Showing papers on "Antibody published in 2002"

Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade

Abstract: PD-1 is a receptor of the Ig superfamily that negatively regulates T cell antigen receptor signaling by interacting with the specific ligands (PD-L) and is suggested to play a role in the maintenance of self-tolerance. In the present study, we examined possible roles of the PD-1/PD-L system in tumor immunity. Transgenic expression of PD-L1, one of the PD-L, in P815 tumor cells rendered them less susceptible to the specific T cell antigen receptor-mediated lysis by cytotoxic T cells in vitro, and markedly enhanced their tumorigenesis and invasiveness in vivo in the syngeneic hosts as compared with the parental tumor cells that lacked endogenous PD-L. Both effects could be reversed by anti-PD-L1 Ab. Survey of murine tumor lines revealed that all of the myeloma cell lines examined naturally expressed PD-L1. Growth of the myeloma cells in normal syngeneic mice was inhibited significantly albeit transiently by the administration of anti-PD-L1 Ab in vivo and was suppressed completely in the syngeneic PD-1-deficient mice. These results suggest that the expression of PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses and that blockade of interaction between PD-1 and PD-L may provide a promising strategy for specific tumor immunotherapy.

Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors

Abstract: Autoreactive B cells are present in the lymphoid tissues of healthy individuals, but typically remain quiescent. When this homeostasis is perturbed, the formation of self-reactive antibodies can have serious pathological consequences. B cells expressing an antigen receptor specific for self-immunoglobulin-gamma (IgG) make a class of autoantibodies known as rheumatoid factor (RF). Here we show that effective activation of RF+ B cells is mediated by IgG2a-chromatin immune complexes and requires the synergistic engagement of the antigen receptor and a member of the MyD88-dependent Toll-like receptor (TLR) family. Inhibitor studies implicate TLR9. These data establish a critical link between the innate and adaptive immune systems in the development of systemic autoimmune disease and explain the preponderance of autoantibodies reactive with nucleic acid-protein particles. The unique features of this dual-engagement pathway should facilitate the development of therapies that specifically target autoreactive B cells.

Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease

Abstract: Activation of naive CD4(+) T-helper cells results in the development of at least two distinct effector populations, Th1 and Th2 cells. Th1 cells produce cytokines (interferon (IFN)-gamma, interleukin (IL)-2, tumour-necrosis factor (TNF)-alpha and lymphotoxin) that are commonly associated with cell-mediated immune responses against intracellular pathogens, delayed-type hypersensitivity reactions, and induction of organ-specific autoimmune diseases. Th2 cells produce cytokines (IL-4, IL-10 and IL-13) that are crucial for control of extracellular helminthic infections and promote atopic and allergic diseases. Although much is known about the functions of these two subsets of T-helper cells, there are few known surface molecules that distinguish between them. We report here the identification and characterization of a transmembrane protein, Tim-3, which contains an immunoglobulin and a mucin-like domain and is expressed on differentiated Th1 cells. In vivo administration of antibody to Tim-3 enhances the clinical and pathological severity of experimental autoimmune encephalomyelitis (EAE), a Th1-dependent autoimmune disease, and increases the number and activation level of macrophages. Tim-3 may have an important role in the induction of autoimmune diseases by regulating macrophage activation and/or function.

Maintenance of Serological Memory by Polyclonal Activation of Human Memory B Cells

Abstract: Production of antibodies can last for a lifetime, through mechanisms that remain poorly understood. Here, we show that human memory B lymphocytes proliferate and differentiate into plasma cells in response to polyclonal stimuli, such as bystander T cell help and CpG DNA. Furthermore, plasma cells secreting antibodies to recall antigens are produced in vivo at levels proportional to the frequency of specific memory B cells, even several years after antigenic stimulation. Although antigen boosting leads to a transient increase in specific antibody levels, ongoing polyclonal activation of memory B cells offers a means to maintain serological memory for a human lifetime.

DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL

Abstract: Immunoglobulin (Ig) class-switch DNA recombination (CSR) is thought to be highly dependent upon engagement of CD40 on B cells by CD40 ligand on T cells. We show here that dendritic cells up-regulate BLyS and APRIL upon exposure to interferon-alpha, interferon-gamma or CD40 ligand. In the presence of interleukin 10 (IL-10) or transforming growth factor-beta, BLyS and APRIL induce CSR from C(mu) to C(gamma) and/or C(alpha) genes in B cells, whereas CSR to C(epsilon) requires IL-4. Secretion of class-switched antibodies requires additional stimulation by B cell antigen receptor engagement and IL-15. By eliciting CD40-independent Ig class switching and plasmacytoid differentiation, BLyS and APRIL critically link the innate and adaptive immune responses.

Anti-CD3 Monoclonal Antibody in New-Onset Type 1 Diabetes Mellitus

Abstract: Background Type 1 diabetes mellitus is a chronic autoimmune disease caused by the pathogenic action of T lymphocytes on insulin-producing beta cells. Previous clinical studies have shown that continuous immune suppression temporarily slows the loss of insulin production. Preclinical studies suggested that a monoclonal antibody against CD3 could reverse hyperglycemia at presentation and induce tolerance to recurrent disease. Methods We studied the effects of a nonactivating humanized monoclonal antibody against CD3 — hOKT3γ1(Ala-Ala) — on the loss of insulin production in patients with type 1 diabetes mellitus. Within 6 weeks after diagnosis, 24 patients were randomly assigned to receive either a single 14-day course of treatment with the monoclonal antibody or no antibody and were studied during the first year of disease. Results Treatment with the monoclonal antibody maintained or improved insulin production after one year in 9 of the 12 patients in the treatment group, whereas only 2 of the 12 controls ...

Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer's disease model

Abstract: We have previously shown that chronic treatment with the monoclonal antibody m266, which is specific for amyloid β-peptide (Aβ), increases plasma concentrations of Aβ and reduces Aβ burden in the PDAPP transgenic mouse model of Alzheimer's disease (AD). We now report that administration of m266 to PDAPP mice can rapidly reverse memory deficits in both an object recognition task and a holeboard learning and memory task, but without altering brain Aβ burden. We also found that an Aβ/antibody complex was present in both the plasma and the cerebrospinal fluid of m266-treated mice. Our data indicate that passive immunization with this anti-Aβ monoclonal antibody can very rapidly reverse memory impairment in certain learning and memory tasks in the PDAPP mouse model of AD, owing perhaps to enhanced peripheral clearance and (or) sequestration of a soluble brain Aβ species.

A Critical Role for IL-21 in Regulating Immunoglobulin Production

Abstract: The cytokine interleukin-21 (IL-21) is closely related to IL-2 and IL-15, and their receptors all share the common cytokine receptor gamma chain, gammac, which is mutated in humans with X-linked severe combined immunodeficiency disease (XSCID) We demonstrate that, although mice deficient in the receptor for IL-21 (IL-21R) have normal lymphoid development, after immunization, these animals have higher production of the immunoglobulin IgE, but lower IgG1, than wild-type animals Mice lacking both IL-4 and IL-21R exhibited a significantly more pronounced phenotype, with dysgammaglobulinemia, characterized primarily by a severely impaired IgG response Thus, IL-21 has a significant influence on the regulation of B cell function in vivo and cooperates with IL-4 This suggests that these gammac-dependent cytokines may be those whose inactivation is primarily responsible for the B cell defect in humans with XSCID

Origins and functions of B-1 cells with notes on the role of CD5.

