bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Broad-Spectrum Caspase Inhibitor Attenuates Allergic Airway Inflammation in Murine Asthma Model
Authors: Iwata Akiko , Nishio Kazumi , Winn Robert K. , Chi Emil Y. , Henderson William R. , Harlan John M. 
Published: April 2014

Abstract
Asthma is characterized by acute and chronic airway inflammation, and the severity of the airway hyperreactivity correlates with the degree of inflammation. Many of the features of lung inflammation observed in human asthma are reproduced in OVA-sensitized/challenged mice. T lymphocytes, particularly Th2 cells, are critically involved in the genesis of the allergic response to inhaled Ag. In addition to antiapoptotic effects, broad-spectrum caspase inhibitors inhibit T cell activation in vitro. We investigated the effect of the broad-spectrum caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), on airway inflammation in OVA-sensitized/challenged mice. OVA-sensitized mice treated with z-VAD-fmk immediately before allergen challenge showed marked reduction in inflammatory cell infiltration in the airways and pulmonary blood vessels, mucus production, and Th2 cytokine production. We hypothesized that the caspase inhibitor prevented T cell activation, resulting in the reduction of cytokine production and eosinophil infiltration. Treatment with z-VAD-fmk in vivo prevented subsequent T cell activation ex vivo. We propose that caspase inhibitors may offer a novel therapeutic approach to T cell-dependent inflammatory airway diseases.
Adenovirus E1A, Not Human Papillomavirus E7, Sensitizes Tumor Cells to Lysis by Macrophages Through Nitric Oxide- and TNF-α-Dependent Mechanisms Despite Up-Regulation of 70-kDa Heat Shock Protein
Authors: Miura Tanya A. , Morris Kristin , Ryan Sharon , Cook James L. , Routes John M. 
Published: April 2014

AbstractExpression of adenovirus (Ad) serotype 2 or 5 (Ad2/5) E1A or human papillomavirus (HPV)16 E7 reportedly sensitizes cells to lysis by macrophages. Macrophages possess several mechanisms to kill tumor cells including TNF-α, NO, reactive oxygen intermediates (ROI), and Fas ligand (FasL). E1A sensitizes cells to apoptosis by TNF-α, and macrophages kill E1A-expressing cells, in part through the elaboration of TNF-α. However, E1A also up-regulates the expression of 70-kDa heat shock protein, a protein that inhibits killing by TNF-α and NO, thereby protecting cells from lysis by macrophages. Unlike E1A, E7 does not sensitize cells to killing by TNF-α, and the effector mechanism(s) used by macrophages to kill E7-expressing cells remain undefined. The purpose of this study was to further define the capacity of and the effector mechanisms used by macrophages to kill tumor cells that express Ad5 E1A or HPV16 E7. We found that Ad5 E1A, but not HPV16 E7, sensitized tumor cells to lysis by macrophages. Using macrophages derived from mice unable to make TNF-α, NO, ROI, or FasL, we determined that macrophages used NO, and to a lesser extent TNF-α, but not FasL or ROI, to kill E1A-expressing cells. Through the use of S-nitroso-N-acetylpenicillamine, which releases NO upon exposure to an aqueous environment, E1A was shown to directly sensitize tumor cells to NO-induced death. E1A sensitized tumor cells to lysis by macrophages despite up-regulating the expression of 70-kDa heat shock protein. In summary, E1A, but not E7, sensitized tumor cells to lysis by macrophages. Macrophages killed E1A-expressing cells through NO- and TNF-α-dependent mechanisms.
Definition of Structural Prerequisites for Lipoteichoic Acid-Inducible Cytokine Induction by Synthetic Derivatives
Authors: Deininger Susanne , Stadelmaier Andreas , von Aulock Sonja , Morath Siegfried , Schmidt Richard R. , Hartung Thomas 
Published: April 2014

Abstract
The controversy about the immune stimulatory properties of lipoteichoic acid (LTA) from Staphylococcus aureus was solved recently by showing decomposition and inactivation of LTA obtained by conventional purification strategies, as well as pronounced LPS contamination of commercial preparations. By introducing a novel preparation method, the structure of bioactive LTA was elucidated. This structure was confirmed by chemical synthesis. In this work, synthetic LTA derivatives were employed to study the structure-function relationship of cytokine induction in human monocytes. Synthetic LTA induced the same cytokine pattern as highly purified natural LTA. The gentiobiose core could be omitted without affecting bioactivity. The polyglycerophosphate backbone amplified the response to the lipid anchor (∼100-fold) only when substituted with d-alanine, whereas α-d-N-acetylglucosamine substituents could be omitted. Replacing d-alanine substituents with l-alanine reduced the activity of the molecule at least 10-fold, indicating stereoselectivity. These results define for the first time the crucial patterns required for the immune recognition of LTA.
Staphylococcal Enterotoxin H Induces Vα-Specific Expansion of T Cells
Authors: Petersson Karin , Pettersson Helen , Skartved Niels Jörgen , Walse Björn , Forsberg Göran 
Published: April 2014

