bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Requirement for B Cells for Development of Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 Mice
Authors: Braley-Mullen Helen , Yu Shiguang 
Published: April 2014

AbstractB cells are known to play an important role in the pathogenesis of several autoimmune diseases. NOD.H-2h4 mice develop spontaneous autoimmune thyroiditis (SAT) and anti-mouse thyroglobulin (MTg) autoantibodies, the levels of which correlate closely with the severity of thyroid lesions. NOD.H-2h4 mice genetically deficient in B cells (NOD.Kμnull) or rendered B cell-deficient by treatment from birth with anti-IgM develop minimal SAT. B cells were required some time in the first 4–6 wk after birth, because NOD.Kμnull or NOD.H-2h4 mice did not develop SAT when they were reconstituted with B cells as adults. The requirement for B cells was apparently not solely to produce anti-MTg autoantibodies, because passive transfer of anti-MTg Ab did not enable B cell-deficient mice to develop SAT, and mice given B cells as adults produced autoantibodies but did not develop SAT. B cell-deficient mice developed SAT if their T cells developed from bone marrow precursors in the presence of B cells. Because B cells are required early in life and their function cannot be replaced by anti-MTg autoantibodies, B cells may be required for the activation or selection of autoreactive T cells. These autoreactive T cells are apparently unable to respond to Ag if B cells are absent in the first 4–6 wk after birth.
Highly Autoproliferative T Cells Specific for 60-kDa Heat Shock Protein Produce IL-4/IL-10 and IFN-γ and Are Protective in Adjuvant Arthritis
Authors: Paul Alberta G. A. , van Kooten Peter J. S. , van Eden Willem , van der Zee Ruurd 
Published: April 2014

Abstract
Previously we have shown that T cell responses to the mycobacterial 60-kDa heat shock protein (hsp60) peptide M256–270 mediated protection against adjuvant arthritis in Lewis rats. We have demonstrated now that M256–270-primed T cells become highly reactive to naive syngeneic APC upon repetitive restimulation in vitro with peptide M256–265, comprising the conserved core of peptide M256–270. These autoproliferative responses in the absence of added Ag were MHC class II restricted and resulted in the production of IL-4/IL-10 and IFN-γ. Enhanced autoproliferation and expression of the cell surface molecule B7.2 by these T cells were observed in response to syngeneic heat-shocked APC, which indicated that the autoproliferation and expression of B7.2 resulted from the recognition of endogenously expressed and processed hsp. Despite their strong autoreactivity, upon transfer such T cells were found to induce a significant disease reduction in adjuvant arthritis. In contrast, T cells both primed and restimulated with peptide M256–270 became unresponsive toward syngeneic APC as well as toward the conserved core peptide M256–265, and they were devoid of protective capacity. This study demonstrates that the loss of self-tolerance toward hsp60 does not necessarily lead to autoimmune disease, but that hsp60-specific self-reactive and autoproliferative T cells may mediate T cell regulation in arthritis.
The Influence of HLA Class I Alleles and Heterozygosity on the Outcome of Human T Cell Lymphotropic Virus Type I Infection
Authors: Jeffery Katie J. M. , Siddiqui Asna A. , Bunce Mike , Lloyd Alun L. , Vine Alison M. , Witkover Aviva D. , Izumo Shuji , Usuku Koichiro , Welsh Kenneth I. , Osame Mitsuhiro , Bangham Charles R. M. 
Published: April 2014