Abstract: Whether B-1a (CD5+) cells are a distinct lineage derived from committed fetal/neonatal precursors or arise from follicular B-2 cells in response to BCR ligation and other, unknown signals remains controversial. Recent evidence indicates that B-1a cells can derive from adult precursors expressing an appropriate specificity when the (self-) antigen is present. Antibody specificity determines whether a B cell expressing immunoglobulin transgenes has a B-2, B-1a or marginal zone (MZ) phenotype. MZ cells share many phenotypic characteristics of B-1 cells and, like them, appear to develop in response to T independent type 2 antigens. Because fetal-derived B cell progenitors fail to express terminal deoxynucleotidyl transferase (TdT) and for other reasons, they are likely to express a repertoire that allows selection into the B-1a population. As it is selected by self-antigen, the B-1 repertoire tends to be autoreactive. This potentially dangerous repertoire is also useful, as B-1 cells are essential for resistance to several pathogens and they play an important role in mucosal immunity. The CD5 molecule can function as a negative regulator of BCR signaling that may help prevent inappropriate activation of autoreactive B-1a cells.

Human Parvovirus B19

Abstract: Parvovirus B19 (B19) was discovered in 1974 and is the only member of the family Parvoviridae known to be pathogenic in humans. Despite the inability to propagate the virus in cell cultures, much has been learned about the pathophysiology of this virus, including the identification of the cellular receptor (P antigen), and the control of the virus by the immune system. B19 is widespread, and manifestations of infection vary with the immunologic and hematologic status of the host. In healthy immunocompetent individuals B19 is the cause of erythema infectiosum and, particularly in adults, acute symmetric polyarthropathy. Due to the tropism of B19 to erythroid progenitor cells, infection in individuals with an underlying hemolytic disorder causes transient aplastic crisis. In the immunocompromised host persistent B19 infection is manifested as pure red cell aplasia and chronic anemia. Likewise, the immature immune response of the fetus may render it susceptible to infection, leading to fetal death in utero, hydrops fetalis, or development of congenital anemia. B19 has also been suggested as the causative agent in a variety of clinical syndromes, but given the common nature, causality is often difficult to infer. Diagnosis is primarily based on detection of specific antibodies by enzyme-linked immunosorbent assay or detection of viral DNA by dot blot hybridization or PCR. Treatment of persistent infection with immunoglobulin reduces the viral load and results in a marked resolution of anemia. Vaccine phase I trials show promising results.

Roles of Fc receptors in autoimmunity.

Abstract: The receptors for the Fc of immunoglobulins, Fc receptors (FcRs), link the humoral and cellular branches of the immune system, and they have important functions in the activation and down-modulation of immune responses. Balanced signalling through activating and inhibitory FcRs regulates the activity of various cells in the immune system. Recent work in animal models indicates that the development of many human autoimmune diseases might be caused by impairment of the FcR regulatory system. This review provides an overview of the mechanisms of FcR-based immune regulation and describes how autoimmune disease might result from its dysfunction.

Enzyme-Linked Immunosorbent Assay Specific to Dengue Virus Type 1 Nonstructural Protein NS1 Reveals Circulation of the Antigen in the Blood during the Acute Phase of Disease in Patients Experiencing Primary or Secondary Infections

Abstract: During flavivirus infection in vitro, nonstructural protein NS1 is released in a host-restricted fashion from infected mammalian cells but not vector-derived insect cells. In order to analyze the biological relevance of NS1 secretion in vivo, we developed a sensitive enzyme-linked immunosorbent assay (ELISA) to detect the protein in the sera of dengue virus-infected patients. The assay was based on serotype 1 NS1-specific mouse and rabbit polyclonal antibody preparations for antigen immunocapture and detection, respectively. With purified dengue virus type 1 NS1 as a protein standard, the sensitivity of our capture ELISA was less than 1 ng/ml. When a panel of patient sera was analyzed, the NS1 antigen was found circulating from the first day after the onset of fever up to day 9, once the clinical phase of the disease is over. The NS1 protein could be detected even when viral RNA was negative in reverse transcriptase-PCR or in the presence of immunoglobulin M antibodies. NS1 circulation levels varied among individuals during the course of the disease, ranging from several nanograms per milliliter to several micrograms per milliliter, and peaked in one case at 50 μg/ml of serum. Interestingly, NS1 concentrations did not differ significantly in serum specimens obtained from patients experiencing primary or secondary dengue virus infections. These findings indicate that NS1 protein detection may allow early diagnosis of infection. Furthermore, NS1 circulation in the bloodstream of patients during the clinical phase of the disease suggests a contribution of the nonstructural protein to dengue virus pathogenesis.

