bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-4 Promotes the Migration of Circulating B Cells to the Spleen and Increases Splenic B Cell Survival
Authors: Mori Masaaki , Morris Suzanne C. , Orekhova Tatyana , Marinaro Mariarosaria , Giannini Edward , Finkelman Fred D. 
Published: April 2014

AbstractWe report that IL-4 causes a redistribution of B cells and modestly increases B cell life span. Intravenous injection of a long-acting formulation of IL-4 induces increases in both spleen cell number and the percentage of splenic B cells. These effects are observed within 1 day of IL-4 administration and plateau after ∼3 days if IL-4 treatment is continued. The increase in splenic B cell number is IL-4 dose dependent, CD4+ T cell independent, FcγRII/FcγRIII independent, and Stat6 independent. Decreases in the number of B cells in the blood and the percentage of mature B cells in the bone marrow, concomitant with the increase in splenic B cell number, suggest that redistribution of circulating B cells to the spleen is partially responsible for IL-4 induction of splenic B cell hyperplasia. Considerable reduction in the effect of 5 days of IL-4 treatment on splenic B cell number when B lymphopoiesis is blocked with anti-IL-7 mAb suggests that generation of new B cells is also involved in IL-4-induced splenic B cell hyperplasia. 5-Bromo-2′-deoxyuridine labeling experiments demonstrate that IL-4 modestly prolongs the life span of newly generated splenic B cells, and experiments that measure B cell HSA (CD24) expression as an indicator of B cell age suggest that IL-4 may also prolong the life span of mature splenic B cells. Thus, IL-4 increases splenic B cell number through two Stat6-independent effects: increased net migration of circulating B cells to the spleen and increased B cell life span. Both effects may promote Ab responses to a systemic Ag challenge.
Regulation of Extrathymic T Cell Development and Turnover by Oncostatin M
Authors: Boileau Catherine , Houde Magali , Dulude Gaël , Clegg Christopher H. , Perreault Claude 
Published: April 2014

AbstractChronic exposure to oncostatin M (OM) has been shown to stimulate extrathymic T cell development. The present work shows that in OM transgenic mice, 1) massive extrathymic T cell development takes place exclusively the lymph nodes (LNs) and not in the bone marrow, liver, intestines, or spleen; and 2) LNs are the sole site where the size of the mature CD4+ and CD8+ T cell pool is increased (6- to 7-fold). Moreover, when injected into OM transgenic mice, both transgenic and nontransgenic CD4+ and CD8+ T cells preferentially migrated to the LNs rather than the spleen. Studies of athymic recipients of fetal liver grafts showed that lymphopoietic pathway modulated by OM was truly thymus independent, and that nontransgenic progenitors could generate extrathymic CD4+CD8+ cells as well as mature T cells under the paracrine influence of OM. The progeny of the thymic-independent differentiation pathway regulated by OM was polyclonal in terms of Vβ usage, exhibited a phenotype associated with previous TCR ligation, and displayed a rapid turnover rate (5-bromo-2′-deoxyuridine pulse-chase assays). This work suggests that chronic exposure to OM 1) discloses a unique ability of LNs to sustain extrathymic T cell development, and 2) increases the number and/or function of LN niches able to support seeding of recirculating mature T cells. Regulation of the lymphopoietic pathway discovered in OM transgenic mice could be of therapeutic interest for individuals with thymic hypoplasia or deficient peripheral T cell niches.
Regulatory Cells Potentiate the Efficacy of IL-4 Gene Transfer by Up-Regulating Th2-Dependent Expression of Protective Molecules in the Infectious Tolerance Pathway in Transplant Recipients
Authors: Ke Bibo , Ritter Thomas , Kato Hirohisa , Zhai Yuan , Li Jiye , Lehmann Manfred , Busuttil Ronald W. , Volk Hans-Dieter , Kupiec-Weglinski Jerzy W. 
Published: April 2014

