bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Relationship Between Allergen-Induced Tissue Eosinophilia and Markers of Repair and Remodeling in Human Atopic Skin
Authors: Phipps Simon , Ying Sun , Wangoo Arun , Ong Yee-Ean , Levi-Schaffer Francesca , Kay A. Barry 
Published: April 2014

AbstractSeveral in vitro studies suggest that eosinophils may play a role in fibrosis, remodeling, and repair processes associated with IgE-mediated hypersensitivity. However, the relationship in vivo, between allergen-induced tissue eosinophilia and markers of repair has yet to be established in human atopic subjects. Using the allergen-induced cutaneous late-phase reaction as a model of allergic inflammation, we have tested the hypothesis that eosinophil-derived TGF-β1 and IL-13 are temporarily associated with myofibroblast formation and deposition of tenascin and procollagen I. Biopsies were taken from atopic volunteers at 1, 3, 6, 24, 48, and 72 h after intradermal allergen challenge and were examined by immunohistochemistry. Following the peak of the late-phase reaction (6 h) there were persisting TGF-β1+ eosinophils, α-smooth muscle actin+ myofibroblasts, tenascin immunoreactivity, and procollagen-I+ cells 24–48 h postchallenge. Direct evidence of generation of repair markers was obtained by coculture of eosinophils and fibroblasts. This resulted in α-smooth muscle actin immunoreactivity that was inhibitable by neutralizing Abs to TGF-β as well as production of tenascin transcripts and protein product. TGF-β1 and IL-13 also induced tenascin expression. We conclude that TGF-β1 and IL-13, provided partially by eosinophils, contribute to repair and remodeling events in allergic inflammation in human atopic skin.
Membrane Attack Complex Contributes to Destruction of Vascular Integrity in Acute Lung Allograft Rejection
Authors: Nakashima Shinji , Qian Zhiping , Rahimi Salma , Wasowska Barbara A. , Baldwin William M. 
Published: April 2014

AbstractThe lung is known to be particularly susceptible to complement-mediated injury. Both C5a and the membrane attack complex (MAC), which is formed by the terminal components of complement (C5b-C9), can cause acute pulmonary distress in nontransplanted lungs. We used C6-deficient rats to investigate whether MAC causes injury to lung allografts. PVG.R8 lungs were transplanted orthotopically to MHC class I-incompatible PVG.1U recipients. Allografts from C6-sufficient (C6+) donors to C6+ recipients were rejected with an intense vascular infiltration and diffuse alveolar hemorrhage 7 days after transplantation (n = 5). Ab and complement (C3d) deposition was accompanied by extensive vascular endothelial injury and intravascular release of von Willebrand factor. In contrast, lung allografts from C6-deficient (C6−) donors to C6− recipients survived 13–17 days (n = 5). In the absence of C6, perivascular mononuclear infiltrates of ED1+ macrophages and CD8+ T lymphocytes were present 7 days after transplantation, but vascular endothelial cells were quiescent, with minimal von Willebrand factor release and no evidence of alveolar hemorrhage or edema. Lung allografts were performed from C6− donors to C6+ recipients (n = 5) and from C6+ donors to C6− recipients (n = 5) to separate the effects of systemic and local C6 production. Lungs transplanted from C6+ donors to C6− recipients had increased alveolar macrophages and capillary injury. C6 production by lung allografts was demonstrated at the mRNA and protein levels. These results demonstrate that MAC causes vascular injury in lung allografts and that the location of injury is dependent on the source of C6.
Constitutive OX40/OX40 Ligand Interaction Induces Autoimmune-Like Diseases
Authors: Murata Kazuko , Nose Masato , Ndhlovu Lishomwa C. , Sato Takayuki , Sugamura Kazuo , Ishii Naoto 
Published: April 2014

