Showing papers on "Antigen published in 2004"
TL;DR: How naturally arising CD25+CD4+ regulatory T cells contribute to the maintenance of immunologic self-tolerance and negative control of various immune responses, and how they can be exploited to prevent and treat autoimmune disease, allergy, cancer, and chronic infection, or establish donor-specific transplantation tolerance are discussed.
Abstract: ▪ Abstract Naturally occurring CD4+ regulatory T cells, the majority of which express CD25, are engaged in dominant control of self-reactive T cells, contributing to the maintenance of immunologic self-tolerance. Their depletion or functional alteration leads to the development of autoimmune disease in otherwise normal animals. The majority, if not all, of such CD25+CD4+ regulatory T cells are produced by the normal thymus as a functionally distinct and mature subpopulation of T cells. Their repertoire of antigen specificities is as broad as that of naive T cells, and they are capable of recognizing both self and nonself antigens, thus enabling them to control various immune responses. In addition to antigen recognition, signals through various accessory molecules and via cytokines control their activation, expansion, and survival, and tune their suppressive activity. Furthermore, the generation of CD25+CD4+ regulatory T cells in the immune system is at least in part developmentally and genetically contro...
3,449 citations
TL;DR: A distinct SP was found in neuroblastoma cells from 15 of 23 patients and showed evidence for asymmetric division, generating both SP and non-SP progeny, suggesting that this phenotype defines a class of cancer stem cells with inherently high resistance to chemotherapeutic agents that should be targeted during the treatment of malignant disease.
Abstract: A subset of stem cells, termed the “side population” (SP), has been identified in several tissues in mammalian species. These cells maintain a high efflux capability for antimitotic drugs. We have investigated whether functionally equivalent stem cells also may be detected in human cancers. We initially examined primary tumor cells from 23 patients with neuroblastoma and cell lines derived from a range of other tumors. A distinct SP was found in neuroblastoma cells from 15 of 23 patients (65%). The SP was capable of sustained expansion ex vivo and showed evidence for asymmetric division, generating both SP and non-SP progeny. These cells also expressed high levels of ABCG2 and ABCA3 transporter genes and had a greater capacity to expel cytotoxic drugs, such as mitoxantrone, resulting in better survival. A SP also was detected in breast cancer, lung cancer, and glioblastoma cell lines, suggesting that this phenotype defines a class of cancer stem cells with inherently high resistance to chemotherapeutic agents that should be targeted during the treatment of malignant disease.
1,288 citations
TL;DR: Small numbers of antigen-specific Tregs from autoimmune-prone nonobese diabetic mice can reverse diabetes after disease onset, suggesting a novel approach to cellular immunotherapy for autoimmunity.
Abstract: The low number of CD4+ CD25+ regulatory T cells (Tregs), their anergic phenotype, and diverse antigen specificity present major challenges to harnessing this potent tolerogenic population to treat autoimmunity and transplant rejection In this study, we describe a robust method to expand antigen-specific Tregs from autoimmune-prone nonobese diabetic mice Purified CD4+ CD25+ Tregs were expanded up to 200-fold in less than 2 wk in vitro using a combination of anti-CD3, anti-CD28, and interleukin 2 The expanded Tregs express a classical cell surface phenotype and function both in vitro and in vivo to suppress effector T cell functions Most significantly, small numbers of antigen-specific Tregs can reverse diabetes after disease onset, suggesting a novel approach to cellular immunotherapy for autoimmunity
1,191 citations
TL;DR: High levels of arginase I production by mature myeloid cells in the tumor microenvironment may be a central mechanism for tumor evasion and may represent a target for new therapies.
