bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elimination of Leukemia in the Absence of Lethal Graft-Versus-Host Disease After Allogenic Bone Marrow Transplantation
Authors: Drobyski William R. , Gendelman Maria , Vodanovic-Jankovic Sanja , Gorski Jack 
Published: April 2014

Abstract
Donor T cells are able to effect a graft-vs-leukemia (GVL) response but also induce graft-vs-host disease (GVHD) after allogeneic bone marrow transplantation. We used an AKR leukemia murine transplant model, analogous to human acute lymphoblastic leukemia, in which donor T cells expressed a thymidine kinase suicide gene, to test whether separation of GVL and graft-vs-host (GVH) responses was feasible by selectively eliminating alloactivated donor T cells at defined time points posttransplant. Under experimental conditions where untreated mice could not be cured of disease without dying from GVHD, mice transplanted with thymidine kinase-positive T cells and subsequently administered ganciclovir (GCV) could eliminate leukemia without lethal GVHD. Timing of GCV administration, donor T cell dose, and preexisting leukemia burden were observed to be critical variables. Eradication of leukemia without lethal GVHD in GCV-treated mice implied that the kinetics of GVL and GVH responses were asynchronous and could therefore be temporally dissociated by timely GCV administration. That this strategy was feasible in a murine leukemia model in which GVHD and GVL reactivity are tightly linked suggests that this approach may be relevant to the treatment of selected human leukemias where similar constraints exist. This strategy represents an alternative approach to separating GVL and GVH reactivity and challenges the current paradigm that separation of these responses is dependent upon the administration of donor T cells with restricted specificity for leukemia as opposed to host Ags.
IgE-Mediated Activation of NK Cells Through FcγRIII
Authors: Arase Noriko , Arase Hisashi , Hirano Satoshi , Yokosuka Tadashi , Sakurai Daiju , Saito Takashi 
Published: April 2014

Abstract
NK cells express FcγRIII (CD16), which is responsible for IgG-dependent cell cytotoxicity and for production of several cytokines and chemokines. Whereas FcγRIII on NK cells is composed of both FcγRIIIα and FcRγ chains, that on mast cells is distinct from NK cells and made of FcγRIIIα, FcRβ, and FcRγ. Mast cells show degranulation and release several mediators, which cause anaphylactic responses upon cross-linking of FcγRIII as well as FcεRI with aggregated IgE. In this paper, we examined whether IgE activates NK cells through FcγRIII on their cell surface. We found that NK cells produce several cytokines and chemokines related to an allergic reaction upon IgE stimulation. Furthermore, NK cells exhibited cytotoxicity against IgE-coated target cells in an FcγRIII-dependent manner. These effects of IgE through FcγRIII were not observed in NK cells from FcRγ-deficient mice lacking FcγRIII expression. Collectively, these results demonstrate that NK cells can be activated with IgE through FcγRIII and exhibit both cytokine/chemokine production and Ab-dependent cell cytotoxicity. These data imply that not only mast cells but also NK cells may contribute to IgE-mediated allergic responses.
Proline-Rich Tyrosine Kinase 2 and Rac Activation by Chemokine and Integrin Receptors Controls NK Cell Transendothelial Migration
Authors: Gismondi Angela , Jacobelli Jordan , Strippoli Raffaele , Mainiero Fabrizio , Soriani Alessandra , Cifaldi Loredana , Piccoli Mario , Frati Luigi , Santoni Angela 
Published: April 2014

