset-depleted and knockout mice. Despite the robust and rapid immune response triggered by intratumoral injection of AdCCL16, the lesions were not completely rejected; however, the same treatment given before surgical excision of primary lesions prevented metastatic spread and cured 63% of mice bearing the 4T1 mammary adenocarcinoma, which is perhaps the most compelling model of spontaneous metastasis.
Proinflammatory Mediators and Genetic Background in Oncogene Mediated Tumor Progression
Authors: Russell John P. , Engiles Julie B. , Rothstein Jay L. 
Published: April 2014

Abstract
RET/PTC3 (RP3) is an oncogenic fusion protein which is frequently expressed in papillary thyroid carcinomas and has been detected in thyroid tissue from patients diagnosed with Hashimoto’s thyroiditis. The constitutive activation of the tyrosine kinase domain in the carboxyl-terminal end of RP3 induces signaling pathways within thyrocytes and causes cellular transformation. One of the signaling pathways activated in RP3-expressing cells involves the activity of the transcription factor NF-κB and the production of downstream targets including GM-CSF and macrophage chemotactic protein 1. These factors are known to be immunostimulatory, making RP3 a molecular adjuvant and potentially promoting tissue-specific immunity. However compelling, these in vitro data do not reliably predict gene function in vivo or the cumulative effects of time-dependent processes such as angiogenesis, inflammation, or the influence of genetic background. To address these issues, we analyzed the production of proinflammatory mediators in mouse thyroid organs and demonstrate consistency with in vitro studies performed previously that Il1α, Il1β, Il6, and Tnfα and the enzyme Cox2 are produced by RP3-transgenic thyroid tissue, but absent from nontransgenic thyroids. Furthermore, we find that that the genetic background of the host is important in the observed RP3-induced inflammation and tumor progression. These findings provide support for the notion that oncogene-induced cytokine secretion is important for the development and progression of thyroid carcinomas in genetically permissive hosts.
Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Substrate 1 Regulates the Migration of Langerhans Cells from the Epidermis to Draining Lymph Nodes
Authors: Fukunaga Atsushi , Nagai Hiroshi , Noguchi Tetsuya , Okazawa Hideki , Matozaki Takashi , Yu Xijun , Lagenaur Carl F. , Honma Nakayuki , Ichihashi Masamitsu , Kasuga Masato , Nishigori Chikako , Horikawa Tatsuya 
Published: April 2014

AbstractSrc homology 2 domain-containing protein tyrosine phosphatase substrate 1 (SHPS-1) is a member of the signal regulatory protein family in which the extracellular region interacts with its ligand, CD47. Recent studies have demonstrated that SHPS-1 plays an important role in cell migration and cell adhesion. We demonstrate in this study, using immunohistochemical and flow cytometric analyses, that murine Langerhans cells (LCs) express SHPS-1. Treatment of mice ears with 2,4-dinitro-1-fluorobenzene significantly reduced the number of epidermal LCs, and that reduction could be reversed by pretreatment with mAb to SHPS-1 or the CD47-Fc fusion protein. Treatment with the SHPS-1 mAb in vivo reduced the number of FITC-bearing cells in the lesional lymph nodes after the application of FITC to the skin. The SHPS-1 mAb inhibited the in vivo TNF-α-induced migration of LCs. The emigration of dendritic cells expressing I-Ab+ from skin explants to the medium was also reduced by the SHPS-1 mAb. We further demonstrate that the chemotaxis of a murine dendritic cell line, XS52, by macrophage inflammatory protein-3β was significantly inhibited by treatment with the SHPS-1 mAb or CD47-Fc recombinant protein. Finally, we show that migration of LCs was attenuated in mutant mice that lack the intracellular domain of SHPS-1. These observations show that the ligation of SHPS-1 with the SHPS-1 mAb or with CD47-Fc abrogates the migration of LCs in vivo and in vitro, which suggests that the SHPS-1-CD47 interaction may negatively regulate LC migration.
Genome-Wide Analysis of Molecular Changes in IL-12-Induced Control of Mammary Carcinoma via IFN-γ-Independent Mechanisms
Authors: Shi Xiaoyan , Cao Shanjin , Mitsuhashi Maki , Xiang Zhaoying , Ma Xiaojing 
Published: April 2014