Abstract
The interaction between OX40 and OX40 ligand (OX40L) is suggested to provide T cells with an effective costimulatory signals during T cell-APC interaction. To examine the in vivo effect of constitutive OX40/OX40L interaction during immune regulation, we report the establishment of OX40L-transgenic (OX40L-Tg) mice that constitutively express OX40L on T cells. Markedly elevated numbers of effector memory CD4+ T cells, but not CD8+ T cells, were observed in the secondary lymphoid organs of OX40L-Tg mice. Upon immunization with keyhole limpet hemocyanin in the absence of adjuvant, profound T cell proliferative responses and cytokine productions were seen in the OX40L-Tg mice as compared with wild-type mice. Furthermore, in OX40L-Tg mice administrated with superantigen, this constitutive OX40/OX40L interaction on CD4+ T cells completely prevented normal in vivo clonal T cell deletion. Interestingly, OX40L-Tg mice on the C57BL/6 background spontaneously developed interstitial pneumonia and inflammatory bowel disease that was accompanied with a significant production of anti-DNA Ab in the sera. Surprisingly, these diseases were not evident on the OX40L-Tg mice on the BALB/c strain. However, such inflammatory diseases were successfully reproducible in recombination-activating gene (RAG)2-deficient mice upon transfer of OX40L-Tg CD4+ T cells. Blockade of OX40/OX40L interaction in the recipient RAG2-deficient mice completely prevented disease development. The present results orchestrated in this study indicate that OX40/OX40L interaction may be a vital link in our understanding of T cell-mediated organ-specific autoimmunity.
MHC Susceptibility Genes to IgA Deficiency Are Located in Different Regions on Different HLA Haplotypes
Authors: De la Concha Emilio G. , Fernandez-Arquero Miguel , Gual Lorena , Vigil Patricia , Martinez Alfonso , Urcelay Elena , Ferreira Antonio , Garcia-Rodriguez Maria C. , Fontan Gumersindo 
Published: April 2014

Abstract
Familial predisposition to IgA deficiency (IgAD) suggests that genetic factors influence susceptibility. Most studies support a polygenic inheritance with a susceptibility locus (designated IGAD1) in the MHC, but its exact location is still controversial. This study aimed to map the predisposing IGAD1 locus (or loci) within the MHC by investigating the pattern of association of the disease with several markers in the region. DNA-based techniques were used to type individual alleles of four polymorphic HLA genes (HLA-DR, -DQA1, -DQB1, and HLA-B), six microsatellites (all located between HLA-DR and HLA-B), and three single nucleotide polymorphisms on the TNF gene. The frequencies of these alleles were compared among ethnically matched populations comprising 182 patients and 343 controls. Additionally, we investigated parents and siblings of 100 of these patients. All four parental haplotypes were established in each family (n = 400), and transmission disequilibrium tests were performed. Surprisingly, our results did not support the hypothesis of a unique susceptibility gene being shared by all MHC susceptibility haplotypes. On HLA-DR1 and -DR7-positive haplotypes IGAD1 mapped to the class II region, whereas on haplotypes carrying HLA-DR3 the susceptibility locus mapped to the telomeric end of the class III region, as reported previously. Our results show how, in complex diseases, individuals may be affected for different genetic reasons and a single linkage signal to a region of a chromosome may actually be the result of disease-predisposing alleles in different linked genes in different pedigrees.
Helper-Dependent Adenoviral Vectors Efficiently Express Transgenes in Human Dendritic Cells but Still Stimulate Antiviral Immune Responses
Authors: Roth Michael D. , Cheng Qingwen , Harui Airi , Basak Saroj K. , Mitani Kohnosuke , Low Teresa A. , Kiertscher Sylvia M. 
Published: April 2014

AbstractAdenoviral (AdV) vectors can be used to transduce a wide range of human cells and tissues. However, pre-existing immunity to AdV, and enhancement of this immunity after repeated administration, limits their clinical application. This may be especially relevant when vectors are loaded into APCs. Helper-dependent AdV (Hd-AdV), in which viral coding regions are replaced by human stuffer DNA, offers a new approach for limiting antiviral responses. To evaluate their immunogenicity, human dendritic cells (DCs) were infected with either an Hd-AdV or a conventional replication-deficient E1-deleted AdV (E1-AdV) and were evaluated for their capacity to stimulate antiviral T cell responses. Hd-AdV proved to be 50- to 275-fold more effective than E1-AdV at expressing the lacZ transgene in human DCs. PCR demonstrated similar transduction efficiencies, but RT-PCR revealed much higher expression of transgene mRNA after transduction with Hd-AdV. Functionally, DCs transduced with Hd-AdV stimulated the proliferation of autologous T cells to the same level as DCs transduced with E1-AdV. Identical viral-specific T cell responder frequencies were observed and T cells stimulated with either type of AdV-transduced DC lysed viral-infected target cells. Disrupting transcription of vector-based genes had no effect on T cell activation, suggesting that responses against both vectors were directed against preformed components of the viral capsid. We conclude that Hd-AdV vectors can be used to obtain higher transgene expression in human DCs but that they still evoke a vector-related immune response similar to that generated by E1-AdV.
Dynamics of T Cells and TCR Excision Circles Differ After Treatment of Acute and Chronic HIV Infection
Authors: Lewin Sharon R. , Ribeiro Ruy M. , Kaufmann Gilbert R. , Smith Don , Zaunders John , Law Matthew , Solomon Ajantha , Cameron Paul U. , Cooper David , Perelson Alan S. 
Published: April 2014

