bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene Transfer of Tissue Inhibitor of Metalloproteinases-3 Reverses the Inhibitory Effects of TNF-α on Fas-Induced Apoptosis in Rheumatoid Arthritis Synovial Fibroblasts
Authors: Drynda Andreas , Quax Paul H. A. , Neumann Manfred , van der Laan Willemijn H. , Pap Géza , Drynda Susanne , Meinecke Ingmar , Kekow Joern , Neumann Wolfram , Huizinga Tom W. J. , Naumann Michael , König Wolfgang , Pap Thomas 
Published: April 2014

Abstract
Apart from counteracting matrix metalloproteinases, tissue inhibitor of metalloproteinases-3 (TIMP-3) has proapoptotic properties. These features have been attributed to the inhibition of metalloproteinases involved in the shedding of cell surface receptors such as the TNFR. However, little is known about effects of TIMP-3 in cells that are not susceptible to apoptosis by TNF-α. In this study, we report that gene transfer of TIMP-3 into human rheumatoid arthritis synovial fibroblasts and MRC-5 human fetal lung fibroblasts facilitates apoptosis and completely reverses the apoptosis-inhibiting effects of TNF-α. Although TNF-α inhibits Fas/CD95-induced apoptosis in untransfected and mock-transfected cells, fibroblasts ectopically expressing TIMP-3 are sensitized most strongly to Fas/CD95-mediated cell death by TNF-α. Neither synthetic MMP inhibitors nor glycosylated bioactive TIMP-3 are able to achieve these effects. Gene transfer of TIMP-3 inhibits the TNF-α-induced activation of NF-κB in rheumatoid arthritis synovial fibroblasts and reduces the up-regulation of soluble Fas/CD95 by TNF-α, but has no effects on the cell surface expression of Fas. Collectively, our data demonstrate that intracellularly produced TIMP-3 not only induces apoptosis, but also modulates the apoptosis-inhibiting effects of TNF-α in human rheumatoid arthritis synovial fibroblast-like cells. Thus, our findings may stimulate further studies on the therapeutic potential of gene transfer strategies with TIMP-3.
The Many Faces of IL-7: From Lymphopoiesis to Peripheral T Cell Maintenance
Authors: Fry Terry J. , Mackall Crystal L. 
Published: April 2014

Abstract
IL-7 is well known as a lymphopoietic cytokine, but recent studies have also identified a critical role for IL-7 in peripheral T cell homeostasis. IL-7 is well poised to serve as a homeostatic cytokine because it is produced by resting stromal cells, the IL-7R is present on most T cells, and IL-7 down-regulates its own receptor. These features allow IL-7 to signal large numbers of resting T cells and to be efficiently used when supplies are limiting. Consistent with this, in normal hosts, IL-7 is required for survival of naive T cell populations, and IL-7 contributes to homeostatic cycling of naive and memory cells. In addition, lymphopenic hosts accumulate increased levels of IL-7, and the supranormal levels are largely responsible for inducing homeostatic peripheral expansion in response to lymphopenia. Thus, IL-7 plays critical and nonredundant roles in both T cell lymphopoiesis and in maintaining and restoring peripheral T cell homeostasis.
Primary Defect in UVB-Induced Systemic Immunomodulation Does Not Relate to Immature or Functionally Impaired APCs in Regional Lymph Nodes
Authors: Gorman Shelley , Tan Jamie W.-Y. , Thomas Jennifer A. , Townley Scott L. , Stumbles Philip A. , Finlay-Jones John J. , Hart Prue H. 
Published: April 2014