AbstractStaphylococcal enterotoxin H (SEH) is a bacterial superantigen secreted by Staphylococcus aureus. Superantigens are presented on the MHC class II and activate large amounts of T cells by cross-linking APC and T cells. In this study, RT-PCR was used to show that SEH stimulates human T cells via the Vα domain of TCR, in particular Vα10 (TRAV27), while no TCR Vβ-specific expansion was seen. This is in sharp contrast to all other studied bacterial superantigens, which are highly specific for TCR Vβ. It was further confirmed by flow cytometry that SEH stimulation does not alter the levels of certain TCR Vβ. In a functional assay addressing cross-reactivity, Vβ binding superantigens were found to form one group, whereas SEH has different properties that fit well with Vα reactivity. As SEH binds on top of MHC class II, an interaction between MHC and TCR upon SEH binding is not likely. This concludes that the specific expansion of TCR Vα is not due to contacts between MHC and TCR, instead we suggest that SEH directly interacts with the TCR Vα domain.
Intracellular Retention of the MHC Class I-Related Chain B Ligand of NKG2D by the Human Cytomegalovirus UL16 Glycoprotein
Authors: Wu Jennifer , Chalupny N. Jan , Manley Thomas J. , Riddell Stanley R. , Cosman David , Spies Thomas 
Published: April 2014

Abstract
Infection by human CMV induces expression of the cellular MHC class I-related chain A (MICA) and chain B (MICB) surface proteins, which function as ligands for the activating NKG2D receptor. Engagement of NKG2D triggers NK cells and costimulates Ag-specific effector CD8 αβ T cells. The potency of MHC class I-related chain-NKG2D in stimulating these anti-viral immune responses may be countered by a CMV-encoded transmembrane glycoprotein, UL16, which specifically binds MICB as well as two of the UL16-binding proteins that are ligands of NKG2D. However, the function and significance of these interactions are undefined. Using a stably transfected B cell line, we show that expression of UL16 results in loss of surface MICB. This effect is caused by the failure of newly synthesized MICB to mature and transit the secretory pathway due to physical association with UL16. The intracellular retention of these protein complexes is mediated by a tyrosine-based motif in the cytoplasmic tail sequence of UL16, which determines localization to or retrieval from the trans-Golgi network. Deletion of this motif restores surface expression of MICB, whereas UL16 may be redirected to endosomal compartments. Predictably, the retention of MICB abrogates the stimulatory function of NKG2D. These results suggest a potential mechanism of viral immune evasion. However, this activity remains to be confirmed with CMV-infected fibroblasts or endothelial cells, in particular because MICB is normally coexpressed with MICA, which is not retained by UL16.
Cutting Edge: Transplantation Tolerance through Enhanced CTLA-4 Expression
Authors: Ariyan Charlotte , Salvalaggio Paolo , Fecteau Scott , Deng Songyan , Rogozinski Linda , Mandelbrot Didier , Sharpe Arlene , Sayegh Mohamed H. , Basadonna Giacomo P. , Rothstein David M. 
Published: April 2014

AbstractKnockout and blocking studies have shown a critical role for CTLA-4 in peripheral tolerance, however, it is unknown whether augmenting CTLA-4 expression actually promotes tolerance. Here we demonstrate a specific and requisite role for CTLA-4 and its up-regulation in tolerance through anti-CD45RB. First, long-term murine islet allograft survival induced by anti-CD45RB is prevented by CTLA4-Ig, which interferes with B7:CTLA-4 interactions. Second, anti-CD45RB is ineffective in recipients lacking CTLA-4, B7-1, and B7-2. In contrast, CTLA4-Ig, which targets B7 on allogeneic cells, promotes long-term engraftment in these mice. Moreover, anti-CD45RB was effective in B7-deficient controls expressing CTLA-4. Finally, in wild-type mice, CTLA-4 expression returned to baseline 17 days after receiving anti-CD45RB, and was refractory to further increase. Transplantation and anti-CD45RB therapy at this time could neither augment CTLA-4 nor prolong engraftment. These data demonstrate a specific role for CTLA-4 in anti-CD45RB-mediated tolerance and indicate that CTLA-4 up-regulation can directly promote allograft survival.
CD40, but Not CD154, Expression on B Cells Is Necessary for Optimal Primary B Cell Responses
Authors: Lee Byung O. , Moyron-Quiroz Juan , Rangel-Moreno Javier , Kusser Kim L. , Hartson Louise , Sprague Frank , Lund Frances E. , Randall Troy D. 
Published: April 2014