Abstract
Protein tyrosine kinase activation is an important requisite for leukocyte migration. Herein we demonstrate that NK cell binding to endothelium activates proline-rich tyrosine kinase 2 (Pyk-2) and the small GTP binding protein Rac that are coupled to integrin and chemokine receptors. Chemokine-mediated, but not integrin-mediated, Pyk-2 and Rac activation was sensitive to pretreatment of NK cells with pertussis toxin, a pharmacological inhibitor of Gi protein-coupled receptors. Both Pyk-2 and Rac are functionally involved in chemokine-induced NK cell migration through endothelium or ICAM-1 or VCAM-1 adhesive proteins, as shown by the use of recombinant vaccinia viruses encoding dominant negative mutants of Pyk-2 and Rac. Moreover, we found that Pyk-2 is associated with the Rac guanine nucleotide exchange factor Vav, which undergoes tyrosine phosphorylation upon integrin triggering. Finally, we provide direct evidence for the involvement of Pyk-2 in the control of both chemokine- and integrin-mediated Rac activation. Collectively, our results indicate that Pyk-2 acts as a receptor-proximal link between integrin and chemokine receptor signaling, and the Pyk-2/Rac pathway plays a pivotal role in the control of NK cell transendothelial migration.
Differential Distribution of HLA-DQβ/DRβ Epitopes in the Two Forms of Guillain-Barré Syndrome, Acute Motor Axonal Neuropathy and Acute Inflammatory Demyelinating Polyneuropathy (AIDP): Identification of DQβ Epitopes Associated with Susceptibility to and Protection from AIDP
Authors: Magira Eleni E. , Papaioakim Miltiadis , Nachamkin Irving , Asbury Arthur K. , Li Chun Y. , Ho Tony W. , Griffin John W. , McKhann Guy M. , Monos Dimitri S. 
Published: April 2014

Abstract
Guillain-Barré syndrome (GBS), an acute, immune-mediated paralytic disorder affecting the peripheral nervous system, is the most common cause of acute flaccid paralysis in the postpolio era. GBS is classified into several subtypes based on clinical and pathologic criteria, with acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN) being the most common forms observed. To better understand the pathogenesis of GBS and host susceptibility to developing the disease, the distribution of HLA class II Ags along with the seroreactivity to Campylobacter jejuni were investigated in a population of GBS patients from northern China. Using DNA-based typing methods, 47 patients with AMAN, 25 patients with AIDP, and 97 healthy controls were studied for the distribution of class II alleles. We found that the DQβ RLD55–57/ED70–71 and DRβ E9V11H13 epitopes were associated with susceptibility to AIDP (p = 0.009 and p = 0.004, respectively), and the DQβ RPD55–57 epitope was associated with protection (p = 0.05) from AIDP. These DQβ/DRβ positional residues are a part of pockets 4 (DQβ 70, 71, DRβ13), 6 (DRβ11), and 9 (DQβ 56, 57, DRβ9); have been demonstrated to be important in peptide binding and T cell recognition; and are associated with other diseases that have a pathoimmunological basis. Class II HLA associations were not identified with AMAN, suggesting a different immunological mechanism of disease induction in the two forms of GBS. These findings provide immunogenetic evidence for differentiating the two disease entities (AMAN and AIDP) and focuses our attention on particular DRβ/DQβ residues that may be instrumental in understanding the pathophysiology of AIDP.
The Four TCR Genes of Teleost Fish: The cDNA and Genomic DNA Analysis of Japanese Flounder (Paralichthys olivaceus) TCR α-, β-, γ-, and δ-Chains
Authors: Nam Bo-Hye , Hirono Ikuo , Aoki Takashi 
Published: April 2014