Abstract
UVB irradiation of the shaved dorsal skin of mice can cause both local and systemic suppression of contact hypersensitivity responses; the former demonstrated by administration of the sensitizing Ag/hapten to the irradiated site and the latter by its administration at least 72 h later to distal unirradiated sites. The immunological basis of systemic immunomodulation is not clear. When haptens (trinitrochlorobenzene, FITC) were administered to the shaved ventral skin 4 days after irradiation (8 kJ/m2) to the shaved dorsum of BALB/c mice, CD11c+/FITC+ cells in the skin-draining lymph nodes from control and irradiated mice produced on a per cell basis similar levels of IL-12 and PGE2 were phenotypically mature and efficient at presenting FITC to lymphocytes from FITC-sensitized mice. Ag presentation by FACS-sorted CD11c+ lymph node cells isolated 4 days after UVB irradiation was as efficient as were cells from unirradiated mice at presentation in vitro of an OVA peptide (OVA323–339) to CD4+ cells from OVA-TCR-transgenic DO11.10 mice. Further, IFN-γ levels were increased in the cultures containing CD11c+ cells from UVB-irradiated mice, suggesting that inflammation may precede downstream immunosuppression. These results suggest that the primary cause of reduced contact hypersensitivity responses in mice in which UV irradiation and the sensitizing Ag are applied to different sites several days apart must originate from cells other than CD11c+ APCs that directly or by production of soluble mediators (IL-12, PGE2) affect cellular responses in the nodes of UVB-irradiated mice.
Intrinsic Tolerance in Autologous Collagen-Induced Arthritis Is Generated by CD152-Dependent CD4+ Suppressor Cells
Authors: Treschow Alexandra P. , Bäcklund Johan , Holmdahl Rikard , Issazadeh-Navikas Shohreh 
Published: April 2014

Abstract
Collagen-induced arthritis is a mouse model of rheumatoid arthritis (RA) and is commonly induced after immunization with type II collagen (CII) of a non-mouse origin. T cell recognition of heterologous CII epitopes has been shown to be critical in development of arthritis, as mice with cartilage-restricted transgenic expression of the heterologous T cell epitope (MMC mice) are partially tolerized to CII. However, the mechanism responsible for tolerance and arthritis resistance in these mice is unclear. The present study investigated the regulatory mechanisms in naturally occurring self-tolerance in MMC mice. We found that expression of heterologous rat CII sequence in the cartilage of mice positively selects autoreactive CD4+ T cells with suppressive capacity. Although CD4+CD25+ cells did not play a prominent role in this suppression, CD152-expressing T cells played a crucial role in this tolerance. MMC CD4+ T cells were able to suppress proliferation of wild-type cells in vitro where this suppression required cell-to-cell contact. The suppressive capability of MMC cells was also demonstrated in vivo, as transfer of such cells into wild-type arthritis susceptible mice delayed arthritis onset. This study also determined that both tolerance and disease resistance were CD152-dependent as demonstrated by Ab treatment experiments. These findings could have relevance for RA because the transgenic mice used express the same CII epitope in cartilage as humans and because autoreactive T cells, specific for this epitope, are present in transgenic mice as well as in patients with RA.
IL-4-Induced Priming of Human Intestinal Mast Cells for Enhanced Survival and Th2 Cytokine Generation Is Reversible and Associated with Increased Activity of ERK1/2 and c-Fos
Authors: Lorentz Axel , Wilke Mikosch , Sellge Gernot , Worthmann Hans , Klempnauer Jürgen , Manns Michael P. , Bischoff Stephan C. 
Published: April 2014