Abstract: T cells infiltrating tumors have a decreased expression of signal transduction proteins, a diminished ability to proliferate, and a decreased production of cytokines. The mechanisms causing these changes have remained unclear. We demonstrated recently that peritoneal macrophages stimulated with interleukin 4 + interleukin 13 produce arginase I, which decreases the expression of the T-cell receptor CD3zeta chain and impairs T-cell responses. Using a 3LL murine lung carcinoma model we tested whether arginase I was produced in the tumor microenvironment and could decrease CD3zeta expression and impair T-cell function. The results show that a subpopulation of mature tumor-associated myeloid cells express high levels of arginase I, whereas tumor cells and infiltrating lymphocytes do not. Arginase I expression in the tumor was seen on day 7 after tumor injection. Tumor-associated myeloid cells also expressed high levels of cationic amino acid transporter 2B, which allowed them to rapidly incorporate L-Arginine (L-Arg) and deplete extracellular L-Arg in vitro. L-Arg depletion by tumor-associated myeloid cells blocked the re-expression of CD3zeta in stimulated T cells and inhibited antigen-specific proliferation of OT-1 and OT-2 cells. The injection of the arginase inhibitor N-hydroxy-nor-L-Arg blocked growth of s.c. 3LL lung carcinoma in mice. High levels of arginase I were also found in tumor samples of patients with non-small cell carcinoma. Therefore, arginase I production by mature myeloid cells in the tumor microenvironment may be a central mechanism for tumor evasion and may represent a target for new therapies.
1,061 citations
TL;DR: It is shown that intrahepatic injection of CD34+ human cord blood cells into conditioned newborn Rag2-/–γc–/– mice leads to de novo development of B, T, and dendritic cells; formation of structured primary and secondary lymphoid organs; and production of functional immune responses.
Abstract: Because ethical restrictions limit in vivo studies of the human hemato-lymphoid system, substitute human to small animal xenotransplantation models have been employed. Existing models, however, sustain only limited development and maintenance of human lymphoid cells and rarely produce immune responses. Here we show that intrahepatic injection of CD34+ human cord blood cells into conditioned newborn Rag2-/-gammac-/- mice leads to de novo development of B, T, and dendritic cells; formation of structured primary and secondary lymphoid organs; and production of functional immune responses. This provides a valuable model to study development and function of the human adaptive immune system in vivo.
990 citations
TL;DR: It is demonstrated that nanoparticle-aptamer bioconjugates can efficiently target and get taken up by the prostate LNCaP epithelial cells, which express the prostate-specific membrane antigen protein (77-fold increase in binding versus control, n = 150 cells per group).
Abstract: Nucleic acid ligands (aptamers) are potentially well suited for the therapeutic targeting of drug encapsulated controlled release polymer particles in a cell- or tissue-specific manner. We synthesized a bioconjugate composed of controlled release polymer nanoparticles and aptamers and examined its efficacy for targeted delivery to prostate cancer cells. Specifically, we synthesized poly(lactic acid)-block-polyethylene glycol (PEG) copolymer with a terminal carboxylic acid functional group (PLA-PEG-COOH), and encapsulated rhodamine-labeled dextran (as a model drug) within PLA-PEG-COOH nanoparticles. These nanoparticles have the following desirable characteristics: (a) negative surface charge (-50 +/- 3 mV, mean +/- SD, n = 3), which may minimize nonspecific interaction with the negatively charged nucleic acid aptamers; (b) carboxylic acid groups on the particle surface for potential modification and covalent conjugation to amine-modified aptamers; and (c) presence of PEG on particle surface, which enhances circulating half-life while contributing to decreased uptake in nontargeted cells. Next, we generated nanoparticle-aptamer bioconjugates with RNA aptamers that bind to the prostate-specific membrane antigen, a well-known prostate cancer tumor marker that is overexpressed on prostate acinar epithelial cells. We demonstrated that these bioconjugates can efficiently target and get taken up by the prostate LNCaP epithelial cells, which express the prostate-specific membrane antigen protein (77-fold increase in binding versus control, n = 150 cells per group). In contrast to LNCaP cells, the uptake of these particles is not enhanced in cells that do not express the prostate-specific membrane antigen protein. To our knowledge, this represents the first report of targeted drug delivery with nanoparticle-aptamer bioconjugates.
954 citations
TL;DR: By better harnessing the immunizing functions of maturing dendritic cells, antibody-mediated antigen targeting via the DEC-205 receptor increases the efficiency of vaccination for T cell immunity, including systemic and mucosal resistance in disease models.