AbstractWe have isolated and identified all four TCR α, β, γ, and δ cDNAs and genomic clones from a Japanese flounder leukocyte cDNA library and bacterial artificial chromosomal genomic library. Numerous TCR transcripts were sequenced to examine the variability against antigenic peptide, and were shown hypervariability on their complementarity-determining region 3 (CDR3) loops. Among CDR3s, CDR3δ showed a long and broad length distribution, indicating greater similarity to that of Ig. From cDNA sequences and genomic gene analysis of each chain, we found that flounder TCR β, γ, and δ have two different C gene segments, while the TCR α C region exists as a single segment. The flounder Cγs and Cδs showed different lengths in the connecting peptide (CP) region between the different types of polypeptides. The Cδ1 gene consists of two exons, one that encodes an extracellular Ig-like domain (exon 1) and the other that encodes either a very short or possibly a lacking CP region, a transmembrane region, and a cytoplasmic tail (exon 2); these are located within TCR α gene locus. Southern blot analysis, using the bacterial artificial chromosomal genomic DNA clones, revealed that the Cδ2 gene segment, which has a long CP region and different genomic organization to the Cδ1 gene, exists on same gene locus as the TCR γ-chain. This suggests that the flounder possesses very unique genomic DNA organization and gene loci for TCR, Cα/Cδ1, and Cγ/Cδ2.
Ikaros Isoform X Is Selectively Expressed in Myeloid Differentiation
Authors: Payne Kimberly J. , Huang Grace , Sahakian Eva , Zhu Judy Y. , Barteneva Natasha S. , Barsky Lora W. , Payne Marvin A. , Crooks Gay M. 
Published: April 2014

AbstractThe Ikaros gene is alternately spliced to generate multiple DNA-binding and nonbinding isoforms that have been implicated as regulators of hematopoiesis, particularly in the lymphoid lineages. Although early reports of Ikaros mutant mice focused on lymphoid defects, these mice also show significant myeloid, erythroid, and stem cell defects. However, the specific Ikaros proteins expressed in these cells have not been determined. We recently described Ikaros-x (Ikx), a new Ikaros isoform that is the predominant Ikaros protein in normal human hematopoietic cells. In this study, we report that the Ikx protein is selectively expressed in human myeloid lineage cells, while Ik1 predominates in the lymphoid and erythroid lineages. Both Ik1 and Ikx proteins are expressed in early human hematopoietic cells (Lin−CD34+). Under culture conditions that promote specific lineage differentiation, Ikx is up-regulated during myeloid differentiation but down-regulated during lymphoid differentiation from human Lin−CD34+ cells. We show that Ikx and other novel Ikaros splice variants identified in human studies are also expressed in murine bone marrow. In mice, as in humans, the Ikx protein is selectively expressed in the myeloid lineage. Our studies suggest that Ikaros proteins function in myeloid, as well as lymphoid, differentiation and that specific Ikaros isoforms may play a role in regulating lineage commitment decisions in mice and humans.
NF-κB Is Required for Surface Ig-Induced Fas Resistance in B Cells
Authors: Schram Brian R. , Rothstein Thomas L. 
Published: April 2014

Abstract
The susceptibility of primary murine B cells to Fas-mediated apoptosis is regulated in a receptor-specific fashion. Whereas CD40 engagement produces marked sensitivity to Fas killing, engagement of the B cell Ag receptor blocks Fas signaling for cell death in otherwise Fas-sensitive, CD40-stimulated targets and thus induces Fas resistance. The signaling pathway that leads from B cell Ag receptor to Fas resistance has not been fully characterized, but has been shown to depend on new gene expression. NF-κB is activated following B cell Ag receptor engagement and is associated with antiapoptosis; thus, it would seem a likely candidate to mediate transcriptional activation for inducible Fas resistance. Inhibition of B cell Ag receptor signaling for NF-κB activation completely blocked induction of Fas resistance by anti-Ig, and this same phenotype was observed both with chemical inhibitors such as lactacystin and pyrrolidinedithiocarbamate as well as with an IκBα dominant negative TAT fusion protein. Antiapoptotic, NF-κB-responsive transcripts include two gene products previously implicated in mediating anti-Ig-induced Fas resistance, Bcl-xL and FLIP. B cell Ag receptor-induced up-regulation of both these gene products was blocked by NF-κB inhibition, suggesting a mechanism by which the loss of nuclear NF-κB alters the sensitivity of B cell Ag receptor-stimulated B cells to Fas-mediated apoptosis. These results indicate that activation of NF-κB plays a key role in mediating Fas resistance produced by B cell Ag receptor engagement.
Identification of a Functionally Impaired Positive Regulatory Domain I Binding Factor 1 Transcription Repressor in Myeloma Cell Lines
Authors: Györy Ildikó , Fejér György , Ghosh Nilanjan , Seto Ed , Wright Kenneth L. 
Published: April 2014