AbstractWe have previously shown that the tolerant state in allograft recipients can be maintained and perpetuated by an “infectious” T cell-dependent regulatory mechanism. Hence, 1) treatment of LEW rats with RIB-5/2, a CD4 nondepleting mAb, produces indefinite survival of LBNF1 cardiac allografts; 2) donor-specific tolerance can be then transferred by spleen cells into new cohorts of test allograft recipients; and 3) putative regulatory CD4+ Th2-like cells are instrumental in this tolerance model. We now report on studies aimed at exposing mechanisms underlying the infectious tolerance pathway, with emphasis on the interactions between intragraft adenovirus-IL-4 gene transfer and systemic infusion of regulatory cells from tolerant hosts. Unlike individual treatment regimens, adjunctive therapy with adenovirus-IL-4 and suboptimal doses of regulatory spleen cells was strongly synergistic and extended donor-type test cardiac allograft survival to about 2 mo. RT-PCR-based expression of intragraft mRNA coding for IL-2 and IFN-γ remained depressed, whereas that of IL-4 and IL-10 reciprocally increased selectively in the combined treatment group, data supported by ELISA studies. In parallel, only adjunctive treatment triggered intragraft induction of molecules with anti-oxidant (HO-1) and anti-apoptotic (Bcl-xL/Bag-1) but not with pro-apoptotic (CPP-32) functions, both in the early and late posttransplant phases. Hence, systemic infusion of regulatory cells potentiates the effects of local adenovirus-IL-4 gene transfer in transplant recipients. Th2-driven up-regulation of protective molecule programs at the graft site, such as of anti-oxidant HO-1 and/or anti-apoptotic Bcl-xL and Bag-1, may contribute, at least in part, to the maintenance of the infectious tolerance pathway in transplant recipients.
Differential Effect of Cytokine Treatment on Fcα Receptor I- and Fcγ Receptor I-Mediated Tumor Cytotoxicity by Monocyte-Derived Macrophages
Authors: Keler Tibor , Wallace Paul K. , Vitale Laura A. , Russoniello Christina , Sundarapandiyan Karuna , Graziano Robert F. , Deo Yashwant M. 
Published: April 2014

AbstractMacrophages represent an important effector cell for Ab-mediated tumor therapy. Previous studies have documented that cytokines can influence Fc receptor (FcR) expression and function. In this study we examined the tumoricidal activities of the type I receptors for IgG (FcγRI) and the IgA FcR (FcαRI) on monocyte-derived macrophages (MDM) cultured in the presence of IFN-γ, M-CSF, or GM-CSF. Bispecific Abs were used to target a Her2/neu breast carcinoma cell line, SKBR-3, to FcαRI or FcγRI on MDM. Although FcαRI and FcγRI share a common signaling pathway contingent on association with the γ-chain (FcRγ subunit), a marked difference in their efficiency in mediating tumoricidal functions was seen in response to specific cytokines. M-CSF- and GM-CSF-treated MDM mediated efficient phagocytosis of SKBR-3 cells by FcαRI and FcγRI; however, IFN-γ-treated MDM phagocytosed tumor cells only with the FcγRI-directed bispecific Abs. Similarly, IFN-γ-cultured MDM lysed tumor cells more efficiently via FcγRI then by FcαRI as measured in Ab-dependent cellular cytotoxicity assays. Conversely, GM-CSF-treated MDM mediated more efficient lysis of tumor cells via FcαRI than FcγRI, while M-CSF-cultured MDM were relatively less efficient in mediating Ab-dependent cellular cytotoxicity through either receptor. With the exception of IFN-γ-mediated enhancement of FcγRI expression and FcγRI γ-chain complexes, the regulation of FcγRI- or FcαRI-mediated activity occurred without significant change in either receptor expression or total complexes with γ subunit. These data suggest that the efficiency of Ab-mediated tumor therapy, which depends on FcR effector cell functions, may be modified by the use of specific cytokines.
Hoxa3 and Pax1 Transcription Factors Regulate the Ability of Fetal Thymic Epithelial Cells to Promote Thymocyte Development
Authors: Su Dong-ming , Manley Nancy R. 
Published: April 2014

AbstractThymocyte maturation into T cells depends on interactions between thymocytes and thymic epithelial cells. In this study, we show that mutations in two transcription factors, Hoxa3 and Pax1, act synergistically to cause defective thymic epithelial cell development, resulting in thymic ectopia and hypoplasia. Hoxa3+/−Pax1−/− compound mutant mice exhibited more severe thymus defects than Pax1−/− single mutants. Fetal liver adoptive transfer experiments revealed that the defect resided in radio-resistant stromal cells and not in hematopoietic cells. Compound mutants have fewer MHC class II+ epithelial cells, and the level of MHC expression detected was lower. Thymic epithelial cells in these mutants have reduced ability to promote thymocyte development, causing a specific block in thymocyte maturation at an early stage that resulted in a dramatic reduction in the number of CD4+8+ thymocytes. This phenotype was accompanied by increased apoptosis of CD4+8+ thymocytes and their immediate precursors, CD44−25−(CD3−4−8−) cells. Our results identify a transcriptional regulatory pathway required for thymic epithelial cell development and define multiple roles for epithelial cell regulation of thymocyte maturation at the CD4−8− to CD4+8+ transition.
Revisiting Tolerance Induced by Autoantigen in Incomplete Freund’s Adjuvant
Authors: Heeger Peter S. , Forsthuber Thomas , Shive Carey , Biekert Earla , Genain Claude , Hofstetter Harald H. , Karulin Alexey , Lehmann Paul V. 
Published: April 2014