Abstract
In synergy with stem cell factor (SCF), IL-4 strongly enhances mast cell proliferation and shifts IgE-dependent cytokine production in mature human mast cells toward an increased release of Th2 cytokines such as IL-3, IL-5, and IL-13 and a decreased IL-6 expression. In this study we analyzed the kinetics and the mechanisms of these IL-4 effects on mast cells purified from intestinal tissue. If the cells were first cultured with IL-4 for 14 days and then without IL-4 for another 14 days, mast cells lost the capacity of producing higher amounts of Th2 cytokines and regained the capacity of producing IL-6. The IL-4-induced up-regulation of mast cell proliferation and FcεRI expression was also reversible if IL-4 was withdrawn for 14 days. Interestingly, in contrast to IL-4, proliferation and phenotype of human intestinal mast cells were not affected by IL-13 although both cytokines were capable of inducing STAT6 activation. Instead, IL-4 treatment (but not IL-13 treatment) was associated with an increased activity of ERK1/2 and c-Fos, the downstream target of ERK1/2 and component of the transcription factor AP-1. Consistently, mast cell proliferation and cytokine expression in response to IL-4 was blocked by the MEK inhibitor PD98059. In summary, our data show that the IL-4 effects on human intestinal mast cell functions are reversible and accompanied by an increased activity of ERK1/2 and c-Fos.
Specific T Regulatory Cells Display Broad Suppressive Functions against Experimental Allergic Encephalomyelitis upon Activation with Cognate Antigen
Authors: Yu Ping , Gregg Randal K. , Bell J. Jeremiah , Ellis Jason S. , Divekar Rohit , Lee Hyun-Hee , Jain Renu , Waldner Hanspeter , Hardaway John C. , Collins Mary , Kuchroo Vijay K. , Zaghouani Habib 
Published: April 2014

Abstract
To date, very few Ag-based regimens have been defined that could expand T regulatory (Treg) cells to reverse autoimmunity. Additional understanding of Treg function with respect to specificity and broad suppression should help overcome these limitations. Ig-proteolipid protein (PLP)1, an Ig carrying a PLP1 peptide corresponding to amino acid residues 139-151 of PLP, displayed potent tolerogenic functions and proved effective against experimental allergic encephalomyelitis (EAE). In this study, we took advantage of the Ig-PLP1 system and the PLP1-specific TCR transgenic 5B6 mouse to define a regimen that could expand Ag-specific Treg cells in vivo and tested for effectiveness against autoimmunity involving diverse T cell specificities. The findings indicate that in vivo exposure to aggregated Ig-PLP1 drives PLP1-specific 5B6 TCR transgenic cells to evolve as Treg cells expressing CD25, CTLA-4, and Foxp3 and producing IL-10. These Treg cells were able to suppress PLP1 peptide-induced EAE in both SJL/J and F1 (SJL/J × C57BL/6) mice. However, despite being effective against disease induced with a CNS homogenate, the Treg cells were unable to counter EAE induced by a myelin basic protein or a myelin oligodendrocyte glycoprotein peptide. Nevertheless, activation with Ag before transfer into the host mice supports suppression of both myelin oligodendrocyte glycoprotein- and myelin basic protein peptide-induced EAE. Thus, it is suggested that activation of Treg cells by the cognate autoantigen is necessary for operation of broad suppressive functions.
Antigen-Specific CD8+ T Cells Mediate a Peptide-Induced Fatal Syndrome
Authors: Johnson Aaron J. , Mendez-Fernandez Yanice , Moyer Ann M. , Sloma Cari R. , Pirko Istvan , Block Matthew S. , Rodriguez Moses , Pease Larry R. 
Published: April 2014

Abstract
Peptide immunotherapy both activates and suppresses the T cell response against known peptide Ags. Although pretreatment with VP2121–130 peptide inhibits the development of antiviral CTL specific for the immunodominant Db:VP2121–130 epitope expressed during acute Theiler’s murine encephalomyelitis virus infection, i.v. injection of this same peptide or MHC tetramers containing the peptide during an ongoing antiviral CTL response results in a peptide-induced fatal syndrome (PIFS) within 48 h. Susceptibility to PIFS is dependent on peptide-specific CD8+ T cells, varies among inbred strains of mice, and is not mediated by traditionally defined mechanisms of shock. Analyses using bone marrow chimeras and mutant mice demonstrate that susceptibility to PIFS is determined by the genotype of bone marrow-derived cells and requires the expression of perforin. Animals responding to peptide treatment with PIFS develop classical stress responses in the brain. These findings raise important considerations for the development of peptide therapies for active diseases to modify immune responses involving expanded populations of T cells. In summary, treatment with peptides or MHC-tetramers during a peptide-specific immune response can result in a fatal shock-like syndrome. Susceptibility to the syndrome is genetically determined, is mediated by CD8+ T cells, and requires expression of perforin. These findings raise concerns about the use of peptides and MHC tetramers in therapeutic schemes.
Visualizing the Onset and Evolution of an Autoantibody Response in Systemic Autoimmunity
Authors: William Jacqueline , Euler Chad , Leadbetter Elizabeth , Marshak-Rothstein Ann , Shlomchik Mark J. 
Published: April 2014