Abstract
B cell differentiation into a plasma cell requires expression of the positive regulatory domain zinc finger protein 1 gene (PRDM1) that encodes the positive regulatory domain I binding factor 1 (PRDI-BF1 or Blimp-1) protein. It represses the transcription of specific target genes, including c-myc, the MHC class II trans-activator, Pax-5, and CD23b. In this study we demonstrate the presence of an alternative protein product of the PRDM1 gene. The new protein, PRDI-BF1β, has a disrupted PR domain and lacks the amino-terminal 101 aa of the originally described protein. PRDI-BF1β has a dramatic loss of repressive function on multiple target genes, but maintains normal DNA-binding activity, nuclear localization, and association with histone deacetylases and deacetylase activity. Myeloma cell lines express the highest levels of PRDM1β mRNA relative to the full-length form, while primary cells and several other cell lines have very low, but detectable, levels of PRDM1β. RNA analysis and analysis of the PRDM1 promoters demonstrate that PRDI-BF1β is generated from the same gene by alternative transcription initiation using an internal promoter. These newly described features of the PRDM1 gene are highly analogous to the PRDM2 (RIZ) and PRDM3 (MDS1-EVI1) genes, in which each express a truncated protein missing the PR domain. The expression of each of the truncated proteins is elevated in cancerous cells and may play an important role in the disease.
Inhibition of NF-κB Activity in T and NK Cells Results in Defective Effector Cell Expansion and Production of IFN-γ Required for Resistance to Toxoplasma gondii
Authors: Tato Cristina M. , Villarino Alejandro , Caamaño Jorge H. , Boothby Mark , Hunter Christopher A. 
Published: April 2014

Abstract
To define the role of NF-κB in the development of T cell responses required for resistance to Toxoplasma gondii, mice in which T cells are transgenic for a degradation-resistant (ΔN) form of IκBα, an inhibitor of NF-κB, were challenged with T. gondii and their response to infection compared with control mice. IκBα(ΔN)-transgenic (Tg) mice succumbed to T. gondii infection between days 12 and 35, and death was associated with an increased parasite burden compared with wild-type (Wt) controls. Analysis of the responses of infected mice revealed that IL-12 responses were comparable between strains, but Tg mice had a marked reduction in systemic levels of IFN-γ, the major mediator of resistance to T. gondii. In addition, the infection-induced increase in NK cell activity observed in Wt mice was absent from Tg mice and this correlated with NK cell expression of the transgene. Infection-induced activation of CD4+ T cells was similar in Wt and Tg mice, but expansion of activated CD4+T cells was markedly reduced in the Tg mice. This difference in T cell numbers correlated with a reduced capacity of these cells to proliferate after stimulation and was associated with a major defect in the ability of CD4+ T cells from infected mice to produce IFN-γ. Together, these studies reveal that inhibition of NF-κB activity in T and NK cells results in defective effector cell expansion and production of IFN-γ required for resistance to T. gondii.
Role of CD1d in Coxsackievirus B3-Induced Myocarditis
Authors: Huber Sally , Sartini Danielle , Exley Mark 
Published: April 2014