AbstractInjection of autoantigens in IFA has been one of the most effective ways of preventing experimental, T cell-mediated, autoimmune disease in mice. The mechanism that underlies this protection has, however, remained controversial, with clonal deletion, induction of suppressor cells or of type 2 immunity being implicated at one time or another. Using high resolution enzyme-linked immunospot (ELISPOT) analysis, we have revisited this paradigm. As models of autoimmunity against sequestered and readily accessible autoantigens, we studied experimental allergic encephalomyelitis, induced by myelin oligodendrocyte glycoprotein, proteolipid protein, myelin basic protein, and renal tubular Ag-induced interstitial nephritis. We showed that the injection of each of these Ags in IFA was immunogenic and CD4 memory cells producing IL-2, IL-4, and IL-5, but essentially no IFN-γ. IgG1, but not IgG2a, autoantibodies were produced. The engaged T cells were not classic Th2 cells in that IL-4 and IL-5 were produced by different cells. The IFA-induced violation of self tolerance, including the deposition of specific autoantibodies in the respective target organs, occurred in the absence of detectable pathology. Exhaustion of the pool of naive precursor cells was shown to be one mechanism of the IFA-induced tolerance. In addition, while the IFA-primed T cells acted as suppressor cells, in that they adoptively transferred disease protection, they did not interfere with the emergence of a type 1 T cell response in the adoptive host. Both active and passive tolerance mechanisms, therefore, contribute to autoantigen:IFA-induced protection from autoimmune disease.
KIR2DL5, a Novel Killer-Cell Receptor with a D0-D2 Configuration of Ig-Like Domains
Authors: Vilches Carlos , Rajalingam Raja , Uhrberg Markus , Gardiner Clair M. , Young Neil T. , Parham Peter 
Published: April 2014

AbstractFour novel killer-cell Ig-like receptor (KIR) genes were discovered by analysis of genomic DNA from a human donor. One gene, KIR2DL5, is expressed by subpopulations of NK cells and T cells, whereas expression of the other three genes could not be detected. KIR2DL5 has two extracellular Ig-like domains of the D0 and D2 type, a structural configuration that was previously unique to KIR2DL4. Although having a similar structure overall, the KIR2DL4 and KIR2DL5 receptors have distinctive amino acid sequences in the ligand-binding extracellular domains and differ in the transmembrane and cytoplasmic motifs that determine signal transduction. Whereas the KIR2DL4 gene is present on all KIR haplotypes and is expressed by all human NK cells, the KIR2DL5 gene is restricted to the “B” subset of KIR haplotypes and is clonally expressed by NK cells within an individual. Chimpanzee genes for KIR2DL4 and KIR2DL5 have been defined and are very similar in sequence to their human orthologs. The donor in whom KIR2DL5 was first detected bears two variants of it that differ by five nucleotide substitutions in the coding region. Although the substitutions are not predicted to affect gene expression, transcription of only one of the two KIR2DL5 variants could be detected.
Localization of Lung Surfactant Protein D on Mucosal Surfaces in Human Tissues
Authors: Madsen Jens , Kliem Anette , Tornøe Ida , Skjødt Karsten , Koch Claus , Holmskov Uffe 
Published: April 2014