Abstract
The onset of systemic autoimmunity is variable, making it difficult to identify early events. In this study, we show in rheumatoid factor (RF) Ig-transgenic autoimmune-prone mice that the appearance of RF B cells in blood signifies the onset of RF B cell activation in spleen, providing a novel window into the initiation of an autoantibody response. This allowed us to study the early and late phases of spontaneous induction of the B cell autoimmune response. Using this approach we showed that extensive Ab-forming cell generation in spleen, accompanied by somatic hypermutation, occurred despite the lack of an early germinal center response. The onset of the RF response correlated with the levels of IgG2a-containing immune complexes but not total IgG2a. By identifying the time of onset in individual mice, we were able to track progression of disease. We found remissions of RF Ab-forming cell production in some mice, suggesting that at the clonal level, chronic autoantibody responses are dynamic and episodic, much like acute pathogen responses. Surprisingly, there was little accumulation of long-lived plasma cells in bone marrow of mice with long-standing RF responses in spleen. These studies are among the first to define the early events of a spontaneous B cell autoimmune response.
Short-Lived Plasmablasts Dominate the Early Spontaneous Rheumatoid Factor Response: Differentiation Pathways, Hypermutating Cell Types, and Affinity Maturation Outside the Germinal Center
Authors: William Jacqueline , Euler Chad , Shlomchik Mark J. 
Published: April 2014

Abstract
We used a newly validated approach to identify the initiation of an autoantibody response to identify the sites and cell differentiation pathways at early and late stages of the rheumatoid factor response. The autoimmune response is mainly comprised of rapidly turning over plasmablasts that, according to BrdU labeling, TUNEL, and hypermutation data, derive from an activated B cell precursor. Surprisingly, few long-lived plasma cells were generated. The response most likely initiates at the splenic T-B zone border and continues in the marginal sinus bridging channels. Both activated B cells and plasmablasts harbor V gene mutations; large numbers of mutations in mice with long-standing response indicate that despite the rapid turnover of responding cells, clones can persist for many weeks. These studies provide insights into the unique nature of an ongoing autoimmune response and may be a model for understanding the response to therapies such as B cell depletion.
The Spermatogenic Ig Superfamily/Synaptic Cell Adhesion Molecule Mast-Cell Adhesion Molecule Promotes Interaction with Nerves
Authors: Furuno Tadahide , Ito Akihiko , Koma Yu-ichiro , Watabe Kenji , Yokozaki Hiroshi , Bienenstock John , Nakanishi Mamoru , Kitamura Yukihiko 
Published: April 2014

