bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteasome Inhibition to Maximize the Apoptotic Potential of Cytokine Therapy for Murine Neuroblastoma Tumors
Authors: Khan Tahira , Stauffer Jimmy K. , Williams Rebecca , Hixon Julie A. , Salcedo Rosalba , Lincoln Erin , Back Timothy C. , Powell Douglas , Lockett Stephen , Arnold Alma C. , Sayers Thomas J. , Wigginton Jon M. 
Published: April 2014

Abstract
Human neuroblastomas possess several mechanisms of self-defense that may confer an ability to resist apoptosis and contribute to the observed difficulty in treating these tumors in the clinical setting. These molecular alterations may include defects in proapoptotic genes as well as the overexpression of prosurvival factors, such as Akt among others. As a key regulator of the turnover of proteins that modulate the cell cycle and mechanisms of apoptosis, the proteasome could serve as an important target for the treatment of neuroblastoma. The present studies provide the first evidence that bortezomib, a newly approved inhibitor of proteasome function, inhibits phosphorylation of Akt, induces the translocation of proapoptotic Bid, and potently enhances the apoptosis of murine neuroblastoma tumor cells in vitro. Furthermore, in that inhibitors of the Akt pathway can sensitize otherwise resistant TBJ/Neuro-2a cells to apoptosis induced by IFN-γ plus TNF-α, we hypothesized that bortezomib also could sensitize these cells to IFN-γ plus TNF-α. We demonstrate for the first time that bortezomib not only up-regulates the expression of receptors for IFN-γ and TNF-α on both TBJ neuroblastoma and EOMA endothelial cell lines, but also markedly enhances the sensitivity of these cells to apoptosis induced by IFN-γ plus TNF-α in vitro. Furthermore, bortezomib enhances the in vivo antitumor efficacy of IFN-γ/TNF-α-inducing cytokines, including both IL-2 and IL-12 in mice bearing well-established primary and/or metastatic TBJ neuroblastoma tumors. Collectively, these studies suggest that bortezomib could be used therapeutically to enhance the proapoptotic and overall antitumor activity of systemic cytokine therapy in children with advanced neuroblastoma.
Galectin-1 Suppresses Autoimmune Retinal Disease by Promoting Concomitant Th2- and T Regulatory-Mediated Anti-Inflammatory Responses
Authors: Toscano Marta A. , Commodaro Alessandra G. , Ilarregui Juan M. , Bianco Germán A. , Liberman Ana , Serra Horacio M. , Hirabayashi Jun , Rizzo Luiz V. , Rabinovich Gabriel A. 
Published: April 2014

Abstract
Intraocular inflammatory diseases are a common cause of severe visual impairment and blindness. In this study, we investigated the immunoregulatory role of galectin-1 (Gal-1), an endogenous lectin found at sites of T cell activation and immune privilege, in experimental autoimmune uveitis (EAU), a Th1-mediated model of retinal disease. Treatment with rGal-1 either early or late during the course of interphotoreceptor retinoid-binding protein-induced EAU was sufficient to suppress ocular pathology, inhibit leukocyte infiltration, and counteract pathogenic Th1 cells. Administration of rGal-1 at the early or late phases of EAU ameliorated disease by skewing the uveitogenic response toward nonpathogenic Th2 or T regulatory-mediated anti-inflammatory responses. Consistently, adoptive transfer of CD4+ regulatory T cells obtained from rGal-1-treated mice prevented the development of active EAU in syngeneic recipients. In addition, increased levels of apoptosis were detected in lymph nodes from mice treated with rGal-1 during the efferent phase of the disease. Our results underscore the ability of Gal-1 to counteract Th1-mediated responses through different, but potentially overlapping anti-inflammatory mechanisms and suggest a possible therapeutic use of this protein for the treatment of human uveitic diseases of autoimmune etiology.
IL-21 Enhances Tumor-Specific CTL Induction by Anti-DR5 Antibody Therapy
Authors: Smyth Mark J. , Hayakawa Yoshihiro , Cretney Erika , Zerafa Nadeen , Sivakumar Pallavur , Yagita Hideo , Takeda Kazuyoshi 
Published: April 2014