Abstract
IL-12 is a major activator of tumor-killing NK cells and CTL. IFN-γ mediates most of the well-known immunological activities of IL-12. In this study, we report IFN-γ-independent activities induced by therapeutic application of rIL-12 in restricting tumor growth and metastasis in the 4T1 murine mammary carcinoma model. IFN-γ-deficient mice carrying 4T1 tumor exhibit no gross defect in the number of tumor-infiltrating lymphocytes but have exaggerated angiogenesis in the tumor. Administration of IL-12 is able to constrict blood vessels in the tumor in the absence of IFN-γ, and retains certain therapeutic efficacy even when applied late during tumor progression. IL-12 exposure in vivo does not irreversibly alter the immunogenicity of the tumor. Finally, global gene expression analysis of primary tumors reveals IL-12-induced molecular patterns and changes, implicating a number of novel genes potentially important for IFN-γ-independent immune responses against the tumor, for IL-12-mediated antiproliferation, antimetastasis, and antiangiogenesis activities.
Intestinal Intraepithelial Lymphocyte γδ-T Cell-Derived Keratinocyte Growth Factor Modulates Epithelial Growth in the Mouse
Authors: Yang Hua , Antony Paul A. , Wildhaber Barbara E. , Teitelbaum Daniel H. 
Published: April 2014

Abstract
Keratinocyte growth factor (KGF) promotes intestinal epithelial growth. To understand the relevance of intraepithelial lymphocyte (IEL)-derived KGF expression on epithelial growth, we used a mouse model of villus atrophy by the administration of total parenteral nutrition, and a model of villus hypertrophy by the creation of a short bowel syndrome. KGF expression was confined to γδ-ΤCR+ IELs. IEL-derived KGF expression was highest in the crypts, somewhat less in the lower portion of villi, and markedly lower in the upper portion of villi. Total parenteral nutrition administration was associated with a down-regulation of IEL-derived KGF expression, and short bowel syndrome was associated with an up-regulation of IEL-derived KGF expression. In the absence of γδ-ΤCR+ IEL, using γδ−/− mice, intestinal epithelial cell proliferation decreased in control, and in both mucosal atrophy (22% decline) and mucosal hypertrophy (14%) models. These results show that KGF from IELs is an important factor for maintenance of intestinal epithelial cell proliferation and villus growth.
Virus-Induced Activation of Self-Specific TCRαβ CD8αα Intraepithelial Lymphocytes Does Not Abolish Their Self-Tolerance in the Intestine
Authors: Saurer Leslie , Seibold Inge , Rihs Silvia , Vallan Claudio , Dumrese Tilman , Mueller Christoph 
Published: April 2014

AbstractTCRαβ CD8αα intestinal intraepithelial lymphocytes (IEL) represent an enigmatic subset of T cells, particularly, in regard to their potential functions and the apparent persistence of cells expressing self-specific TCR. We have used mice that are transgenic for the TCRαβ specific for the lymphocytic choriomeningitis virus (LCMV)-derived peptide gp33, and TCRαβ-transgenic mice that coexpress the gp33 Ag ubiquitously, to analyze the functional properties of TCRαβ CD8αα IEL in the presence, or absence, of their specific MHC-restricted Ag, and to assess the impact of molecular mimicry during a potent LCMV infection on potentially self-reactive TCRαβ CD8αα IEL. In this study, we show that the presence of the specific self-Ag results in reduced expression of IL-2, IFN-γ, and IL-10 by resident TCRαβ CD8αα IEL while expression of mRNA for TGFβ is not affected. We further demonstrate that despite their secluded location in the epithelium, TCRαβ CD8αα IEL are activated after infection of the intestinal mucosa with LCMV. Importantly, LCMV-induced activation of self-specific TCRαβ CD8αα IEL does not reverse their tolerance as no cytotoxic activity or up-regulated expression of proinflammatory cytokines is detected and no overt signs of autoimmunity are seen. Taken together, these results are in support of an immunoregulatory role for self-specific TCRαβ CD8αα in the intestinal mucosa and clearly speak against an involvement of this cell subset in inflammatory reactions and tissue destruction.
CTLA-4+CD8+ T Cells That Encounter B7-2+ Iris Pigment Epithelial Cells Express Their Own B7-2 to Achieve Global Suppression of T Cell Activation
Authors: Sugita Sunao , Ng Tat Fong , Schwartzkopff Johannes , Streilein J. Wayne 
Published: April 2014