Abstract: The prevention and treatment of prevalent infectious diseases and tumors should benefit from improvements in the induction of antigen-specific T cell immunity. To assess the potential of antigen targeting to dendritic cells to improve immunity, we incorporated ovalbumin protein into a monoclonal antibody to the DEC-205 receptor, an endocytic receptor that is abundant on these cells in lymphoid tissues. Simultaneously, we injected agonistic α-CD40 antibody to mature the dendritic cells. We found that a single low dose of antibody-conjugated ovalbumin initiated immunity from the naive CD4+ and CD8+ T cell repertoire. Unexpectedly, the αDEC-205 antigen conjugates, given s.c., targeted to dendritic cells systemically and for long periods, and ovalbumin peptide was presented on MHC class I for 2 weeks. This was associated with stronger CD8+ T cell–mediated immunity relative to other forms of antigen delivery, even when the latter was given at a thousand times higher doses. In parallel, the mice showed enhanced resistance to an established rapidly growing tumor and to viral infection at a mucosal site. By better harnessing the immunizing functions of maturing dendritic cells, antibody-mediated antigen targeting via the DEC-205 receptor increases the efficiency of vaccination for T cell immunity, including systemic and mucosal resistance in disease models.
928 citations
TL;DR: The U.S. Food and Drug administration has approved several polyclonal antibody preparations and at least 18 monoclonal antibody preparations (antibodies, antibody fragments, antibody fusion proteins, etc.) which are associated with several interesting pharmacokinetic characteristics.
886 citations
TL;DR: This review will explore the diverse influences of NKT cells in various disease models, their ability to suppress or enhance immunity, and the potential for manipulating these cells as a novel form of immunotherapy.
Abstract: NKT cells are a unique T lymphocyte sublineage that has been implicated in the regulation of immune responses associated with a broad range of diseases, including autoimmunity, infectious diseases, and cancer. In stark contrast to both conventional T lymphocytes and other types of Tregs, NKT cells are reactive to the nonclassical class I antigen-presenting molecule CD1d, and they recognize glycolipid antigens rather than peptides. Moreover, they can either up- or downregulate immune responses by promoting the secretion of Th1, Th2, or immune regulatory cytokines. This review will explore the diverse influences of these cells in various disease models, their ability to suppress or enhance immunity, and the potential for manipulating these cells as a novel form of immunotherapy.
856 citations
TL;DR: Analysis of class I restricted CD8+ T-cell responses against human immunodeficiency virus (HIV-1) indicates that the principal focus of HIV-specific activity is at the HLA-B locus, consistent with the observation that B alleles evolve more rapidly than A alleles.
Abstract: The extreme polymorphism in the human leukocyte antigen (HLA) class I region of the human genome is suggested to provide an advantage in pathogen defence mediated by CD8+ T cells. HLA class I molecules present pathogen-derived peptides on the surface of infected cells for recognition by CD8+ T cells. However, the relative contributions of HLA-A and -B alleles have not been evaluated. We performed a comprehensive analysis of the class I restricted CD8+ T-cell responses against human immunodeficiency virus (HIV-1), immune control of which is dependent upon virus-specific CD8+ T-cell activity. In 375 HIV-1-infected study subjects from southern Africa, a significantly greater number of CD8+ T-cell responses are HLA-B-restricted, compared to HLA-A (2.5-fold; P = 0.0033). Here we show that variation in viral set-point, in absolute CD4 count and, by inference, in rate of disease progression in the cohort, is strongly associated with particular HLA-B but not HLA-A allele expression (P < 0.0001 and P = 0.91, respectively). Moreover, substantially greater selection pressure is imposed on HIV-1 by HLA-B alleles than by HLA-A (4.4-fold, P = 0.0003). These data indicate that the principal focus of HIV-specific activity is at the HLA-B locus. Furthermore, HLA-B gene frequencies in the population are those likely to be most influenced by HIV disease, consistent with the observation that B alleles evolve more rapidly than A alleles. The dominant involvement of HLA-B in influencing HIV disease outcome is of specific relevance to the direction of HIV research and to vaccine design.
835 citations
TL;DR: The varied mechanisms used by Treg cells to suppress the immune system are discussed and suggested to result from the induction of anergy in peripheral self-reactive lymphocytes.