Abstract
Tumor cell apoptosis is the basis of many cancer therapies, and tumor-specific T cells are the principal effectors of successful anti-tumor immunotherapies. In this study, we show that induction of tumor cell apoptosis by agonistic mAb against DR5, combined with delayed IL-21 treatment, suppressed tumor growth and pre-established tumor metastases. Synergistic effects of the combination were observed in several tumor models where the target tumor was sensitive to DR5-mediated apoptosis. IL-21 promoted tumor-specific CTL activity and enhanced memory responses to tumor rechallenge. These results indicate that a rational combination of Ab-based therapy that causes tumor cell apoptosis and a cytokine that promotes T cell memory is a useful new strategy for cancer immunotherapy.
Cutting Edge: Enhancement of Antibody Responses Through Direct Stimulation of B and T Cells by Type I IFN
Authors: Le Bon Agnes , Thompson Clare , Kamphuis Elisabeth , Durand Vanessa , Rossmann Cornelia , Kalinke Ulrich , Tough David F. 
Published: April 2014

Abstract
Type I IFN (IFN-αβ) is induced rapidly by infection and plays a key role in innate antiviral defense. IFN-αβ also exerts stimulatory effects on the adaptive immune system and has been shown to enhance Ab and T cell responses. We have investigated the importance of B and T cells as direct targets of IFN-αβ during IFN-α-mediated augmentation of the Ab response against a soluble protein Ag. Strikingly, the ability of IFN-α to stimulate the Ab response and induce isotype switching was markedly reduced in mice in which B cells were selectively deficient for the IFN-αβR. Moreover, IFN-α-mediated enhancement of the Ab response was also greatly impaired in mice in which T cells were selectively IFN-αβR-deficient. These results indicate that IFN-αβR signaling in both B and T cells plays an important role in the stimulation of Ab responses by IFN-αβ.
A Major Lung CD103 (αE)-β7 Integrin-Positive Epithelial Dendritic Cell Population Expressing Langerin and Tight Junction Proteins
Authors: Sung Sun-Sang J. , Fu Shu Man , Rose C. Edward , Gaskin Felicia , Ju Shyr-Te , Beaty Steven R. 
Published: April 2014

AbstractDendritic cells (DC) mediate airway Ag presentation and play key roles in asthma and infections. Although DC subsets are known to perform different functions, their occurrence in mouse lungs has not been clearly defined. In this study, three major lung DC populations have been found. Two of them are the myeloid and plasmacytoid DC (PDC) well-characterized in other lymphoid organs. The third and largest DC population is the integrin αE (CD103) β7-positive and I-AhighCD11chigh-DC population. This population was found to reside in the lung mucosa and the vascular wall, express a wide variety of adhesion and costimulation molecules, endocytose avidly, present Ag efficiently, and produce IL-12. Integrin αEβ7+ DC (αE-DC) were distinct from intraepithelial lymphocytes and distinguishable from CD11bhigh myeloid and mPDCA-1+B220+Gr-1+ PDC populations in surface marker phenotype, cellular functions, and tissue localization. Importantly, this epithelial DC population expressed high levels of the Langerhans cell marker Langerin and the tight junction proteins Claudin-1, Claudin-7, and ZO-2. In mice with induced airway hyperresponsiveness and eosinophilia, αE-DC numbers were increased in lungs, and their costimulation and adhesion molecules were up-regulated. These studies show that αE-DC is a major and distinct lung DC population and a prime candidate APC with the requisite surface proteins for migrating across the airway epithelia for Ag and pathogen capture, transport, and presentation. They exhibit an activated phenotype in allergen-induced lung inflammation and may play significant roles in asthma pathogenesis.
Distinct Mechanisms Control Human Naive and Antigen-Experienced CD8+ T Lymphocyte Proliferation
Authors: Migliaccio Marco , Alves Pedro Miguel Sousa , Romero Pedro , Rufer Nathalie 
Published: April 2014

Abstract
Human Ag-specific CD8+ T lymphocytes are heterogeneous and include functionally distinct populations. In this study, we report that at least two distinct mechanisms control the expansion of circulating naive, memory, and effector CD8+ T lymphocytes when exposed to mitogen or Ag stimulation. The first one leads to apoptosis and occurs shortly after in vitro stimulation. Susceptibility to cell death is prominent among primed T cell subsets, and it is inversely correlated with the size of the ex vivo Bcl-2high population within these subsets. Importantly, the Bcl-2high phenotype is associated to the proportion of responsive CD8+ T cells, independently of their differentiation stage. The second one depends on the expression of newly synthesized cyclin-dependent kinase inhibitor p16INK4a that occurs in a significant fraction of T cells that had been actively cycling, leading to their cell cycle arrest upon stimulation. Strikingly, accumulation of p16INK4a protein preferentially occurs in naive as opposed to primed derived T lymphocytes and is not related to apoptosis. Significant levels of p16 are readily detectable in a small number of ex vivo CD8+ T cells. Our observations reveal that activation-induced p16 expression represents an alternative process to apoptosis, limiting the proliferation potential of activated naive derived T lymphocytes.
CD8 T Cells Specific for a Donor-Derived, Self-Restricted Transplant Antigen Are Nonpathogenic Bystanders after Vascularized Heart Transplantation in Mice
Authors: Valujskikh Anna , Zhang Qiwei , Heeger Peter S. 
Published: April 2014