Abstract
The myocarditic (H3) variant of Coxsackievirus B3 (CVB3) causes severe myocarditis in BALB/c mice and BALB/c mice lacking the invariant Jα281 gene, but minimal disease in BALB/c CD1d−/− animals. This indicates that CD1d expression is important in this disease but does not involve the invariant NKT cell often associated with CD1d-restricted immunity. The H3 variant of the virus increases CD1d expression in vitro in neonatal cardiac myocytes whereas a nonmyocarditic (H310A1) variant does not. Vγ4+ T cells show increased activation in both H3-infected BALB/c and Jα281−/− mice compared with CD1d−/− animals. The activated BALB/c Vγ4+ T cells from H3-infected mice kill H3-infected BALB/c myocytes and cytotoxicity is blocked with anti-CD1d but not with anti-MHC class I (Kd/Dd) or class II (IA/IE) mAbs. In contrast, H3 virus-infected CD1d−/− myocytes are not killed. These studies demonstrate that CD1d expression is essential for pathogenicity of CVB3-induced myocarditis, that CD1d expression is increased early after infection in vivo in CD1d+ mice infected with the myocarditic but not with the nonmyocarditic CVB3 variant, and that Vγ4+ T cells, which are known to promote myocarditis susceptibility, appear to recognize CD1d expressed by CVB3-infected myocytes.
Dendritic Cell (DC)-Based Protection Against an Intracellular Pathogen Is Dependent Upon DC-Derived IL-12 and Can Be Induced by Molecularly Defined Antigens
Authors: Berberich Christof , Ramírez-Pineda José R. , Hambrecht Christine , Alber Gottfried , Skeiky Yasir A. W. , Moll Heidrun 
Published: April 2014

Abstract
Upon loading with microbial Ag and adoptive transfer, dendritic cells (DC) are able to induce immunity to infections. This offers encouragement for the development of DC-based vaccination strategies. However, the mechanisms underlying the adjuvant effect of DC are not fully understood, and there is a need to identify Ag with which to arm DC. In the present study, we analyzed the role of DC-derived IL-12 in the induction of resistance to Leishmania major, and we evaluated the protective efficacy of DC loaded with individual Leishmania Ag. Using Ag-pulsed Langerhans cells (LC) from IL-12-deficient or wild-type mice for immunization of susceptible animals, we showed that the inability to release IL-12 completely abrogated the capacity of LC to mediate protection against leishmaniasis. This suggests that the availability of donor LC-derived IL-12 is a requirement for the development of protective immunity. In addition, we tested the protective effect of LC loaded with Leishmania homolog of receptor for activated C kinase, gp63, promastigote surface Ag, kinetoplastid membrane protein-11, or Leishmania homolog of eukaryotic ribosomal elongation and initiation factor 4a. The results show that mice vaccinated with LC that had been pulsed with selected molecularly defined parasite proteins are capable of controlling infection with L. major. Moreover, the protective potential of DC pulsed with a given Leishmania Ag correlated with the level of their IL-12 expression. Analysis of the cytokine profile of mice after DC-based vaccination revealed that protection was associated with a shift toward a Th1-type response. Together, these findings emphasize the critical role of IL-12 produced by the sensitizing DC and suggest that the development of a DC-based subunit vaccine is feasible.
CD4+ T Cell-Induced Differentiation of EBV-Transformed Lymphoblastoid Cells Is Associated with Diminished Recognition by EBV-Specific CD8+ Cytotoxic T Cells
Authors: Khanolkar Aaruni , Fu Zheng , Underwood L. Joey , Bondurant Kristy L. , Rochford Rosemary , Cannon Martin J. 
Published: April 2014