Abstract
Pigment epithelial (PE) cells cultured from the eye possess the novel property of suppressing TCR-dependent activation of T cells in vitro. Iris PE (IPE) cells accomplish this suppression by a direct cell contact mechanism in which B7-2 expressed by the PE cells interacts with CTLA-4 on responding T cells. Because CTLA-4 expression is constitutively expressed on a very small proportion of naive splenic T cells and since exposure of splenic T cells to IPE leads to global T cell suppression, we have inquired into the mechanism by which suppression is achieved. Using splenic T cells and IPE from donor mice with disrupted genes for CD80 (B7-1), CD86 (B7-2), CTLA-4, and/or CD28, we report that B7-2+ IPE in the presence of anti-CD3 supported selectively the activation of CTLA-4+ CD8+ T cells that express their own B7-2 and secrete enhanced amounts of active TGFβ. By contrast, activation of CTLA-4-negative T cells, especially CD4+ cells, in these cultures was profoundly suppressed. Because global suppression of T cell activation in these cultures was obtained only when both IPE and T cells possessed B7-2 genes and expressed the costimulators as surface molecules, we propose that T cells activated in the presence of parenchymal cells from the eye (an immune privileged site) express B7-2 in a manner that equips them to suppress bystander T cells. Thus, B7-2 expression on T cells participates in their eventual ability to function as regulators in vitro.
Monocyte Surface-Bound IL-15 Can Function as an Activating Receptor and Participate in Reverse Signaling
Authors: Neely Graham G. , Epelman Slava , Ma Ling Ling , Colarusso Pina , Howlett Christopher J. , Amankwah Ernest K. , McIntyre Amanda C. , Robbins Stephen M. , Mody Christopher H. 
Published: April 2014

Abstract
IL-15 is a short chain, four-α helix cytokine that shares some biological function with IL-2. One striking difference between IL-2 and IL-15 is the ability of monocytes to express IL-15 on their cell surface after activation. In the current study we have investigated the ability of human monocyte cell surface IL-15 to participate in reverse signaling. Cross-linking anti-IL-15 Abs were used as a surrogate ligand for surface IL-15 engagement. Ligation of cell surface-expressed IL-15 induced monocyte adhesion that required the activity of small m.w. GTPases. Reverse signals through surface IL-15 activated the Rho-GTPase Rac3. In addition, engagement of cell surface IL-15 was found to activate a number of signaling pathways, including both extracellular signal-regulated kinase 1/2 and p38, and resulted in the secretion of IL-8. IL-8 production required mitogen-activated protein kinase activity. Thus, the current study has established that cell surface IL-15 is more than just a ligand; it can function as a receptor and participate in reverse signaling that results in cellular adhesion and production of inflammatory cytokines.
Thymocytes between the β-Selection and Positive Selection Checkpoints Are Nonresponsive to IL-7 as Assessed by STAT-5 Phosphorylation
Authors: Van De Wiele C. Justin , Marino Julie H. , Murray Bryce W. , Vo Stephen S. , Whetsell Michael E. , Teague T. Kent 
Published: April 2014