Abstract: The immune system evolved to protect the host against the attack of foreign, potentially pathogenic, microorganisms. It does so by recognizing antigens expressed by those microorganisms and mounting an immune response against all cells expressing them, with the ultimate aim of their elimination. Various mechanisms have been reported to control and regulate the immune system to prevent or minimize reactivity to self-antigens or an overexuberant response to a pathogen, both of which can result in damage to the host. Deletion of autoreactive cells during T- and B-cell development allows the immune system to be tolerant of most self-antigens. Peripheral tolerance to self was suggested several years ago to result from the induction of anergy in peripheral self-reactive lymphocytes. More recently, however, it has become clear that avoidance of damage to the host is also achieved by active suppression mediated by regulatory T (T(reg)) cell populations. We discuss here the varied mechanisms used by T(reg) cells to suppress the immune system.
TL;DR: It is shown that both myeloid and plasmacytoid DCs take up inhaled antigen in the lung and present it in an immunogenic or tolerogenic form to draining node T cells, showing intrinsic protection against inflammatory responses to harmless antigen.
Abstract: Tolerance is the usual outcome of inhalation of harmless antigen, yet T helper (Th) type 2 cell sensitization to inhaled allergens induced by dendritic cells (DCs) is common in atopic asthma. Here, we show that both myeloid (m) and plasmacytoid (p) DCs take up inhaled antigen in the lung and present it in an immunogenic or tolerogenic form to draining node T cells. Strikingly, depletion of pDCs during inhalation of normally inert antigen led to immunoglobulin E sensitization, airway eosinophilia, goblet cell hyperplasia, and Th2 cell cytokine production, cardinal features of asthma. Furthermore, adoptive transfer of pDCs before sensitization prevented disease in a mouse asthma model. On a functional level, pDCs did not induce T cell division but suppressed the generation of effector T cells induced by mDCs. These studies show that pDCs provide intrinsic protection against inflammatory responses to harmless antigen. Therapies exploiting pDC function might be clinically effective in preventing the development of asthma.
TL;DR: The data suggest that MM "stem cells" are CD138- B cells with the ability to replicate and subsequently differentiate into malignant CD138+ plasma cells.
TL;DR: Similar to other aspects of immunity, their clonal expansion and survival depend on the activity of CD4+ T cells, although the mechanism(s) of 'help' for CTL responses is still debated.
Abstract: Cytotoxic T lymphocytes (CTLs) that express the CD8 co-receptor are the guided missiles of the immune system. They express clonally distributed receptors for foreign antigen, undergo marked proliferation in response to infection and kill any cell that expresses their target antigen. When an infection is cleared or brought under control, the progeny of these cytolytic effectors are retained as an essential component of immunological memory. As I discuss here, similar to other aspects of immunity, their clonal expansion and survival depend on the activity of CD4+ T cells, although the mechanism(s) of 'help' for CTL responses is still debated.
TL;DR: In this article, a small population of human prostate basal cells express the cell surface marker CD133 and are restricted to the alpha(2)beta(1)(hi) population, previously identified as a marker of stem cells in prostate epithelia.
Abstract: Stem cells are clonogenic cells with self-renewal and differentiation properties, which may represent a major target for genetic damage leading to prostate cancer and benign prostatic hyperplasia. Stem cells remain poorly characterised because of the absence of specific molecular markers that permit us to distinguish them from their progeny, the transit amplifying cells, which have a more restricted proliferative potential. Human CD133 antigen, also known as AC133, was recently identified as a haematopoietic stem cell marker. Here we show that a small population (approximately 1%) of human prostate basal cells express the cell surface marker CD133 and are restricted to the alpha(2)beta(1)(hi) population, previously shown to be a marker of stem cells in prostate epithelia. alpha(2)beta(1)(hi)/CD133(+) cells exhibit two important attributes of epithelial stem cells: they possess a high in vitro proliferative potential and can reconstitute prostatic-like acini in immunocompromised male nude mice.
TL;DR: It is shown that UC is associated with an atypical Th2 response mediated by nonclassical NKT cells producing IL-13 and having cytotoxic potential for epithelial cells and that this cytotoxicity is augmented by IL- 13.