Abstract
EBV transformation of human B cells in vitro results in establishment of immortalized cell lines (lymphoblastoid cell lines (LCL)) that express viral transformation-associated latent genes and exhibit a fixed, lymphoblastoid phenotype. In this report, we show that CD4+ T cells can modify the differentiation state of EBV-transformed LCL. Coculture of LCL with EBV-specific CD4+ T cells resulted in an altered phenotype, characterized by elevated CD38 expression and decreased proliferation rate. Relative to control LCL, the cocultured LCL were markedly less susceptible to lysis by EBV-specific CD8+ CTL. In contrast, CD4+ T cell-induced differentiation of LCL did not diminish sensitivity of LCL to lysis by CD8+ CTL specific for an exogenously loaded peptide Ag or lysis by alloreactive CD8+ CTL, suggesting that differentiation is not associated with intrinsic resistance to CD8+ T cell cytotoxicity and that evasion of lysis is confined to EBV-specific CTL responses. CD4+ T cell-induced differentiation of LCL and concomitant resistance of LCL to lysis by EBV-specific CD8+ CTL were associated with reduced expression of viral latent genes. Finally, transwell cocultures, in which direct LCL-CD4+ T cell contact was prevented, indicated a major role for CD4+ T cell cytokines in the differentiation of LCL.
The Dendritic Cell-Specific Chemokine, Dendritic Cell-Derived CC Chemokine 1, Enhances Protective Cell-Mediated Immunity to Murine Malaria
Authors: Bruna-Romero Oscar , Schmieg John , Del Val Margarita , Buschle Michael , Tsuji Moriya 
Published: April 2014

Abstract
Cell-mediated immunity plays a crucial role in the control of many infectious diseases, necessitating the need for adjuvants that can augment cellular immune responses elicited by vaccines. It is well established that protection against one such disease, malaria, requires strong CD8+ T cell responses targeted against the liver stages of the causative agent, Plasmodium spp. In this report we show that the dendritic cell-specific chemokine, dendritic cell-derived CC chemokine 1 (DC-CK1), which is produced in humans and acts on naive lymphocytes, can enhance Ag-specific CD8+ T cell responses when coadministered with either irradiated Plasmodium yoelii sporozoites or a recombinant adenovirus expressing the P. yoelii circumsporozoite protein in mice. We further show that these enhanced T cell responses result in increased protection to malaria in immunized mice challenged with live P. yoelii sporozoites, revealing an adjuvant activity for DC-CK1. DC-CK1 appears to act preferentially on naive mouse lymphocytes, and its adjuvant effect requires IL-12, but not IFN-γ or CD40. Overall, our results show for the first time an in vivo role for DC-CK1 in the establishment of primary T cell responses and indicate the potential of this chemokine as an adjuvant for vaccines against malaria as well as other diseases in which cellular immune responses are important.
Serum-Resistant Strains of Borrelia burgdorferi Evade Complement-Mediated Killing by Expressing a CD59-Like Complement Inhibitory Molecule
Authors: Pausa Mario , Pellis Valentina , Cinco Marina , Giulianini Piero G. , Presani Gianni , Perticarari Sandra , Murgia Rossella , Tedesco Francesco 
Published: April 2014

Abstract
Borrelia burgdorferi, the etiological agent of Lyme disease, comprises three genospecies, Borrelia garinii, afzelii, and burgdorferi sensu strictu, that exhibit different pathogenicity and differ in the susceptibility to C-mediated killing. We examined C-sensitive and C-resistant strains of B. burgdorferi for deposition of C3 and late C components by fluorescence microscope and flow cytometry. Despite comparable deposition of C3 on the two strains, the resistant strain exhibited reduced staining for C6 and C7, barely detectable C9, and undetectable poly C9. Based on these findings, we searched for a protein that inhibits assembly of C membrane attack complex and documented an anti-human CD59-reactive molecule on the surface of C-resistant spirochetes by flow cytometry and electron microscopy. A molecule of 80 kDa recognized by polyclonal and monoclonal anti-CD59 Abs was identified in the membrane extract of C-resistant strains by SDS-PAGE and Western blot analysis. The molecule was released from the bacterial wall using deoxycholate and trypsin, suggesting its insertion into the bacterial membrane. The CD59-like molecule acts as C inhibitor on Borrelia because incubation with F(ab′)2 anti-CD59 renders the serum-resistant strain exquisitely susceptible to C-mediated killing and guinea pig erythrocytes bearing C5b-8, unlike the RBC coated with C5b-7, are protected from reactive lysis by the bacterial extract. Western blot analysis revealed preferential binding of the C inhibitory molecule to C9 and weak interaction with C8β.