Abstract
We quantified T cell proliferation and thymic function in primary HIV infection (PHI; n = 19) and chronic HIV infection (CHI; n = 14) by measuring Ki67 staining and TCR excision circle (TREC) number. After antiretroviral therapy of PHI there is a profound decrease in the number and percentage of Ki67+ T cells (&lt;6% Ki67+) with no significant increase in TREC per million cells and a transient increase in TREC per milliliter. In contrast, after antiretroviral therapy of CHI there is a reduction in the percentage but little change in the total number of Ki67+CD4+ T cells associated with increases in both TREC per million cells and TREC per milliliter. Using a mathematical model that accounts for proliferation, death, and redistribution of T cells, we find that redistribution is consistent with the TREC changes observed during treatment of PHI and that an increase in thymic output is needed to explain the increase in TREC during treatment of CHI. Consideration of TREC per milliliter shows that changes in proliferation alone cannot explain the changes in TREC. In addition, although increased proliferation of memory cells in HIV infection has been established, we find no difference in TREC per million CD45RA− “memory” T cells between healthy and infected individuals (p = 0.154 for CD4+; p = 0.383 for CD8+). Finally, although the number of TREC per million cells is always much lower in memory T cells than in naive T cells, in the setting of HIV infection, given that memory cells make up a larger proportion of total T cells, we find that 50% of TREC per milliliter in CD4+ T cells is harbored in the CD45RA− “memory” subset of our infected subjects.
Allograft Rejection by Primed/Memory CD8+ T Cells Is CD154 Blockade Resistant: Therapeutic Implications for Sensitized Transplant Recipients
Authors: Zhai Yuan , Meng Lingzhong , Gao Feng , Busuttil Ronald W. , Kupiec-Weglinski Jerzy W. 
Published: April 2014

AbstractWe have shown that CD8+ CTLs are the key mediators of accelerated rejection, and that CD8+ T cells represent the prime targets of CD154 blockade in sensitized mouse recipients of cardiac allografts. However, the current protocols require CD154 blockade at the time of sensitization, whereas delayed treatment fails to affect graft rejection in sensitized recipients. To elucidate the mechanisms of costimulation blockade-resistant rejection and to improve the efficacy of CD154-targeted therapy, we found that alloreactive CD8+ T cells were activated despite the CD154 blockade in sensitized hosts. Comparative CD8 T cell activation study in naive vs primed hosts has shown that although both naive and primed/memory CD8+ T cells relied on the CD28 costimulation for their activation, only naive, not primed/memory, CD8+ T cells depend on CD154 signaling to differentiate into CTL effector cells. Adjunctive therapy was designed accordingly to deplete primed/memory CD8+ T cells before the CD154 blockade. Indeed, unlike anti-CD154 monotherapy, transient depletion of CD8+ T cells around the time of cardiac engraftment significantly improved the efficacy of delayed CD154 blockade in sensitized hosts. Hence, this report provides evidence for 1) differential requirement of CD154 costimulation signals for naive vs primed/memory CD8+ T cells, and 2) successful treatment of clinically relevant sensitized recipients to achieve stable long term graft acceptance.
Cutting Edge: Impaired Toll-Like Receptor Expression and Function in Aging
Authors: Renshaw Mary , Rockwell Julie , Engleman Carrie , Gewirtz Andrew , Katz Jacqueline , Sambhara Suryaprakash 
Published: April 2014