Abstract
CD8 T cell cross-priming, an established mechanism of protective antiviral immunity, was originally discovered during studies involving minor transplantation Ags. It is unclear whether or how cross-primed CD8 T cells, reactive to donor-derived, but recipient class I MHC-restricted epitopes, could injure a fully MHC-disparate, vascularized transplant. To address this question we studied host class I MHC-restricted, male transplantation Ag-reactive T cell responses in female recipients of fully MHC-disparate, male heart transplants. Cross-priming to the immune-dominant determinant HYUtyp occurred at low frequency after heart transplantation. CD8 T cell preactivation through immunization with HYUtyp mixed in CFA did not alter the kinetics of acute rejection. Furthermore, neither HYUtyp immunization nor adoptive transfer of HYUtyp-specific TCR-transgenic T cells affected outcome in 1) a model of chronic rejection in the absence of immunosuppression or 2) a model of allograft acceptance induced by costimulatory blockade. The results support the contention that CD8 T cells reactive to host-restricted, but donor-derived, Ags are highly specific and are nonpathogenic bystanders during rejection of MHC-disparate cardiac allografts.
Re-evaluating the Generation of a “Proteasome-Independent” MHC Class I-Restricted CD8 T Cell Epitope
Authors: Wherry E. John , Golovina Tatiana N. , Morrison Susan E. , Sinnathamby Gomathinayagam , McElhaugh Michael J. , Shockey David C. , Eisenlohr Laurence C. 
Published: April 2014

AbstractThe proteasome is primarily responsible for the generation of MHC class I-restricted CTL epitopes. However, some epitopes, such as NP147–155 of the influenza nucleoprotein (NP), are presented efficiently in the presence of proteasome inhibitors. The pathways used to generate such apparently “proteasome-independent” epitopes remain poorly defined. We have examined the generation of NP147–155 and a second proteasome-dependent NP epitope, NP50–57, using cells adapted to growth in the presence of proteasome inhibitors and also through protease overexpression. We observed that: 1) Ag processing and presentation proceeds in proteasome-inhibitor adapted cells but may become more dependent, at least in part, on nonproteasomal protease(s), 2) tripeptidyl peptidase II does not substitute for the proteasome in the generation of NP147–155, 3) overexpression of leucine aminopeptidase, thymet oligopeptidase, puromycin-sensitive aminopeptidase, and bleomycin hydrolase, has little impact on the processing and presentation of NP50–57 or NP147–155, and 4) proteasome-inhibitor treatment altered the specificity of substrate cleavage by the proteasome using cell-free digests favoring NP147–155 epitope preservation. Based on these results, we propose a central role for the proteasome in epitope generation even in the presence of proteasome inhibitors, although such inhibitors will likely alter cleavage patterns and may increase the dependence of the processing pathway on postproteasomal enzymes.
Temporal and Dose-Dependent Relationships between In Vivo B Cell Receptor-Targeted Proliferation and Deletion-Induced by a Microbial B Cell Toxin
Authors: Goodyear Carl S. , Sugiyama Fujimi , Silverman Gregg J. 
Published: April 2014

Abstract
The effective functioning of the adaptive immune system requires careful clonal regulation within the B cell compartment. Some microbial pathogens produce virulence factors, like staphylococcal protein A, which interact at high frequencies with B lymphocyte through unconventional binding sites in BCR variable region frameworks conserved during evolution. We have characterized the in vivo effect of staphylococcal protein A treatment on peripheral B cells bearing susceptible BCR, and found a dose-dependent direct relationship over the range of 2 mg to &lt;0.2 μg in the magnitude of induced BCR-targeted supraclonal cell death. Significantly, some level of targeted B cell proliferation was always detectable, with greatest interim supraclonal expansion demonstrated at 2 days after 20-μg treatment. Subsequently, this transient expansion always collapsed. In direct comparisons, i.p. treatment was more efficacious than i.v. treatment, although at higher doses this finding was less marked. These studies elucidate a general paradigm in which in vivo encounters with a B cell superantigen are uniformly associated with proliferative expansion followed by deletion that is more rapid and complete with higher doses, whereas lower doses lead to greater transient in vivo expansion with delayed deletion to levels at later times that are still quantitatively proportional to the dose. Our results document the potent in vivo B cell-targeted properties of a microbial B cell superantigen, even at submicrogram doses associated with great molar excess of circulating Ig, and clearly illustrate the intertwined relationships between targeted proliferative cycling and apoptotic death that is induced by a microbial B cell superantigen.
Antigen Exposure during Enhanced CTLA-4 Expression Promotes Allograft Tolerance In Vivo
Authors: Salvalaggio Paolo R. O. , Camirand Geoffrey , Ariyan Charlotte E. , Deng Songyan , Rogozinski Linda , Basadonna Giacomo P. , Rothstein David M. 
Published: April 2014