Abstract: While Crohn disease (CD) has been clearly identified as a Th1 inflammation, the immunopathogenesis of its counterpart inflammatory bowel disease, ulcerative colitis (UC), remains enigmatic. Here we show that lamina propria T (LPT) cells from UC patients produce significantly greater amounts of IL-13 (and IL-5) than control cells and little IFN-γ, whereas comparable cells from CD patients produce large amounts of IFN-γ and small amounts of IL-13. We then show that stimulation of UC LPT cells bearing an NK marker (CD161) with anti-CD2/anti-CD28 or with B cells expressing transfected CD1d induces substantial IL-13 production. While this provided firm evidence that the IL-13–producing cell is an NK T (NKT) cell, it became clear that this cell does not express invariant NKT cell receptors characteristic of most NKT cells since there was no increase in cells binding α-galactosylceramide–loaded tetramers, and α-galactosylceramide did not induce IL-13 secretion. Finally, we show that both human NKT cell lines as well as UC CD161+ LPT cells are cytotoxic for HT-29 epithelial cells and that this cytotoxicity is augmented by IL-13. These studies show that UC is associated with an atypical Th2 response mediated by nonclassical NKT cells producing IL-13 and having cytotoxic potential for epithelial cells.
TL;DR: Longer subcutaneous infusion of low doses of peptide by means of osmotic pumps transforms mature T cells into CD4+25+ suppressor cells that can persist for long periods of time in the absence of antigen and confer specific immunologic tolerance upon challenge with antigen.
Abstract: The induction of antigen-specific tolerance in the mature immune system of the intact organism has met with limited success. Therefore, nonspecific immunosuppression has been the treatment of choice to prevent unwanted immunity. Here, it is shown that prolonged subcutaneous infusion of low doses of peptide by means of osmotic pumps transforms mature T cells into CD4+25+ suppressor cells that can persist for long periods of time in the absence of antigen and confer specific immunologic tolerance upon challenge with antigen. The described procedure resembles approaches of tolerance induction used decades ago, induces tolerance in the absence of immunity, and holds the promise to become an effective means of inducing antigen-specific tolerance prospectively, whereas its power to suppress already ongoing immune responses remains to be determined.
TL;DR: This review examines the molecular basis for cross‐presentation, discusses the role of DC subsets, and examines the contribution of this process to immunity, with some emphasis on DNA vaccination.
Abstract: Cross-presentation involves the uptake and processing of exogenous antigens within the major histocompatibility complex (MHC) class I pathway. This process is primarily performed by dendritic cells (DCs), which are not a single cell type but may be divided into several distinct subsets. Those expressing CD8alpha together with CD205, found primarily in the T-cell areas of the spleen and lymph nodes, are the major subset responsible for cross-presenting cellular antigens. This ability is likely to be important for the generation of cytotoxic T-cell immunity to a variety of antigens, particularly those associated with viral infection, tumorigenesis, and DNA vaccination. At present, it is unclear whether the CD8alpha-expressing DC subset captures antigen directly from target cells or obtains it indirectly from intermediary DCs that traffic from peripheral sites. In this review, we examine the molecular basis for cross-presentation, discuss the role of DC subsets, and examine the contribution of this process to immunity, with some emphasis on DNA vaccination.
TL;DR: The results demonstrate that FUT8−/− cells are ideal host cell lines to stably produce completely defucosylated high‐ADCC antibodies with fixed quality and efficacy for therapeutic use.
Abstract: To generate industrially applicable new host cell lines for antibody production with optimizing antibody-dependent cellular cytotoxicity (ADCC) we disrupted both FUT8 alleles in a Chinese hamster ovary (CHO)/DG44 cell line by sequential homologous recombination. FUT8 encodes an alpha-1,6-fucosyltransferase that catalyzes the transfer of fucose from GDP-fucose to N-acetylglucosamine (GlcNAc) in an alpha-1,6 linkage. FUT8(-/-) cell lines have morphology and growth kinetics similar to those of the parent, and produce completely defucosylated recombinant antibodies. FUT8(-/-)-produced chimeric anti-CD20 IgG1 shows the same level of antigen-binding activity and complement-dependent cytotoxicity (CDC) as the FUT8(+/+)-produced, comparable antibody, Rituxan. In contrast, FUT8(-/-)-produced anti-CD20 IgG1 strongly binds to human Fcgamma-receptor IIIa (FcgammaRIIIa) and dramatically enhances ADCC to approximately 100-fold that of Rituxan. Our results demonstrate that FUT8(-/-) cells are ideal host cell lines to stably produce completely defucosylated high-ADCC antibodies with fixed quality and efficacy for therapeutic use.