AbstractThe inflammatory disease human T cell lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM/TSP) occurs in only 1–2% of HTLV-I-infected individuals and is associated with a high provirus load of HTLV-I. We hypothesize that a person’s risk of developing HAM/TSP depends upon the efficiency of their immune response to the virus, which differs between individuals because of polymorphism in genes that influence this response. Previously we showed that the possession of HLA-A*02 was associated with a lower risk of HAM/TSP, and with a lower provirus load in healthy carriers of HTLV-I. However, HLA-A*02 did not account for all the observed difference in the risk of HAM/TSP. Here we present evidence, in the same study population in Japan, that HLA-Cw*08 was also associated with disease protection (probability value, two-tailed test = 0.002) and with a lower proviral load in healthy carriers. Possession of the A*02 and/or Cw*08 genes prevented 36% of potential HAM/TSP cases. In contrast, HLA-B*5401 was associated with a higher susceptibility to HAM/TSP (probability value, two-tailed test = 0.0003) and with a higher provirus load in HAM/TSP patients. At a given provirus load, B*5401 appeared to increase the risk of disease. The fraction of HAM/TSP cases attributable to B*5401 was 17%. Furthermore, individuals who were heterozygous at all three HLA class I loci have a lower HTLV-I provirus load than those who were homozygous at one or more loci. These results are consistent with the proposal that a strong class I-restricted CTL response to HTLV-I reduces the proviral load and hence the risk of disease.
Direct Detection and Magnetic Isolation ofChlamydia trachomatisMajor Outer Membrane Protein-Specific CD8+ CTLs with HLA Class I Tetramers
Authors: Kim Seon-Kyeong , Devine Lesley , Angevine Mark , DeMars Robert , Kavathas Paula B. 
Published: April 2014

AbstractWe recently identified HLA class I-presented epitopes in the major outer membrane protein (MOMP) of Chlamydia trachomatis that elicit CTL responses in human genital tract infections. T cells possessing cytolytic activities specific for these epitopes could be detected following in vitro stimulation of peripheral blood CD8+ T cells with peptides. In the present study we used HLA-A2 tetramers for detailed characterization of MOMP-specific CTL responses. Ex vivo tetramer analysis detected MOMP-specific T cells in the peripheral blood of infected individuals at significant frequencies (0.01–0.20% of CD8+ T cells). After in vitro stimulation with peptides, the frequencies of MOMP peptide-specific T cells increased up to 2.34% of CD8+ T cells in bulk cultures. In contrast, HLA-A2/MOMP tetramer-binding T cells were virtually undetectable in the peripheral blood from uninfected individuals, either ex vivo or after 3 wk of in vitro peptide stimulation of their T cells. Magnetically sorted, tetramer-bound T cells specifically lysed peptide-pulsed targets as well as C. trachomatis-infected epithelial cells with nearly 50-fold greater per cell efficiency than that of unsorted populations. This study provides conclusive evidence of in vivo induction of HLA class I-restricted CD8+ CTL responses to C. trachomatis MOMP. Direct detection of these cells with tetramers will allow their further characterization without prior manipulation and facilitate monitoring of CTL responses during infections and in immunization trials with MOMP-based vaccines.
IL-12 Treatment of Endogenously Arising Murine Brain Tumors
Authors: Roy Edward J. , Gawlick Ute , Orr Brent A. , Rund Laurie A. , Webb Andrew G. , Kranz David M. 
Published: April 2014

AbstractA number of recent studies have indicated that T cells can be stimulated to attack transplanted brain tumors in rodent models. As IL-12 has been shown to activate cytotoxic T cell responses, we tested the idea that it might stimulate a T cell response against endogenous brain tumors that arise in SV40 large T Ag transgenic mice (SV11). SV11 mice develop tumors of the choroid plexus, a specialization of the ependymal lining of the brain ventricles. They are a particularly relevant model of human disease, because they are immunocompetent but immunologically tolerant of the tumors. SV11 mice were treated with recombinant murine IL-12 for 10 days. Tumors grew more slowly than in control treated mice, and in some cases were reduced in size, as assessed by magnetic resonance imaging before and after treatment. At the end of treatment, tumors, but not brain parenchyma, exhibited extensive infiltration of activated CD8+ and CD4+ T cells. Tumors also showed a reduction in vascular density. Mice treated with IL-12 lived significantly longer than control mice. Tumors that progressed were nearly devoid of T cells, indicating that the T cell response was not sustained. In addition, some mice that had a substantial tumor burden at the beginning of treatment displayed evidence of immunosuppression, which might be related to TGF-β2 detected in tumors. We conclude that IL-12 treatment can initiate an anti-tumor response even against endogenously arising brain tumors, but factors that will allow a sustained and more effective anti-tumor response need to be determined.
Human and Murine CD4 T Cell Reactivity to a Complex Antigen: Recognition of the Synthetic Random Polypeptide Glatiramer Acetate
Authors: Duda Petra W. , Krieger Jeffrey I. , Schmied Mascha C. , Balentine Courtney , Hafler David A. 
Published: April 2014