AbstractThe role of CTLA-4 in tolerance is primarily inferred from knockout and blocking studies. Anti-CD45RB mediates allograft tolerance in mice by inducing CTLA-4 expression on CD4 cells, providing a novel opportunity to determine how therapeutic enhancement of CTLA-4 promotes tolerance. We now show that induced CTLA-4 expression normally resolves by day 17. Although thymectomy prolongs enhanced CTLA-4 expression, long-term engraftment is unaffected. To address the temporal relationship between increased CTLA-4 expression and engraftment, transplantation was delayed for various times after anti-CD45RB treatment. Delaying transplantation for 7 days (when CTLA-4 expression had peaked but treatment mAb was no longer detectable), resulted in long-term engraftment comparable to transplantation with no delay (day 0). Delaying transplantation from 10 to 18 days led to a progressively poorer outcome as CTLA-4 expression returned to baseline. This suggested that Ag exposure while CTLA-4 expression is enhanced is sufficient to induce long-term engraftment. To substantiate this, on day 0, anti-CD45RB-treated mice received BALB/c vs unrelated alloantigen, followed by transplantation of BALB/c islets 10 days later. Whereas recipients exposed to unrelated Ag experienced acute rejection, recipients exposed to donor Ag achieved long-term engraftment. Anti-CD45RB-treated mice exposed to alloantigen exhibited anergic CD4+CD25− effector cells and regulatory CD4+CD25+ cells. Moreover, CD25 depletion in the peritransplant period prevented anti-CD45RB-mediated engraftment. Thus, exposure of CD4 cells expressing CTLA-4 to donor Ag is necessary and sufficient to induce long-term engraftment which appears to be mediated by both regulation and anergy.
CD4-Dependent Potentiation of a High Molecular Weight-Melanoma-Associated Antigen-Specific CTL Response Elicited in HLA-A2/Kb Transgenic Mice
Authors: Peng Liaomin , Ko Eric , Luo Wei , Wang Xinhui , Shrikant Protul A. , Ferrone Soldano 
Published: April 2014

Abstract
The human high m.w.-melanoma-associated Ag (HMW-MAA) is an attractive target for the immunotherapy of melanoma, due to its relatively high expression in a high percentage of melanoma lesions and its restricted distribution in normal tissues. Active immunization with HMW-MAA mimics has been previously shown to induce a HMW-MAA-specific, T cell-dependent Ab response associated with an apparent clinically beneficial effect in advanced melanoma patients. Although T cells play an important role in controlling tumor growth, only limited information is available to date about the induction of HMW-MAA-specific CTL. In this report, we show that immunization of HLA-A2/Kb transgenic mice with HMW-MAA cDNA-transfected syngeneic dendritic cells elicited a CD8+ CTL response specific for HMW-MAA peptides with HLA-A2 Ag-binding motifs. The elicited CTL lysed HLA-A2+HMW-MAA+ melanoma cells in vitro, and mouse HLA-A2/Kb cells pulsed with HMW-MAA-derived peptides in vitro and in vivo. Although this CTL response could be generated in the absence of CD4+ T cell help, harnessing CD4+ T cell help in a noncognate Ag-specific manner with the polyclonal activator staphylococcal enterotoxin A augmented the CTL response. These results imply that dendritic cell-based immunization, in combination with CD4+ T cell help, represents an effective strategy to implement T cell-based immunotherapy targeting HMW-MAA in patients with HMW-MAA-bearing tumors.
Effector and Memory CD8+ T Cells Can Be Generated in Response to Alloantigen Independently of CD4+ T Cell Help
Authors: Jones Nick D. , Carvalho-Gaspar Manuela , Luo Shiqiao , Brook Matthew O. , Martin Laurent , Wood Kathryn J. 
Published: April 2014