TL;DR: The concept that normal pregnancy is associated with an elevation in the number of TReg cells which may be important in maintaining materno‐fetal tolerance is supported.
Abstract: Summary CD4+ CD25+ T regulatory cells (TReg), suppress antigen-specific immune responses and are important for allograft tolerance. During pregnancy the mother tolerates an allograft expressing paternal antigens (the fetus) requiring substantial changes in immune regulation over a programmed period of time. We analysed whether immune-suppressive TReg cells were altered during pregnancy and therefore might play a part in this tolerant state. The presence of TReg cells was assessed in the blood of 25 non-pregnant, 63 pregnant and seven postnatal healthy women by flow cytometry. We observed an increase in circulating TReg cells during early pregnancy, peaking during the second trimester and then a decline postpartum. Isolated CD25+ CD4+ cells expressed FoxP3 messenger RNA, a marker of TReg cells, and suppressed proliferative responses of autologous CD4+ CD25- T cells to allogeneic dendritic cells. These data support the concept that normal pregnancy is associated with an elevation in the number of TReg cells which may be important in maintaining materno-fetal tolerance.
TL;DR: It is shown that early human pregnancy decidua contains an abundance of CD4(+)CD25(bright) T cells, which express CD152(CTLA-4) at a high level, and these cells mediate potent inhibition of autologous T-cell proliferation by anti-CD3 stimulation and contribute to the mechanisms mediating maternal immune tolerance of conceptus antigens.
Abstract: Human pregnancy represents a situation of semiallograft to maternal host. Therefore, it has been reported that tolerance to the fetal allograft represents a mechanism for maintaining a pregnancy. CD4 + CD25 bright regulatory T cells are known to play an important role in the development and maintenance of tolerance in peripheral tissues. However, the potential role of CD4 + CD25 bright T cells in maintaining human pregnancy has not been reported. In this study, we show that early human pregnancy decidua contains an abundance of CD4 + CD25 bright T cells, which express CD152(CTLA-4) at a high level. CD4 + CD25 bright T cells mediate potent inhibition of autologous T-cell proliferation by anti-CD3 stimulation. Furthermore, these cells inhibit the proliferation of autologous CD4 + CD25 - T cells in a dose-dependent fashion. This suppressive function of decidual CD4 + CD25 + T cells required cell-to-cell contact. The proportion of decidual CD4 + CD25 bright T cells was significantly lower in specimens from spontaneous abortion compared to those from specimens from induced abortions. These results suggest that decidual CD4 + CD25 bright T cells contribute to the mechanisms mediating maternal immune tolerance of conceptus antigens and therefore might contribute to the maintenance of pregnancy.
TL;DR: Serological expression cloning was used to identify commensal bacterial proteins that could contribute to the pathogenesis of IBD and identify flagellins as a class of immunodominant antigens that stimulate pathogenic intestinal immune reactions in genetically diverse hosts.
Abstract: Chronic intestinal inflammation, as seen in inflammatory bowel disease (IBD), results from an aberrant and poorly understood mucosal immune response to the microbiota of the gastrointestinal tract in genetically susceptible individuals. Here we used serological expression cloning to identify commensal bacterial proteins that could contribute to the pathogenesis of IBD. The dominant antigens identified were flagellins, molecules known to activate innate immunity via Toll-like receptor 5 (TLR5), and critical targets of the acquired immune system in host defense. Multiple strains of colitic mice had elevated serum anti-flagellin IgG2a responses and Th1 T cell responses to flagellin. In addition, flagellin-specific CD4(+) T cells induced severe colitis when adoptively transferred into naive SCID mice. Serum IgG to these flagellins, but not to the dissimilar Salmonella muenchen flagellin, was elevated in patients with Crohn disease, but not in patients with ulcerative colitis or in controls. These results identify flagellins as a class of immunodominant antigens that stimulate pathogenic intestinal immune reactions in genetically diverse hosts and suggest new avenues for the diagnosis and antigen-directed therapy of patients with IBD.