AbstractThe capacity of glatiramer acetate (GA), a random copolymer of alanine, lysine, glutamic acid, and tyrosine to stimulate primary in vitro human and murine T cell proliferation was examined. PBMCs isolated from healthy humans and relapsing remitting multiple sclerosis patients and spleen cells from inbred strains of mice, expressing different H-2 haplotypes, were used as sources of non-GA-primed lymphocytes. GA functioned as a universal Ag, inducing dose-dependent proliferation of all non-GA-primed human and murine T cell populations tested. Moreover, GA stimulated PBMCs derived ex vivo from human cord blood, strongly suggesting that GA can activate both naive and memory T cells. The human T cell proliferative responses to GA were HLA class II DR-restricted by virtue of the ability of anti-class II Ab to inhibit T cell proliferation, and the demonstration that individual GA specific human T cell clones were HLA class II DR-restricted by either restriction element but not both. Furthermore, GA-reactive T cells secreted Th0 cytokines and expressed a diverse repertoire of TCR. Limiting dilution analysis indicated that the T cell precursor frequency among the healthy human adults tested ranged from 1:5,000 to 1:125,000. Given that all of the T cell populations tested were isolated from non-GA-primed donors, it appears that virtually all humans and murine strains contain significant numbers of T cell populations cross-reactive with GA. These findings may explain the recent clinical finding that daily s.c. administration of GA ameliorates the progression of multiple sclerosis.
Adoptive T Cell Immunotherapy of Human Uveal Melanoma Targeting gp100
Authors: Sutmuller Roger P. M. , Schurmans Luc R. H. M. , van Duivenvoorde Leonie M. , Tine John A. , van der Voort Ellen I. H. , Toes René E. M. , Melief Cornelis J. M. , Jager Martine J. , Offringa Rienk 
Published: April 2014

AbstractHLA-A*0201-restricted CTL against human gp100 were isolated from HLA-A*0201/Kb (A2/Kb)-transgenic mice immunized with recombinant canarypox virus (ALVAC-gp100). These CTL strongly responded to the gp100154–162 epitope, in the context of both the chimeric A2/Kb and the wild-type HLA-A*0201− molecule, and efficiently lysed human HLA-A*0201+, gp100+ melanoma cells in vitro. The capacity of the CTL to eradicate these tumors in vivo was analyzed in A2/Kb-transgenic transgenic mice that had received a tumorigenic dose of human uveal melanoma cells in the anterior chamber of the eye. This immune-privileged site offered the unique opportunity to graft xenogeneic tumors into immunocompetent A2/Kb-transgenic mice, a host in which they otherwise would not grow. Importantly, systemic (i.v.) administration of the A2/Kb-transgenic gp100154–162-specific CTL resulted in rapid elimination of the intraocular uveal melanomas, indicating that anti-tumor CTL are capable of homing to the eye and exerting their tumoricidal effector function. Flow cytometry analysis of ocular cell suspensions with HLA-A*0201-gp100154–162 tetrameric complexes confirmed the homing of adoptively transferred CTL. Therefore, the immune-privileged state of the eye permitted the outgrowth of xenogeneic uveal melanoma cells, but did not protect these tumors against adoptive immunotherapy with highly potent anti-tumor CTL. These data constitute the first direct indication that immunotherapy of human uveal melanoma may be feasible.
CD40 Signaling Replaces CD4+ Lymphocytes and Its Blocking Prevents Chronic Rejection of Heart Transplants
Authors: Fischbein Michael P. , Ardehali Abbas , Yun James , Schoenberger Stephen , Laks Hillel , Irie Yoshihito , Dempsey Paul , Cheng Genhong , Fishbein Michael C. , Bonavida Benjamin 
Published: April 2014