Abstract
Nerve-mast cell interaction is involved in both homeostatic and pathologic regulations. The molecules that sustain this association have not been identified. Because synaptic cell adhesion molecule (SynCAM), alternatively named spermatogenic Ig superfamily (SgIGSF), is expressed on both nerves and mast cells and because it binds homophilically, this molecule may be a candidate. To examine this possibility, mast cells with or without SgIGSF/SynCAM were cocultured with superior cervical ganglion neurons that express SgIGSF/SynCAM, and the number of mast cells attached to neurites was counted. The attachment of mast cells with SgIGSF/SynCAM, i.e., bone marrow-derived mast cells (BMMC) from wild-type mice, was inhibited dose-dependently by blocking Ab to SgIGSF/SynCAM. Mast cells without SgIGSF/SynCAM, i.e., BMMC from microphthalmia transcription factor-deficient mice and BMMC-derived cell line IC-2 cells, were defective in attachment to neurite, and transfection with SgIGSF/SynCAM normalized this. When the nerves were specifically activated by scorpion venom, one-quarter of the attached IC-2 cells mobilized Ca2+ after a few dozen seconds, and ectopic SgIGSF/SynCAM doubled this proportion. At points of contact between neurites and wild-type BMMC, SgIGSF/SynCAM was locally concentrated in both neurites and BMMC. SgIGSF/SynCAM on mast cells appeared to predominantly mediate attachment and promote communication with nerves.
Susceptibility of Mice Genetically Deficient in the Surfactant Protein (SP)-A or SP-D Gene to Pulmonary Hypersensitivity Induced by Antigens and Allergens of Aspergillus fumigatus
Authors: Madan Taruna , Reid Kenneth B. M. , Singh Mamta , Sarma P. Usha , Kishore Uday 
Published: April 2014

Abstract
Lung surfactant protein A (SP-A) and D (SP-D) are innate immune molecules which are known to interact with allergens and immune cells and modulate cytokine and chemokine profiles during host hypersensitivity response. We have previously shown therapeutic effects of SP-A and SP-D using a murine model of lung hypersensitivity to Aspergillus fumigatus (Afu) allergens. In this study, we have examined the susceptibility of SP-A (AKO) or SP-D gene-deficient (DKO) mice to the Afu allergen challenge, as compared with the wild-type mice. Both AKO and DKO mice exhibited intrinsic hypereosinophilia and several-fold increase in levels of IL-5 and IL-13, and lowering of IFN-γ to IL-4 ratio in the lungs, suggesting a Th2 bias of immune response. This Th2 bias was reversible by treating AKO or DKO mice with SP-A or SP-D, respectively. The AKO and DKO mice showed distinct immune responses to Afu sensitization. DKO mice were found more susceptible than wild-type mice to pulmonary hypersensitivity induced by Afu allergens. AKO mice were found to be nearly resistant to Afu sensitization. Intranasal treatment with SP-D or rhSP-D (a recombinant fragment of human SP-D containing trimeric C-type lectin domains) was effective in rescuing the Afu-sensitized DKO mice, while SP-A-treated Afu-sensitized AKO mice showed several-fold elevated levels of IL-13 and IL-5, resulting in increased pulmonary eosinophilia and damaged lung tissue. These data reaffirm an important role for SP-A and SP-D in offering resistance to pulmonary allergenic challenge.
In Vivo IL-10 Gene Delivery Suppresses Airway Eosinophilia and Hyperreactivity by Down-Regulating APC Functions and Migration without Impairing the Antigen-Specific Systemic Immune Response in a Mouse Model of Allergic Airway Inflammation
Authors: Nakagome Kazuyuki , Dohi Makoto , Okunishi Katsuhide , Komagata Yoshinori , Nagatani Katsuya , Tanaka Ryoichi , Miyazaki Jun-ichi , Yamamoto Kazuhiko 
Published: April 2014