TL;DR: Se sequencing of TRAV14 (Valpha2) TCRalpha chains associated with a transgenic TCRbeta chain finds that naturally arising TR have substantially more efficient interactions with MHC class II bound peptides from the peripheral self than CD25- T cells.
TL;DR: Gene-based vaccination for the SARS-CoV elicits effective immune responses that generate protective immunity in an animal model, and induces T cell and neutralizing antibody responses, as well as protective immunity, in a mouse model.
Abstract: Public health measures have successfully identified and contained outbreaks of the severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), but concerns remain over the possibility of future recurrences. Finding a vaccine for this virus therefore remains a high priority. Here, we show that a DNA vaccine encoding the spike (S) glycoprotein of the SARS-CoV induces T cell and neutralizing antibody responses, as well as protective immunity, in a mouse model. Alternative forms of S were analysed by DNA immunization. These expression vectors induced robust immune responses mediated by CD4 and CD8 cells, as well as significant antibody titres, measured by enzyme-linked immunosorbent assay. Moreover, antibody responses in mice vaccinated with an expression vector encoding a form of S that includes its transmembrane domain elicited neutralizing antibodies. Viral replication was reduced by more than six orders of magnitude in the lungs of mice vaccinated with these S plasmid DNA expression vectors, and protection was mediated by a humoral but not a T-cell-dependent immune mechanism. Gene-based vaccination for the SARS-CoV elicits effective immune responses that generate protective immunity in an animal model.
TL;DR: It is found that the innate monocyte network depletes B cells through FcγR-dependent pathways during anti-CD20 immunotherapy has important clinical implications for anti- CD20 and other antibody-based therapies.
Abstract: Anti-CD20 antibody immunotherapy effectively treats non-Hodgkin9s lymphoma and autoimmune disease. However, the cellular and molecular pathways for B cell depletion remain undefined because human mechanistic studies are limited. Proposed mechanisms include antibody-, effector cell–, and complement-dependent cytotoxicity, the disruption of CD20 signaling pathways, and the induction of apoptosis. To identify the mechanisms for B cell depletion in vivo, a new mouse model for anti-CD20 immunotherapy was developed using a panel of twelve mouse anti–mouse CD20 monoclonal antibodies representing all four immunoglobulin G isotypes. Anti-CD20 antibodies rapidly depleted the vast majority of circulating and tissue B cells in an isotype-restricted manner that was completely dependent on effector cell Fc receptor expression. B cell depletion used both FcγRI- and FcγRIII-dependent pathways, whereas B cells were not eliminated in FcR common γ chain–deficient mice. Monocytes were the dominant effector cells for B cell depletion, with no demonstrable role for T or natural killer cells. Although most anti-CD20 antibodies activated complement in vitro, B cell depletion was completely effective in mice with genetic deficiencies in C3, C4, or C1q complement components. That the innate monocyte network depletes B cells through FcγR-dependent pathways during anti-CD20 immunotherapy has important clinical implications for anti-CD20 and other antibody-based therapies.
TL;DR: The integrin αEβ7 discriminates distinct subsets of murine CD4+ regulatory T cells as discussed by the authors, and αE−CD25+ cells expressed L-selectin and CCR7, enabling recirculation through lymphoid tissues.
Abstract: Regulatory T cells (Tregs) fulfill a central role in immune regulation. We reported previously that the integrin αEβ7 discriminates distinct subsets of murine CD4+ regulatory T cells. Use of this marker has now helped to unravel a fundamental dichotomy among regulatory T cells. αE−CD25+ cells expressed L-selectin and CCR7, enabling recirculation through lymphoid tissues. In contrast, αE-positive subsets (CD25+ and CD25−) displayed an effector/memory phenotype expressing high levels of E/P-selectin–binding ligands, multiple adhesion molecules as well as receptors for inflammatory chemokines, allowing efficient migration into inflamed sites. Accordingly, αE-expressing cells were found to be the most potent suppressors of inflammatory processes in disease models such as antigen-induced arthritis.