AbstractChronic rejection remains the major obstacle to long term survival in heart transplant recipients. The cellular and molecular mechanisms that underlie chronic rejection are not known, and their discovery can form the basis of clinical intervention. Several investigators have suggested that the development of chronic rejection in solid organ transplants is dependent on help mediated by CD4+ lymphocytes. Importantly, the mechanism through which help is provided has not been fully delineated in transplant rejection. Using a murine heterotopic heart transplant model without immunosuppression, this study defines the functional role of CD4+ lymphocytes in chronic rejection. In an MHC class II-mismatched model, we demonstrate that chronic rejection was absolutely contingent on the presence of CD4+ lymphocytes. Importantly, here we report that signaling through CD40 can replace the requirement of CD4+ lymphocytes, demonstrated by the development of chronic rejection in CD4 knockout recipients treated with a CD40-activating mAb (FGK45). The return of rejection appears to be a CD8+ lymphocyte-dependent process, noted by the absence of rejection in FGK45-treated recombinase-activated gene knockout (CD4+ and CD8+ lymphocyte-deficient) recipients. The CD40 signaling pathway works independently of B7-CD28 costimulation, as indicated by the development of severe chronic rejection in CD28 knockout recipients. Importantly, this study provides evidence that CD40 ligand-targeted therapies may prevent chronic rejection only in strain combinations where CD4+ lymphocyte help is absolutely required.
Tyrosinase Family Proteins Are Antigens Specific to Vogt-Koyanagi-Harada Disease
Authors: Yamaki Kunihiko , Gocho Kiyoko , Hayakawa Koichi , Kondo Isao , Sakuragi Shozo 
Published: April 2014

Abstract
Vogt-Koyanagi-Harada (VKH) disease (and sympathetic ophthalmia) is an ocular inflammatory disease that is considered to be a cell-mediated autoimmune disease against melanocytes. The purpose of this study was to determine the Ags specific to VKH disease and to develop an animal model of VKH disease. We found that exposure of lymphocytes from patients with VKH disease to peptides (30-mer) derived from the tyrosinase family proteins led to significant proliferation of the lymphocytes. Immunization of these peptides into pigmented rats induced ocular and extraocular changes that highly resembled human VKH disease, and we suggest that an experimental VKH disease was induced in these rats. We conclude that VKH disease is an autoimmune disease against the tyrosinase family proteins.
A Mechanism for IL-10-Mediated Diabetes in the Nonobese Diabetic (NOD) Mouse: ICAM-1 Deficiency Blocks Accelerated Diabetes
Authors: Balasa Balaji , La Cava Antonio , Van Gunst Kurt , Mocnik Lorraine , Balakrishna Deepika , Nguyen Nancy , Tucker Lee , Sarvetnick Nora 
Published: April 2014