Abstract
IL-10 is an immunosuppressive cytokine. Although previous studies have reported that exogenous delivery of IL-10 reduced airway inflammation in experimental allergic airway inflammation, the mechanism of action has not been fully clarified. In this report, we elucidated a mechanism of action of IL-10 in vivo. BALB/c mice were immunized and aerosol challenged with OVA-Ag. We delivered the IL-10 gene to the mice before systemic sensitization or during aerosol Ag challenge by administering an IL-10-producing plasmid vector. Not only presensitization delivery of IL-10, as reported, but also delivery during inflammation strongly suppressed the development of airway eosinophilia and hyperreactivity. Presensitization delivery suppressed the Ag-specific Th2-type immune response in both the lung and spleen. In contrast, delivery in the effector phase suppressed the Th2 response only in the lung, whereas that in the spleen was not affected. IL-10 gene delivery did not induce the development of a regulatory phenotype of T cells or dendritic cells; rather, it suppressed the overall functions of CD11c+ APCs of the lung such as Ag-presenting capacity, cytokine production, and transportation of OVA-Ag to lymph nodes, thus attenuating Th2-mediated allergic airway inflammation. Further, IL-10 revealed a distinct immunosuppressive effect in the presence of Ag and APCs. These results suggest that suppression of APC function in the lung, the site of immune response, played a critical role in the IL-10-mediated suppression of Ag-induced airway inflammation and hyperreactivity. Therefore, if delivered selectively, IL-10 could site specifically suppress the Ag-specific immune response without affecting systemic immune responses.
Liposome-Mediated Combinatorial Cytokine Gene Therapy Induces Localized Synergistic Immunosuppression and Promotes Long-Term Survival of Cardiac Allografts
Authors: Furukawa Hiroshi , Oshima Kiyohiro , Tung Thomas , Cui Guanggen , Laks Hillel , Sen Luyi 
Published: April 2014

Abstract
Localized gene transfer has the potential to introduce immunosuppressive molecules only into the transplanted allograft, which would limit systemic side effects, and prolong allograft survival. However, an applicable gene transfer strategy is not available, and the feasible therapeutic gene(s) has not yet been determined. We developed an ex vivo liposome-mediated gene therapy strategy that is able to intracoronary deliver the combination of IL-4 and IL-10 cDNA expression vectors to the allograft simultaneously. We examined the efficiency, efficacy, and cardiac adverse effects of this combinatorial gene therapy protocol using a rabbit functional cervical heterotopic heart transplant model. Although the efficiency was moderate, the expression of both transgenes was long lasting and localized only in the target organ. The mean survival of cardiac allograft was prolonged from 7 to &gt;100 days. Synergism of overexpressed IL-4 and IL-10 in the inhibition of T lymphocyte infiltration and cytoxicity, and modulation of Th1/Th2 cytokine production promote long-term survival of cardiac allografts.
Lymph Node Occupancy Is Required for the Peripheral Development of Alloantigen-Specific Foxp3+ Regulatory T Cells
Authors: Ochando Jordi C. , Yopp Adam C. , Yang Yu , Garin Alexandre , Li Yansui , Boros Peter , Llodra Jaime , Ding Yaozhong , Lira Sergio A. , Krieger Nancy R. , Bromberg Jonathan S. 
Published: April 2014

Abstract
We previously demonstrated that L-selectin (CD62L)-dependent T cell homing to lymph nodes (LN) is required for tolerance induction to alloantigen. To explore the mechanisms of this observation, we analyzed the development and distribution of regulatory T cells (Treg), which play an important protective role against allograft rejection in transplantation tolerance. Alloantigen-specific tolerance was induced using either anti-CD2 plus anti-CD3 mAbs, or anti-CD40L mAbs plus donor-specific transfusion, in fully mismatched (BALB/c donor, C57BL/6 recipient) vascularized cardiac allografts. An expansion of CD4+CD25+CD62Lhigh T cells was observed specifically within the LN of tolerant animals, but not in other anatomic sites or under nontolerizing conditions. These cells exhibited a substantial up-regulation of Foxp3 expression as measured by real-time PCR and by fluorescent immunohistochemistry, and possessed alloantigen-specific suppressor activity. Neither LN nor other lymphoid cells expressed the regulatory phenotype if recipients were treated with anti-CD62L mAbs, which both prevented LN homing and caused early allograft rejection. However, administration of FTY720, a sphingosine 1-phosphate receptor modulator that induces CD62L-independent T cell accumulation in the LNs, restored CD4+CD25+ Treg in the LNs along with graft survival. These data suggest that alloantigen-specific Foxp3+CD4+CD25+ Treg develop and are required within the LNs during tolerization, and provide compelling evidence that distinct lymphoid compartments play critical roles in transplantation tolerance.