AbstractCD40 is an important costimulatory molecule for B cells as well as dendritic cells, monocytes, and other APCs. The ligand for CD40, CD154, is expressed on activated T cells, NK cells, mast cells, basophils, and even activated B cells. Although both CD40−/− and CD154−/− mice have impaired ability to isotype switch, form germinal centers, make memory B cells, and produce Ab, it is not entirely clear whether these defects are intrinsic to B cells, to other APCs, or to T cells. Using bone marrow chimeric mice, we investigated whether CD40 or CD154 must be expressed on B cells for optimal B cell responses in vivo. We demonstrate that CD40 expression on B cells is required for the generation of germinal centers, isotype switching, and sustained Ab production, even when other APCs express CD40. In contrast, the expression of CD154 on B cells is not required for the generation of germinal centers, isotype switching, or sustained Ab production. In fact, B cell responses are completely normal when CD154 expression is limited exclusively to Ag-specific T cells. These results suggest that the interaction of CD154 expressed by activated CD4 T cells with CD40 expressed by B cells is the primary pathway necessary to achieve B cell activation and differentiation and that CD154 expression on B cells does not noticeably facilitate B cell activation and differentiation.
Peroxisome Proliferator-Activated Receptor-γ-Deficient Heterozygous Mice Develop an Exacerbated Neural Antigen-Induced Th1 Response and Experimental Allergic Encephalomyelitis
Authors: Bright John J. , Natarajan Chandramohan , Muthian Gladson , Barak Yaavov , Evans Ronald M. 
Published: April 2014

Abstract
Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear receptor transcription factor that regulates cell growth, differentiation, and homeostasis. PPARγ agonists are potent therapeutic agents for type 2 diabetes, obesity, and inflammation. Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated inflammatory demyelinating autoimmune disease model of multiple sclerosis. We have shown recently that PPARγ agonists inhibit EAE by blocking IL-12 production, IL-12 signaling, and neural Ag-induced Th1 differentiation. In this study, we show that the PPARγ-deficient heterozygous mice develop an exacerbated EAE with prolonged clinical symptoms than the wild-type littermates, following immunization with myelin oligodendrocyte glycoprotein (MOG) p35–55 peptide. The exacerbation of EAE in PPARγ+/− mice associates with an increased expansion of CD4+ and CD8+ T cells and expression of CD40 and MHC class II molecules in response to MOGp35–55 Ag. The PPARγ+/− mice also showed an increase in T cell proliferation and Th1 response to MOGp35–55 Ag than the wild-type littermates. These findings suggest that PPARγ be a critical physiological regulator of CNS inflammation and demyelination in EAE and perhaps multiple sclerosis and other Th1 cell-mediated autoimmune diseases.
TNF Receptor-Associated Factor 6 Deficiency during Hemopoiesis Induces Th2-Polarized Inflammatory Disease
Authors: Chiffoleau Elise , Kobayashi Takashi , Walsh Matthew C. , King Carolyn G. , Walsh Patrick T. , Hancock Wayne W. , Choi Yongwon , Turka Laurence A. 
Published: April 2014

Abstract
Toll-like receptors (TLR) initiate rapid innate immune responses by recognizing microbial products. These events in turn lead to the development of an efficient adaptive immune response through the up-regulation of a number of costimulatory molecules, including members of the TNF/TNFR superfamily, on the surface of an APC. TNFR-associated factor 6 (TRAF6) is a common signaling adapter used by members of both the TNFR and the TLR/IL-1R superfamilies, and as such plays a critical role in the development of immune responses. As TRAF6-deficient mice die prematurely, we generated chimeras reconstituted with TRAF6-deficient fetal liver cells to analyze functions of TRAF6 in vivo in the hemopoietic compartment. We found that TRAF6-deficient chimeras develop a progressive lethal inflammatory disease associated with massive organ infiltration and activation of CD4+ T cells in a Th2-polarized phenotype, and a defect in IL-18 responsiveness. When recombination-activating gene 2−/− blastocysts were complemented with TRAF6-deficient embryonic stem cells, a marked elevation of activated CD4+ T cells and progressive inflammatory disease were also observed. Moreover, T cell activation and lethal inflammation were not reversed in mixed chimeric mice generated from normal and TRAF6-deficient fetal liver cells. These results suggest that deletion of TRAF6 induces a dominant Th2-type polarized autoimmune response. Therefore, in addition to playing a critical role in innate and adaptive immunity, TRAF6 is likely to play a previously unrecognized role in the maintenance of self-tolerance.
Human CD25+ Regulatory T Cells Maintain Immune Tolerance to Nickel in Healthy, Nonallergic Individuals
Authors: Cavani Andrea , Nasorri Francesca , Ottaviani Chiara , Sebastiani Silvia , De Pità Ornella , Girolomoni Giampiero 
Published: April 2014