Abstract
Interleukin-7 is widely accepted as a major homeostatic factor involved in T cell development. To assess the IL-7 responsiveness of thymocytes involved in selection processes, we used a new sensitive flow cytometry-based assay to detect intracellular phosphorylation of STAT-5 induced by IL-7 in defined mouse thymocyte subsets. Using this method, we found the earliest thymocyte subset (CD4−CD8−CD25−CD44+) to contain both IL-7-responsive and nonresponsive cells. Transition through the next stages of development (CD4−CD8−CD25+CD44+ and −) was associated with responsiveness of all thymocytes within these populations. Passage of thymocytes through β-selection resulted in a significant reduction in IL-7 sensitivity. In the next phases of development (TCR− and TCRlowCD69−), thymocytes were completely insensitive to the effects of IL-7. STAT-5 phosphorylation in response to IL-7 was again observed, however, in thymocytes involved in the positive selection process (TCRlowCD69+ and TCRintermediate). As expected, CD4 and CD8 single-positive thymocytes were responsive to IL-7. These findings delineate an IL-7-insensitive population between the β-selection and positive selection checkpoints encompassing thymocytes predicted to die by neglect due to failure of positive selection. This pattern of sensitivity suggests a two-signal mechanism by which survival of thymocytes at these checkpoints is governed.
IFN-γ Stimulates the Expression of a Novel Secretoglobin That Regulates Chemotactic Cell Migration and Invasion
Authors: Choi Moonsuk S. , Ray Rabindranath , Zhang Zhongjian , Mukherjee Anil B. 
Published: April 2014

Abstract
IFNs are a family of cytokines that alert the immune system against viral infections of host cells. The IFNs (IFN-α, IFN-β, and IFN-γ) interact with specific cellular receptors and stimulate the production of second messengers, leading to the expression of antiviral and immunomodulatory proteins. We report in this study that IFN-γ stimulates the expression of a novel gene that encodes a protein with 30% amino acid sequence identity with uteroglobin, the founding member of the newly formed Secretoglobin (SCGB) superfamily. We named this protein IFN-γ-inducible SCGB (IIS), because its expression in lymphoblast cells is augmented by IFN-γ treatment. IIS is expressed in virtually all tissues, and the highest level of expression is detectable in lymph nodes, tonsil, cultured lymphoblasts, and the ovary. Interestingly, although the expression of IIS mRNA is not significantly different in resting lymphoid cells, it is markedly elevated in activated CD8+ and CD19+ cells. Furthermore, treatment of lymphoblast cells with IIS antisense phosphorothioate (S)-oligonucleotides prevents chemotactic migration and invasion. Taken together, these results raise the possibility that this novel SCGB has immunological functions.
Plasmacytoid Dendritic Cells Regulate Th Cell Responses through OX40 Ligand and Type I IFNs
Authors: Ito Tomoki , Amakawa Ryuichi , Inaba Muneo , Hori Toshiyuki , Ota Maiko , Nakamura Kengo , Takebayashi Masashi , Miyaji Michihiko , Yoshimura Tomoo , Inaba Kayo , Fukuhara Shirou 
Published: April 2014

Abstract
Dendritic cells (DCs) show a functional plasticity in determining Th responses depending on their maturational stage or on maturational signals delivered to the DCs. Human plasmacytoid DCs (PDCs) can induce either Th1- or Th2-type immune responses upon exposure to viruses or IL-3, respectively. In this study we have investigated the Th-polarizing capacity of PDCs after short (24-h) or long (72-h) culture with stimuli and have assessed the expression and function of OX40 ligand (OX40L) in PDC-mediated Th polarization in addition to type I IFN-dependent responses. IL-3-treated PDCs expressed OX40L, but produced almost no IFN-α in response to T cell stimulation (CD40 ligand or T cell interaction), resulting in the preferential priming of Th2 cells through OX40L-dependent mechanisms. Meanwhile, PDCs were rapidly endowed by viral infection (Sendai virus) with a high potency to develop IFN-γ-producing Th cells depending on their capacity to residually produce IFN-α. Although Sendai virus-stimulated PDCs simultaneously expressed OX40L in their maturational process, the Th1-inducing effect of endogenous type I IFNs may overcome and thus conceal the OX40L-dependent Th2 responses. However, during maturation in response to Sendai virus over the longer 72-h period, the expression level of OX40L was up-regulated, whereas the residual IFN-α-producing ability was down-regulated, and consequently, the PDCs with prolonged Sendai virus stimulation induced Th2 responses to some extent. Thus, PDCs have the distinct means to dictate an appropriate response to environmental stimuli.
Smad3 Is Essential for TGF-β1 to Suppress IL-2 Production and TCR-Induced Proliferation, but Not IL-2-Induced Proliferation
Authors: McKarns Susan C. , Schwartz Ronald H. , Kaminski Norbert E. 
Published: April 2014