Abstract
Lung surfactant protein-D (SP-D), a collectin mainly produced by alveolar type II cells, initiates the effector mechanisms of innate immunity on binding to microbial carbohydrates. A panel of mRNAs from human tissues was screened for SP-D mRNA by RT-PCR. The lung was the main site of synthesis, but transcripts were readily amplified from trachea, brain, testis, salivary gland, heart, prostate gland, kidney, and pancreas. Minor sites of synthesis were uterus, small intestine, placenta, mammary gland, and stomach. The sequence of SP-D derived from parotid gland mRNA was identical with that of pulmonary SP-D. mAbs were raised against SP-D, and one was used to locate SP-D in cells and tissues by immunohistochemistry. SP-D immunoreactivity was found in alveolar type II cells, Clara cells, on and within alveolar macrophages, in epithelial cells of large and small ducts of the parotid gland, sweat glands, and lachrymal glands, in epithelial cells of the gall bladder and intrahepatic bile ducts, and in exocrine pancreatic ducts. SP-D was also present in epithelial cells of the skin, esophagus, small intestine, and urinary tract, as well as in the collecting ducts of the kidney. SP-D is generally present on mucosal surfaces and not restricted to a subset of cells in the lung. The localization and functions of SP-D indicate that this collectin is the counterpart in the innate immune system of IgA in the adaptive immune system.
β2 Integrins Are Involved in Cytokine Responses to Whole Gram-Positive Bacteria
Authors: Cuzzola Maria , Mancuso Giuseppe , Beninati Concetta , Biondo Carmelo , Genovese Francesco , Tomasello Francesco , Flo Trude H. , Espevik Terje , Teti Giuseppe 
Published: April 2014

AbstractProinflammatory cytokines have an important pathophysiologic role in septic shock. CD14 is involved in cytokine responses to a number of purified bacterial products, including LPS. However, little is known of monocyte receptors involved in cytokine responses to whole bacteria. To identify these receptors, human monocytes were pretreated with different mAbs and TNF-α was measured in culture supernatants after stimulation with whole heat-killed bacteria. Human serum and anti-CD14 Abs significantly increased and decreased, respectively, TNF-α responses to the Gram-negative Escherichia coli. However, neither treatment influenced responses to any of the Gram-positive bacteria tested, including group A and B streptococci, Listeria monocytogenes, and Staphylococcus aureus. Complement receptor type III (CR3 or CD18/CD11b) Abs prevented TNF-α release induced by heat-killed group A or B streptococci. In contrast, the same Abs had no effects when monocytes were stimulated with L. monocytogenes or S. aureus. Using either of the latter bacteria, significant inhibition of TNF-α release was produced by Abs to CD11c, one of the subunits of CR4. To confirm these blocking Ab data, IL-6 release was measured in CR3-, CR4-, or CD14-transfected Chinese hamster ovary cells after bacterial stimulation. Accordingly, streptococci triggered moderate IL-6 production (p &lt; 0.05) in CR3 but not CD14 or CR4 transfectants. In contrast, L. monocytogenes and S. aureus induced IL-6 release in CR4 but not CR3 or CD14 transfectants. Collectively our data indicate that β2 integrins, such as CR3 and CR4, may be involved in cytokine responses to Gram-positive bacteria. Moreover, CD14 may play a more important role in responses to whole Gram-negative bacteria relative to Gram-positive ones.
The Role of CD40-CD154 Interaction in Antiviral T Cell-Independent IgG Responses
Authors: Szomolanyi-Tsuda Eva , Brien James D. , Dorgan Jill E. , Welsh Raymond M. , Garcea Robert L. 
Published: April 2014

AbstractPolyomavirus (PyV) infection elicits protective T cell-independent (TI) IgG responses in T cell-deficient mice. The question addressed in this report is whether CD40 signaling plays a role in this TI antiviral IgG response. Because CD40 ligand (CD40L) can be expressed on numerous cell types in addition to activated T cells, it is possible that cells other than T cells provide CD40L to signal through CD40 on B cells and hence positively influence the antiviral TI IgG responses. In this study we show, by blocking CD40-CD40L interactions in vivo with anti-CD40L Ab treatment in TCR β×δ−/− mice and by using SCID mice reconstituted with CD40−/− B cells, that the lack of CD40 signaling in B cells results in a 50% decrease in TI IgG secreted in response to PyV. SCID mice reconstituted with CD40L−/− B cells also responded to PyV infection with diminished IgG secretion compared with that of SCID mice reconstituted with wild-type B cells. This finding suggests that B cells may provide the CD40L for CD40 signaling in the absence of T cell help during acute virus infection. Our studies demonstrate that, although about half of the TI IgG responses to PyV are independent of CD40-CD40L interactions, these interactions occur in T cell-deficient mice and enhance antiviral TI Ab responses.
Genetically Resistant Mice Lacking IL-18 Gene Develop Th1 Response and Control CutaneousLeishmania majorInfection
Authors: Monteforte Gina M. , Takeda Kiyoshi , Rodriguez-Sosa Miriam , Akira Shizuo , David John R. , Satoskar Abhay R. 
Published: April 2014