TL;DR: With increasing evidence that mAb therapeutic activity in vivo depends on complement activation, these new CD20 reagents with their slow off-rates and increased potency in CDC hold considerable promise for improved clinical activity.
TL;DR: In vivo, HMGB1 enhances the primary antibody responses to soluble antigens and transforms poorly immunogenic apoptotic lymphoma cells into efficient vaccines and reduces the activation induced by necrotic wild‐type cell supernatants.
Abstract: Immune responses against pathogens require that microbial components promote the activation of antigen-presenting cells (APCs). Autoimmune diseases and graft rejections occur in the absence of pathogens; in these conditions, endogenous molecules, the so-called 'innate adjuvants', activate APCs. Necrotic cells contain and release innate adjuvants; necrotic cells also release high-mobility group B1 protein (HMGB1), an abundant and conserved constituent of vertebrate nuclei. Here, we show that necrotic HMGB1(-/-) cells have a reduced ability to activate APCs, and HMGB1 blockade reduces the activation induced by necrotic wild-type cell supernatants. In vivo, HMGB1 enhances the primary antibody responses to soluble antigens and transforms poorly immunogenic apoptotic lymphoma cells into efficient vaccines.
TL;DR: Some parameters like route of administration, dose, or promoter type have been extensively described as critical factors influencing vector immunity, and strategies to fight against vector-induced immunity can come from the immunology field, since tolerance induction or immunosuppression are a possibility.
Abstract: Circumventing the immune response to the vector is a major challenge with all vector types. Viral vectors are the most likely to induce an immune response, especially those, like adenovirus and AAV, which express immunogenic epitopes within the organism. The first immune response occurring after vector transfer emerges from the innate immune system, mainly consisting in a rapid (few hours) inflammatory cytokines and chemokines secretion around the administration site. This reaction is high with adenoviral vectors and almost null with AAV. It is noteworthy that plasmid DNA vectors, because of CpG stimulatory islets, also stimulate the innate immunity via the stimulation of TLR receptors on leukocytes. Specific immune response leading to antibodies production and T lymphocytes activation also occurs within a few days after vector introduction. Capsid antigens are mostly responsible for specific immunity toward adenoviruses, and are also involved in the response against AAV. In the former case only, however, viral gene-encoded proteins can also be immunogenic. The pre-existing humoral immunity coming from early infections with wild-type AAV or adenovirus can prevent efficient gene transfer with the corresponding vectors. In all cases, some parameters like route of administration, dose, or promoter type have been extensively described as critical factors influencing vector immunity. Strategies to fight against vector-induced immunity can come from the immunology field, since tolerance induction or immunosuppression are a possibility. Alterations to vector structure have also been extensively performed to circumvent the immune system and thus enhance gene transfer efficiency and safety.
TL;DR: Recombinant modified vaccinia virus Ankara expressing antigen 85A (MVA85A) was found to induce high levels of antigen-specific IFN-γ-secreting T cells when used alone in bacille Calmette-Guérin (BCG)-naive healthy volunteers.
Abstract: Protective immunity against Mycobacterium tuberculosis depends on the generation of a T(H)1-type cellular immune response, characterized by the secretion of interferon-gamma (IFN-gamma) from antigen-specific T cells. The induction of potent cellular immune responses by vaccination in humans has proven difficult. Recombinant viral vectors, especially poxviruses and adenoviruses, are particularly effective at boosting previously primed CD4(+) and CD8(+) T-cell responses against a number of intracellular pathogens in animal studies. In the first phase 1 study of any candidate subunit vaccine against tuberculosis, recombinant modified vaccinia virus Ankara (MVA) expressing antigen 85A (MVA85A) was found to induce high levels of antigen-specific IFN-gamma-secreting T cells when used alone in bacille Calmette-Guerin (BCG)-naive healthy volunteers. In volunteers who had been vaccinated 0.5-38 years previously with BCG, substantially higher levels of antigen-specific IFN-gamma-secreting T cells were induced, and at 24 weeks after vaccination these levels were 5-30 times greater than in vaccinees administered a single BCG vaccination. Boosting vaccinations with MVA85A could offer a practical and efficient strategy for enhancing and prolonging antimycobacterial immunity in tuberculosis-endemic areas.