Abstract
Transforming growth factor-β1 is essential to maintain T cell homeostasis, as illustrated by multiorgan inflammation in mice deficient in TGF-β1 signaling. Despite the physiological importance, the mechanisms that TGF-β1 uses to regulate T cell expansion remain poorly understood. TGF-β1 signals through transmembrane receptor serine/threonine kinases to activate multiple intracellular effector molecules, including the cytosolic signaling transducers of the Smad protein family. We used Smad3−/− mice to investigate a role for Smad3 in IL-2 production and proliferation in T cells. Targeted disruption of Smad3 abrogated TGF-β1-mediated inhibition of anti-CD3 plus anti-CD28-induced steady state IL-2 mRNA and IL-2 protein production. CFSE labeling demonstrated that TGF-β1 inhibited entry of wild-type anti-CD3 plus anti-CD28-stimulated cells into cycle cell, and this inhibition was greatly attenuated in Smad3−/− T cells. In contrast, disruption of Smad3 did not affect TGF-β1-mediated inhibition of IL-2-induced proliferation. These results demonstrate that TGF-β1 signals through Smad3-dependent and -independent pathways to inhibit T cell proliferation. The inability of TGF-β1 to inhibit TCR-induced proliferation of Smad3−/− T cells suggests that IL-2 is not the primary stimulus driving expansion of anti-CD3 plus anti-CD28-stimulated T cells. Thus, we establish that TGF-β1 signals through multiple pathways to suppress T cell proliferation.
Lupus IgG VH4.34 Antibodies Bind to a 220-kDa Glycoform of CD45/B220 on the Surface of Human B Lymphocytes
Authors: Cappione Amedeo J. , Pugh-Bernard Aimee E. , Anolik Jennifer H. , Sanz Iñaki 
Published: April 2014

Abstract
Anti-lymphocyte autoantibodies are a well-recognized component of the autoimmune repertoire in human systemic lupus erythematosus (SLE) and have been postulated to have pathogenic consequences. Early studies indicated that IgM anti-lymphocyte autoantibodies mainly recognized T cells and identified CD45, a protein tyrosine phosphatase of central significance in the modulation of lymphocyte function, as the main antigenic target on T cells. However, more recent work indicates that lupus autoantibodies can also recognize B cells and that CD45 may also represent their antigenic target. In particular, IgM Abs encoded by VH4.34 appear to have special tropism for B cells, and strong, but indirect evidence suggests that they may recognize a B cell-specific CD45 isoform. Because VH4.34 Abs are greatly expanded in SLE, in the present study we investigated the antigenic reactivity of lupus sera VH4.34 IgG Abs and addressed their contribution to the anti-lymphocyte autoantibody repertoire in this disease. Our biochemical studies conclusively demonstrate that lupus IgG VH4.34 Abs target a developmentally regulated B220-specific glycoform of CD45, and more specifically, an N-linked N-acetyllactosamine determinant preferentially expressed on naive B cells that is sterically masked by sialic acid on B220-positive memory B cells. Strikingly, our data also indicate that this reactivity in SLE sera is restricted to VH4.34 Abs and can be eliminated by depleting these Abs. Overall, our data indicate that VH4.34 Abs represent a major component of the lupus IgG autoantibody repertoire and suggest that the carbohydrate moiety they recognize may act as a selecting Ag in SLE.