Abstract
We investigated the capacity of CD25+ T regulatory cells (Treg) to modulate T cell responses to nickel, a common cause of allergic contact dermatitis. CD4+ T cells isolated from the peripheral blood of six healthy, nonallergic individuals showed a limited capacity to proliferate in response to nickel in vitro, but responsiveness was strongly augmented (mean increment ± SD, 240 ± 60%) when cells were depleted of CD25+ Treg. Although CD25+ Treg were anergic to nickel, a small percentage up-regulated membrane CTLA-4 upon nickel exposure. CD25+ Treg strongly and dose-dependently inhibited nickel-specific activation of CD25− T lymphocytes in coculture experiments in a cytokine-independent, but cell-to-cell contact-dependent, manner. Approximately 30% of circulating CD25+ Treg expressed the cutaneous lymphocyte-associated Ag (CLA), and CLA+CD25+ Treg were more efficient than CLA−CD25+ cells in suppressing nickel responsiveness of CD25− T cells. The site of a negative patch test in response to nickel showed an infiltrate of CD4+CLA+ cells and CD25+ cells, which accounted for ∼20% of the total T cells isolated from the tissue. Skin-derived T cells suppressed nickel-specific responses of peripheral blood CD25− T cells. In addition, 60 ± 14% of peripheral blood CD25+ Treg expressed the chemokine receptor CCR7 and strongly inhibited naive T cell activation in response to nickel. Finally, CD25+ T cells isolated from peripheral blood of nickel-allergic patients showed a limited or absent capacity to suppress metal-specific CD4+ and CD8+ T cell responses. The results indicates that in healthy individuals CD25+ Treg can control the activation of both naive and effector nickel-specific T cells.
Ultraviolet B Radiation-Induced Cell Death: Critical Role of Ultraviolet Dose in Inflammation and Lupus Autoantigen Redistribution
Authors: Caricchio Roberto , McPhie Lenese , Cohen Philip L. 
Published: April 2014

AbstractThe nuclear self-Ags targeted in systemic lupus erythematosus translocate to the cell membrane of UV-irradiated apoptotic keratinocytes and may represent an important source of self-immunization. It is hard to understand how the noninflammatory milieu accompanying most apoptosis might provoke an immunogenic response leading to autoantibodies. We have found that the precise amount of keratinocyte UV exposure is crucial in determining the rate of apoptosis, the amount of inflammatory cytokine production, and the degree of autoantigen translocation. Low doses of UVB (≤15 mJ/cm2) promptly induced a normal, caspase-dependent apoptosis, while intermediate doses of UV-B (35 mJ/cm2) caused apoptosis with altered morphology, slower DNA fragmentation, and poly(ADP-ribose) polymerase degradation accompanied by increased Bcl-2. High doses of UVB (80 mJ/cm2) induced instead necrosis. We observed IL-1 production upon intermediate and high UVB doses. Nuclear Ag redistribution was also markedly UV dose dependent: at low doses, Sm, Ku, and DNA translocated to the surfaces of early apoptotic cells. At intermediate doses, these Ags concentrated on the cell membrane when the nucleus was still visible. At high doses, these autoantigens diffused into the cytoplasm and were released into the supernatant. Taken together, the results show that low-dose UVB induces prompt noninflammatory apoptosis. In contrast, intermediate and high doses of UVB induce proinflammatory apoptosis and necrosis, where the production of inflammatory cytokines is accompanied by exposure and release of autoantigens. The key importance of the UV dose on the fate of apoptotic keratinocytes and on their potential immunogenicity should help clarify the role of UVB in inducing systemic lupus erythematosus autoimmunity.
Increased Severity of Murine Lupus in Female Mice Is Due to Enhanced Expansion of Pathogenic T Cells
Authors: Lang Thomas J. , Nguyen Phuong , Papadimitriou John C. , Via Charles S. 
Published: April 2014