Abstract
Toll-like receptors (TLR) are pattern recognition receptors that recognize conserved molecular patterns on microbes and link innate and adaptive immune systems. We investigated whether the enhanced susceptibility to bacterial, yeast, and viral infections and poor adaptive immune responses in aging are a result of diminished expression and function of TLRs. We examined the expression and function of all murine TLRs on macrophages from young and aged mice. Both splenic and activated peritoneal macrophages from aged mice expressed significantly lower levels of all TLRs. Furthermore, macrophages from aged mice secreted significantly lower levels of IL-6 and TNF-α when stimulated with known ligands for TLR1 and 2, 2 and 6,TLR3, TLR4, TLR5, and TLR9 when compared with those from young mice. These results support the concept that increased susceptibility to infections and poor adaptive immune responses in aging may be due to the decline in TLR expression and function.
Cutting Edge: CD4+CD25+ Regulatory T Cells Suppress Antigen-Specific Autoreactive Immune Responses and Central Nervous System Inflammation During Active Experimental Autoimmune Encephalomyelitis
Authors: Kohm Adam P. , Carpentier Pamela A. , Anger Holly A. , Miller Stephen D. 
Published: April 2014

Abstract
Autoreactive CD4+ T cells exist in normal individuals and retain the capacity to initiate autoimmune disease. The current study investigates the role of CD4+CD25+ T-regulatory (TR) cells during autoimmune disease using the CD4+ T cell-dependent myelin oligodendrocyte glycoprotein (MOG)-specific experimental autoimmune encephalomyelitis model of multiple sclerosis. In vitro, TR cells effectively inhibited both the proliferation of and cytokine production by MOG35–55-specific Th1 cells. In vivo, adoptive transfer of TR cells conferred significant protection from clinical experimental autoimmune encephalomyelitis which was associated with normal activation of autoreactive Th1 cells, but an increased frequency of MOG35–55-specific Th2 cells and decreased CNS infiltration. Lastly, transferred TR cells displayed an enhanced ability to traffic to the peripheral lymph nodes and expressed increased levels of the adhesion molecules ICAM-1 and P-selectin that may promote functional interactions with target T cells. Collectively, these findings suggest that TR cells contribute notably to the endogenous mechanisms that regulate actively induced autoimmune disease.
Most Murine CD8+ Intestinal Intraepithelial Lymphocytes Are Partially But Not Fully Activated T Cells
Authors: Wang Heuy-Ching , Zhou Qin , Dragoo Jolene , Klein John R. 
Published: April 2014

AbstractMurine small intestine intraepithelial lymphocytes (IELs) bear properties of both activated and nonactivated T cells, although the significance of that dichotomy remains unclear. In this study, we show that although IELs express CD69 in situ and ex vivo, and have cytotoxic activity ex vivo, most CD8+ IELs from normal mice are phenotypically similar to naive T cells in that they are CD45RBhigh, CD44low/int, and lack or have low levels of expression of CD25, Ly-6C, OX40, Fas ligand (FasL), and intracellular IFN-γ synthesis. Unlike CD8+ lymph node cells, IELs express high levels of the FasL gene, but do not express surface FasL until after CD3-mediated stimulation has occurred. Additionally, anti-CD3 stimulation of IELs in the presence of actinomycin-D did not inhibit FasL expression, suggesting that regulation FasL expression on IELs is controlled at least partially at the posttranscriptional level. Following CD3-mediated stimulation, IELs synthesize and secrete IFN-γ more rapidly and to greater levels than CD8+ lymph node cells, and they acquire the phenotype of fully activated effector cells as seen by an up-regulation of CD44, Ly-6C, OX40, FasL, and CD25 with the kinetics of memory T cells, with down-regulation of CD45RB expression. These findings indicate that contrary to previous interpretations, most small intestine IELs are not fully activated T cells, but rather that they are semiactivated T cells ready to shift to a fully activated state once a CD3-mediated signal has been received. These data also imply that under appropriate conditions it is possible for T cells to be sustained in a state of partial activation.
T Cell Hyporesponsiveness Induced by Oral Administration of Ovalbumin Is Associated with Impaired NFAT Nuclear Translocation and p27kip1Degradation
Authors: Asai Kazumi , Hachimura Satoshi , Kimura Motoko , Toraya Terumasa , Yamashita Masakatsu , Nakayama Toshinori , Kaminogawa Shuichi 
Published: April 2014