AbstractNeonatal islet-specific expression of IL-10 in nonobese diabetic (NOD) mice accelerates the onset of diabetes, whereas systemic treatment of young NOD mice with IL-10 prevents diabetes. The mechanism for acceleration of diabetes in IL-10-NOD mice is not known. Here we show, by adoptive transfers, that prediabetic or diabetic NOD splenocytes upon encountering IL-10 in the pancreatic islets readily promoted diabetes. This outcome suggests that the compartment of exposure, not the timing, confers proinflammatory effects on this molecule. Moreover, injection of IL-10-deficient NOD splenocytes into transgenic IL-10-NOD.scid/scid mice elicited accelerated disease, demonstrating that pancreatic IL-10 but not endogenous IL-10 is sufficient for the acceleration of diabetes. Immunohistochemical analysis revealed hyperexpression of ICAM-1 on the vascular endothelium of IL-10-NOD mice. The finding suggests that IL-10 may promote diabetes via an ICAM-1-dependent pathway. We found that introduction of ICAM-1 deficiency into IL-10-NOD mice as well as into NOD mice prevented accelerated insulitis and diabetes. Failure to develop insulitis and diabetes was preceded by the absence of GAD65-specific T cell responses. The data suggest that ICAM-1 plays a role in the formation of the “immunological synapse”, thereby affecting the generation and/or expansion of islet-specific T cells. In addition, ICAM-1 also played a role in the effector phase of autoimmune diabetes because adoptive transfer of diabetogenic BDC2.5 T cells failed to elicit clinical disease in ICAM-1-deficient IL-10-NOD and NOD mice. These findings provide evidence that pancreatic IL-10 is sufficient to drive pathogenic autoimmune responses and accelerates diabetes via an ICAM-1-dependent pathway.
Fas and Fas Ligand Mutations Inhibit Autoantibody Production in Pristane-Induced Lupus
Authors: Satoh Minoru , Weintraub Jory P. , Yoshida Hideo , Shaheen Victoria M. , Richards Hanno B. , Shaw Melody , Reeves Westley H. 
Published: April 2014

AbstractMutations of Fas (lpr) or Fas ligand (gld) cause a limited lupus-like syndrome in B6 mice by interfering with the deletion of autoreactive B and/or T cells. A more generalized lupus syndrome reminiscent of that of MRL mice can be induced in nonautoimmune strains by pristane, which causes a nonspecific inflammatory response in the peritoneal cavity. We hypothesized that, as in MRL mice, the lpr and gld mutations might accelerate lupus in pristane-treated mice. Pristane-treated B6 mice developed anti-nRNP/Sm, Su, and ribosomal P Abs, but little anti-ssDNA or chromatin. In contrast, B6/lpr and B6/gld mice spontaneously developed anti-ssDNA/chromatin Abs, but not anti-nRNP/Sm/Su/ribosomal P. Unexpectedly, B6/lpr and B6/gld mice were highly resistant to the induction by pristane of IgM anti-ssDNA (2 wk) and IgG anti-nRNP/Sm/Su/ribosomal P autoantibodies (6 mo), suggesting that intact Fas signaling is necessary. Interestingly, pristane did not enhance IgG chromatin Ab production in B6/lpr or B6/gld mice, suggesting that it did not influence the production of autoantibodies that develop spontaneously in the setting of Fas deficiency. Pristane treatment also decreased lymphoproliferation in B6/lpr mice. Increased production of IL-12 was associated consistently with the production of anti-nRNP/Sm/Su/ribosomal P as well as anti-DNA/chromatin. In contrast, production of anti-DNA/chromatin Abs was associated with IL-6 overproduction in pristane-treated mice, but not in lpr mice. The data strongly support the idea that different subsets of autoantibodies are regulated differentially by cytokine stimulation and/or Fas signaling.
Latent Murine γ-Herpesvirus Infection Is Established in Activated B Cells, Dendritic Cells, and Macrophages
Authors: Flaño Emilio , Husain S. Mazher , Sample Jeffery T. , Woodland David L. , Blackman Marcia A. 
Published: April 2014