Abstract
A strong female predominance is a well-recognized feature of human lupus. The mechanism by which sex influences disease expression and severity is not fully understood. To address this question, we used the parent-into-F1 (p→F1) model of chronic graft-vs-host disease (cGVHD) in which lupus-like humoral autoimmunity and renal disease are induced in normal F1 mice. An advantage of this model is that the pathogenic T cells driving disease (donor strain) can be studied separately from nonspecifically activated T cells (host strain). We observed that lupus-like disease using female donor and host mice (f→F cGVHD) is characterized by more severe long-term disease (glomerulonephritis) than with male donor and host (m→M cGVHD). Interestingly, differences in disease parameters could be seen at 2 wk after parental cell transfer, as evidenced by a 2- to 3-fold greater engraftment of donor CD4+ T cells in f→F cGVHD mice, which persisted throughout disease course. Enhanced engraftment of donor CD4+ T cells in f→F cGVHD mice was not due to differences in splenic homing, alloreactive precursor frequency, initial proliferation rates, or apoptotic rates, but rather to sustained high proliferation rates during wk 2 of disease compared with m→M cGVHD mice. Crossover studies (m→F, f→M) demonstrated that enhanced donor CD4+ T cell proliferation and engraftment segregate with the sex of the host. These results demonstrate that the sex of the recipient can influence the expansion of pathogenic T cells, thus increasing long-term the burden of autoreactive T cells and resulting in greater disease severity.
MHC Class II-Peptide Complexes in Dendritic Cell Lipid Microdomains Initiate the CD4 Th1 Phenotype
Authors: Buatois Vanessa , Baillet Marjorie , Bécart Stéphane , Mooney Nuala , Leserman Lee , Machy Patrick 
Published: April 2014

AbstractWe investigated differentiation of CD4 T cells responding to Ag presented by bone marrow-derived dendritic cells (DC) in association with MHC class II (MHC II) molecules. Peptides encapsulated in liposomes opsonized by IgG were taken up by endocytosis. MHC II-peptide-specific T cells responding to this Ag were polarized to a Th1 cytokine profile in a CD40-, CD28-, MyD88-, and IL-12-dependent manner. Th2 responses were obtained from the same transgenic T cell population exposed to the same DC on which MHC-peptide complexes had dispersed for 48 h following uptake of FcR-targeted liposomes. DC that took up the same FcR-targeted liposomes and then were exposed to methyl-β-cyclodextrin, which chelates cholesterol and dissociates lipid microdomains, also stimulated Th2 differentiation. Incubation of T cells with DC incubated with peptides directly binding to MHC II resulted in Th2 responses, whether or not the DC were coincubated with opsonized liposomes as a maturation stimulus. CD4 Th1 polarization thus appears to depend on MHC II-peptide complex clustering in DC lipid microdomains and the time between peptide loading and T cell encounter.
The Duration of Signaling through CD40 Directs Biological Ability of Dendritic Cells to Induce Antitumor Immunity
Authors: Watanabe Satoshi , Kagamu Hiroshi , Yoshizawa Hirohisa , Fujita Nanae , Tanaka Hiroshi , Tanaka Junta , Gejyo Fumitake 
Published: April 2014

AbstractAlthough it has been demonstrated that the functions of dendritic cells (DCs), including Ag capture, Ag presentation, and migratory activity, change dynamically with their maturation, the most appropriate conditioning of DCs for anticancer immunotherapy is still unclear. The help signal is one of the most potent stimuli for DC maturation and is provided by the interaction of CD40 expressed on DCs with CD40 ligand on CD4+ T cells. To elucidate the appropriate conditioning of DCs for anticancer immunotherapy, we examined the biological activity of DCs stimulated with immobilized anti-CD40 Ab. DCs stimulated for 3 h (3h-DCs) still showed an immature phenotype, but exhibited augmented migration toward secondary lymphoid tissues. Subcutaneous injection of 3h-DCs facilitated priming of T cells, which could mediate potent antitumor therapeutic efficacy, in draining lymph nodes and successfully induced protective immunity. In contrast, 24h-DCs showed a mature phenotype with good Ag presentation ability to induce cell killing by adoptively transferred CD8+ T cells when injected at tumor sites; however, they showed no migratory activity and were unable to induce protective immunity when injected s.c.. This is the first report that functionally distinct DCs, either for the priming phase or for the effector phase, could be obtained by conditioning with CD40 stimulation and that the duration of stimulation determines the biological outcome. The usage of DCs conditioned for the priming phase might provide significant advantages in anticancer immunotherapy.