AbstractOral tolerance is an important physiological component of the immune system whereby the organism avoids dangerous reactions such as hypersensitivity to ingested food proteins and other luminal Ags which may cause tissue damage and inflammation. In addition, it has been shown in animal models and in humans that oral tolerance can be applied to controlling undesired immune responses, including autoimmune diseases, allergies, and organ transplant rejections. However, the molecular mechanisms of oral tolerance have been poorly defined. In this study, we investigated the molecular basis underlying the hyporesponsiveness of orally tolerant CD4 T cells using a TCR transgenic mouse system in which oral tolerance was induced by long-term feeding with high dose Ag. We demonstrate that the hyporesponsive state of the CD4 T cells was maintained by a selective impairment in the TCR-induced calcium/NFAT signaling pathway and in the IL-2R-induced degradation of p27kip1 and cell cycle progression. Thus, physiological mucosal tolerance is revealed to be associated with a unique type of T cell hyporesponsiveness which differs from previously described anergic T cells.
Allelic Variation in the Ectodomain of the Inhibitory Ly-49G2 Receptor Alters Its Specificity for Allogeneic and Xenogeneic Ligands
Authors: Silver Elizabeth T. , Lavender Kerry J. , Gong Dong-Er , Hazes Bart , Kane Kevin P. 
Published: April 2014

AbstractThe Ly-49 multigene receptor family regulates mouse NK cell functions. A number of Ly-49 genes exhibit allelic variation, but the functional significance of allelic differences in extracellular domains of Ly-49 receptors regarding ligand specificity is largely unknown. Amino acid differences exist in the extracellular domains of the B6 and BALB/c allele products of the inhibitory Ly-49G receptor. We constructed chimeric Ly-49 receptors consisting of common cytoplasmic and transmembrane regions of the activating Ly-49W receptor fused with the ectodomains of the B6 and BALB/c alleles of Ly-49G. Expression of these chimeras in the RNK-16 rat NK cell line allowed us to study the specificity of inhibitory receptor ectodomains as they stimulated NK lytic activity. We found that the ectodomain of the BALB/c allele of Ly-49G recognizes both H-2Dd and Dk class I MHC alleles, whereas the ectodomain of the B6 allele of Ly-49G recognizes Dd, and not Dk. The specificity for Dk as well as Dd of the wild-type Ly-49GBALB/c allele product was confirmed with RNK-16 transfectants of this inhibitory receptor. Furthermore, the ectodomain of the Ly-49GBALB/c allele recognizes a distinct repertoire of xenogeneic ligands that only partially overlaps with that recognized by Ly-49GB6. Our results indicate that allelic variation in Ly-49 extracellular domains can have functional significance by altering Ly-49 receptor specificity for mouse class I MHC and xenogeneic ligands.
CD1 Molecules Efficiently Present Antigen in Immature Dendritic Cells and Traffic Independently of MHC Class II During Dendritic Cell Maturation
Authors: Cao Xiaochun , Sugita Masahiko , van der Wel Nicole , Lai Jean , Rogers Rick A. , Peters Peter J. , Brenner Michael B. 
Published: April 2014

Abstract
Upon exposure to Ag and inflammatory stimuli, dendritic cells (DCs) undergo a series of dynamic cellular events, referred to as DC maturation, that involve facilitated peptide Ag loading onto MHC class II molecules and their subsequent transport to the cell surface. Besides MHC molecules, human DCs prominently express molecules of the CD1 family (CD1a, -b, -c, and -d) and mediate CD1-dependent presentation of lipid and glycolipid Ags to T cells, but the impact of DC maturation upon CD1 trafficking and Ag presentation is unknown. Using monocyte-derived immature DCs and those stimulated with TNF-α for maturation, we observed that none of the CD1 isoforms underwent changes in intracellular trafficking that mimicked MHC class II molecules during DC maturation. In contrast to the striking increase in surface expression of MHC class II on mature DCs, the surface expression of CD1 molecules was either increased only slightly (for CD1b and CD1c) or decreased (for CD1a). In addition, unlike MHC class II, DC maturation-associated transport from lysosomes to the plasma membrane was not readily detected for CD1b despite the fact that both molecules were prominently expressed in the same MIIC lysosomal compartments before maturation. Consistent with this, DCs efficiently presented CD1b-restricted lipid Ags to specific T cells similarly in immature and mature DCs. Thus, DC maturation-independent pathways for lipid Ag presentation by CD1 may play a crucial role in host defense, even before DCs are able to induce maximum activation of peptide Ag-specific T cells.