AbstractIntranasal infection of mice with the murine γ-herpesvirus MHV-68 results in an acute lytic infection in the lung, followed by the establishment of lifelong latency. Development of an infectious mononucleosis-like syndrome correlates with the establishment of latency and is characterized by splenomegaly and the appearance of activated CD8+ T cells in the peripheral blood. Interestingly, a large population of activated CD8+ T cells in the peripheral blood expresses the Vβ4+ element in their TCR. In this report we show that MHV-68 latency in the spleen after intranasal infection is harbored in three APC types: B cells, macrophages, and dendritic cells. Surprisingly, since latency has not previously been described in dendritic cells, these cells harbored the highest frequency of latent virus. Among B cells, latency was preferentially associated with activated B cells expressing the phenotype of germinal center B cells, thus formally linking the previously reported association of latency gene expression and germinal centers to germinal center B cells. Germinal center formation, however, was not required for the establishment of latency. Significantly, although three cell types were latently infected, the ability to stimulate Vβ4+CD8+ T cell hybridomas was limited to latently infected, activated B cells.
CD40-CD40 Ligand-Independent Activation of CD8+ T Cells Can Trigger Allograft Rejection
Authors: Jones Nick D. , Van Maurik Andre , Hara Masaki , Spriewald Bernd M. , Witzke Oliver , Morris Peter J. , Wood Kathryn J. 
Published: April 2014

AbstractIn experimental transplantation, blockade of CD40-CD40 ligand (CD40L) interactions has proved effective at permitting long-term graft survival and has recently been approved for clinical evaluation. We show that CD4+ T cell-mediated rejection is prevented by anti-CD40L mAb therapy but that CD8+ T cells remain fully functional. Furthermore, blocking CD40L interactions has no effect on CD8+ T cell activation, proliferation, differentiation, homing to the target allograft, or cytokine production. We conclude that CD40L is not an important costimulatory molecule for CD8+ T cell activation and that following transplantation donor APC can activate recipient CD8+ T cells directly without first being primed by CD4+ T cells.
Cutting Edge: DNA Immunization with Minigenes of Carbohydrate Mimotopes Induce Functional Anti-Carbohydrate Antibody Response
Authors: Kieber-Emmons Thomas , Monzavi-Karbassi Behjatolah , Wang Bin , Luo Ping , Weiner David B. 
Published: April 2014

Abstract
To date, the generation of anti-carbohydrate Th1 immune responses, which would be useful for both tumor immunotherapy as well as in pathogen vaccine strategies, has been elusive. To augment Th1 immune responses to carbohydrate Ags, we describe results of DNA vaccination studies in mice using plasmids encoding designed peptide mimotopes (minigenes) of the neolactoseries Ag Lewis Y (LeY). In contrast to LeY immunization, immunization with mimotope-encoded plasmids induced LeY cross-reactive IgG2a Abs. Minigene immunization primed for a LeY-specific response that is rapidly activated upon encounter with nominal Ag upon subsequent boost. The resulting IgG2a response mediated complement-dependent cytotoxicity of a LeY-expressing human tumor cell line in the presence of human complement. These studies establish that peptide mimotopes of carbohydrate Ags encoded as DNA plasmids are novel immunogens providing a means to manipulate carbohydrate cross-reactive Th1 responses.
Cutting Edge: Chandra, a Novel Four-Transmembrane Domain Protein Differentially Expressed in Helper Type 1 Lymphocytes
Authors: Venkataraman Chandrasekar , Schaefer Gabriele , Schindler Ulrike 
Published: April 2014

Abstract
Development of naive Th cells into Th1 and Th2 effector populations requires coordinated expression of a complex set of genes. In this study, we have identified a novel four-transmembrane domain protein, Chandra, that is differentially expressed in Th1 cells. Chandra expression is observed in STAT4- and IFN-γ-deficient mice, indicating that Chandra is not an IL-12- or IFN-γ-responsive gene. Interestingly, Chandra mRNA is detected in anti-CD3-activated T cells from STAT6-deficient mice in the absence of any differentiation conditions. Furthermore, neutralization of IL-4 signaling is sufficient to induce transcription of Chandra in anti-CD3-activated T cells from wild-type mice, demonstrating that STAT6 signaling is required to repress Chandra expression in activated T cells and Th2 subsets. This is the first demonstration of a differentially expressed four-transmembrane domain protein in Th1 cells.