AbstractThere is now considerable evidence suggesting that CD8+ T cells are able to generate effector but not functional memory T cells following pathogenic infections in the absence of CD4+ T cells. We show that following transplantation of allogeneic skin, in the absence of CD4+ T cells, CD8+ T cells become activated, proliferate, and expand exclusively in the draining lymph nodes and are able to infiltrate and reject skin allografts. CD44+CD8+ T cells isolated 100 days after transplantation rapidly produce IFN-γ following restimulation with alloantigen in vitro. In vivo CD44+CD8+ T cells rejected donor-type skin allografts more rapidly than naive CD8+ T cells demonstrating the ability of these putative memory T cells to mount an effective recall response in vivo. These data form the first direct demonstration that CD8+ T cells are able to generate memory as well as effector cells in response to alloantigen during rejection in the complete absence of CD4+ T cells. These data have important implications for the design of therapies to combat rejection and serve to reinforce the view that CD8+ T cell responses to allografts require manipulation in addition to CD4+ T cell responses to completely prevent the rejection of foreign organ transplants.
Chemokine Receptor CXCR3 Desensitization by IL-16/CD4 Signaling Is Dependent on CCR5 and Intact Membrane Cholesterol
Authors: Rahangdale Shilpa , Morgan Roger , Heijens Claudia , Ryan Thomas C. , Yamasaki Hisato , Bentley Elizabeth , Sullivan Elizabeth , Center David M. , Cruikshank William W. 
Published: April 2014

Abstract
Previous work has shown that IL-16/CD4 induces desensitization of both CCR5- and CXCR4-induced migration, with no apparent effect on CCR2b or CCR3. To investigate the functional relationship between CD4 and other chemokine receptors, we determined the effects of IL-16 interaction with CD4 on CXCR3-induced migration. In this study we demonstrate that IL-16/CD4 induced receptor desensitization of CXCR3 on primary human T cells. IL-16/CD4 stimulation does not result in surface modulation of CXCR3 or changes in CXCL10 binding affinity. This effect does require p56lck enzymatic activity and the presence of CCR5, because desensitization is not transmitted in the absence of CCR5. Treatment of human T cells with methyl-β-cyclodextrin, a cholesterol chelator, prevented the desensitization of CXCR3 via IL-16/CD4, which was restored after reloading of cholesterol, indicating a requirement for intact cholesterol. These studies demonstrate an intimate functional relationship among CD4, CCR5, and CXCR3, in which CCR5 can act as an adaptor molecule for CD4 signaling. This process of regulating Th1 cell chemoattraction may represent a mechanism for orchestrating cell recruitment in Th1-mediated diseases.
Langerhans-Type Dendritic Cells Genetically Modified to Express Full-Length Antigen Optimally Stimulate CTLs in a CD4-Dependent Manner
Authors: Yuan Jianda , Latouche Jean-Baptiste , Hodges Joanna , Houghton Alan N. , Heller Glenn , Sadelain Michel , Riviere Isabelle , Young James W. 
Published: April 2014

Abstract
Oncoretroviral vectors encoding either full-length Ag or a corresponding immunodominant peptide were expressed in Langerhans-type dendritic cells (LCs) differentiated from CD34+ progenitors. We used human CMV as a model Ag restricted by HLA-A*0201 to define parameters for eventual expression of cancer Ags by LCs for active immunization against tumors. Stimulation by CMVpp65495–503-pulsed LCs, CMVpp65495–503-transduced LCs, and full-length CMVpp65-transduced LCs respectively increased tetramer-reactive T cells with an effector memory phenotype by 10 ± 11, 34 ± 21, and 51 ± 24-fold (p &lt; 0.05) from CMV-seropositive donors. CMV-specific CD8+ CTLs achieved respective frequencies of 231 ± 102, 583 ± 219, and 714 ± 281 spot-forming cells per 105 input cells (p &lt; 0.01) in ELISPOT assays for IFN-γ secretion. LCs expressing full-length Ag stimulated greater lytic activity than either peptide-transduced or peptide-pulsed LCs (p &lt; 0.05), all in the absence of exogenous cytokines. pp65-transduced LCs presenting class I and II MHC-restricted epitopes expanded IFN-γ-secreting CD4+ T cells, whereas pp65495–503-transduced LCs did not. CD4+ T cell numbers even declined after stimulation by pp65495–503 peptide-pulsed LCs. CD4+ T cell depletion confirmed their contribution to the more robust CTL responses. LCs, transduced with a retroviral vector encoding full-length Ag, stimulate potent CTLs directed against multiple epitopes in a CD4+ Th cell-dependent manner.