AbstractIL-18 has been shown to play a critical role in the development of a Th1 response and immunity against intracellular pathogens. To determine the role of IL-18 in the development of protective immunity against Leishmania major, we have analyzed the course of cutaneous L. major in IL-18-deficient C57BL/6 mice (IL-18−/−) compared with similarly infected wild-type mice (IL-18+/+). After L. major infection, IL-18−/− mice may develop larger lesions during early phase of infection but eventually will resolve them as efficiently as IL-18+/+ mice. By 2 wk after infection, although Ag-stimulated lymph node cells from L. major-infected IL-18+/+ and IL-18−/− mice produced similar levels of IFN-γ, those from IL-18−/− mice produced significantly more IL-12 and IL-4. By 10 wk after infection, both IL-18+/+ and IL-18−/− mice had resolved L. major infection. At this time, lymph node cells from both IL-18+/+ and IL-18−/− mice produced IL-12 and IFN-γ but no IL-4. Furthermore, administration of anti-IFN-γ Abs to IL-18−/− mice rendered them susceptible to L. major. These results indicate that despite the role IL-18 may play in early control of cutaneous L. major lesion growth, this cytokine is not critical for development of protective Th1 response and resolution of L. major infection.
Salmonella typhimuriumInfection and Lipopolysaccharide Stimulation Induce Similar Changes in Macrophage Gene Expression
Authors: Rosenberger Carrie M. , Scott Monisha G. , Gold Michael R. , Hancock Robert E. W. , Finlay B. Brett 
Published: April 2014

AbstractChanges in macrophage phenotype induced during infection result from the recognition of bacterial products as well as the action of bacterial virulence factors. We used the unprecedented opportunity provided by gene arrays to simultaneously study the expression of hundreds of genes during Salmonella typhimurium infection of macrophages and to assess the contribution of the bacterial virulence factor, LPS, in initiating the host responses to Salmonella. We found that S. typhimurium infection caused significant changes in the expression of numerous genes encoding chemokines, cell surface receptors, signaling molecules, and transcriptional activators at 4 h postinfection of the RAW 264.7 murine macrophage cell line. Our results revealed changes in the expression of several genes that had not been previously implicated in the host responses to S. typhimurium infection, as well as changes in the expression of several genes previously shown to be regulated by S. typhimurium infection. An overlapping spectrum of genes was expressed in response to virulent S. typhimurium and purified S. typhimurium LPS, reinforcing the major role of this surface molecule in stimulating the early response of macrophages to bacterial infection. The macrophage gene expression profile was further altered by activation with IFN-γ, indicating that host cell responses depend on the activation state of the cell.
Prevention of Experimental Colitis in SCID Mice Reconstituted with CD45RBhigh CD4+ T Cells by Blocking the CD40-CD154 Interactions
Authors: Liu Zhanju , Geboes Karel , Colpaert Stefaan , Overbergh Lut , Mathieu Chantal , Heremans Hubertine , de Boer Mark , Boon Louis , D’Haens Geert , Rutgeerts Paul , Ceuppens Jan L. 
Published: April 2014

AbstractIncreased expression of CD40 and CD40 ligand (CD40L or CD154) has been found in inflamed mucosa of human inflammatory bowel disease (IBD), and interactions between these molecules seem to be involved in local cytokine production by macrophages. However, the precise role of CD40 signaling in the pathogenesis of IBD is still poorly understood. The aim of the present study was to investigate the in vivo relevance of CD40 signaling in experimental colitis in SCID mice reconstituted with syngeneic CD45RBhighCD4+ T cells. The results demonstrated that CD40+ and CD40L+ cells as well as their mRNA levels were significantly increased in inflamed mucosa. Administration of anti-CD40L neutralizing mAb over an 8-wk period starting immediately after CD45RBhighCD4+ T cell reconstitution completely prevented symptoms of wasting disease. Intestinal mucosal inflammation was effectively prevented, as revealed by abrogated leukocyte infiltration and decreased CD54 expression and strongly diminished mRNA levels of the proinflammatory cytokines IFN-γ, TNF, and IL-12. When colitic SCID mice were treated with anti-CD40L starting at 5 wk after T cell transfer up to 8 wk, this delayed treatment still led to significant clinical and histological improvement and down-regulated proinflammatory cytokine secretion. These data suggest that the CD40-CD40L interactions are essential for the Th1 inflammatory responses in the bowel in this experimental model of colitis. Blockade of CD40 signaling may be beneficial to human IBD.