Increasing antibody affinity by altering glycosylation of immunoglobulin variable region

Abstract: The present invention provides methods for producing mutationally-altered immunoglobulins and compositions containing such mutationally-altered immunoglobulins, wherein the mutationally-altered immunoglobulins have at least one mutation that alters the pattern of glycosylation in a variable region and thereby modifies the affinity of the immunoglobulin for a preselected antigen. The methods and compositions of the invention provide immunoglobulins that possess increased affinity for antigen. Such glycosylation-altered immunoglobulins are suitable for diagnostic and therapeutic applications.

Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells.

Abstract: Allergic asthma is a chronic inflammatory disease and despite the introduction of potent and effective drugs, the prevalence has increased substantially over the past few decades(1). The explanation that has attracted the most attention is the 'hygiene hypothesis', which suggests that the increase in allergic diseases is caused by a cleaner environment and fewer childhood infections(2-4). Indeed, certain mycobacterial strains can cause a shift from T-helper cell 2 (Th2) to Th1 immune responses, which may subsequently prevent the development of allergy in mice(5-7). Although the reconstitution of the balance between Th1 and Th2 is an attractive theory, it is unlikely to explain the whole story, as autoimmune diseases characterized by Th1 responses can also benefit from treatment with mycobacteria and their prevalence has also increased in parallel to allergies(8). Here we show that treatment of mice with SRP299, a killed Mycobacterium vaccae-suspension, gives rise to allergen-specific CD4(+)CD45RB(Lo) regulatory T cells, which confer protection against airway inflammation. This specific inhibition was mediated through interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta), as antibodies against IL-10 and TGF-beta completely reversed the inhibitory effect of CD4(+)CD45RB(Lo) T cells. Thus, regulatory T cells generated by mycobacteria treatment may have an essential role in restoring the balance of the immune system to prevent and treat allergic diseases.

Progressive differentiation and selection of the fittest in the immune response

Abstract: T cells are stimulated by stochastic exposure to antigen-presenting cells and cytokines. We review evidence that the level of signal that is accumulated determines progression through hierarchical thresholds for proliferation and differentiation, leading to the generation of various intermediates and effector T cells. These cells are then selected to enter the memory pool according to their fitness--that is, their capacity to access and use survival signals. We suggest that the intermediates that are generated by antigenic stimulation of T and B cells persist as central memory cells, which can mount secondary responses to antigen and maintain appropriate levels of effector cells and antibodies throughout the lifetime of an individual.

Contribution of Human α-Defensin-1, -2 and -3 to the Anti-HIV-1 Activity of CD8 Antiviral Factor

Abstract: It has been known since 1986 that CD8 T lymphocytes from certain HIV-1-infected individuals who are immunologically stable secrete a soluble factor, termed CAF, that suppresses HIV-1 replication. However, the identity of CAF remained elusive despite an extensive search. By means of a protein-chip technology, we identified a cluster of proteins that were secreted when CD8 T cells from long-term nonprogressors with HIV-1 infection were stimulated. These proteins were identified as alpha-defensin 1, 2, and 3 on the basis of specific antibody recognition and amino acid sequencing. CAF activity was eliminated or neutralized by an antibody specific for human alpha-defensins. Synthetic and purified preparations of alpha-defensins also inhibited the replication of HIV-1 isolates in vitro. Taken together, our results indicate that alpha-defensin 1, 2, and 3 collectively account for much of the anti-HIV-1 activity of CAF that is not attributable to beta-chemokines.

Lack of Antibody Production Following Immunization in Old Age: Association with CD8+CD28− T Cell Clonal Expansions and an Imbalance in the Production of Th1 and Th2 Cytokines

Abstract: Although it is generally recognized that the function of the immune system declines with age, the nature of the underlying defects is still poorly understood We now demonstrate the predominance of CD8(+)CD28(-) T cell clonal expansions in elderly persons who fail to produce specific Abs following influenza vaccination These clones express effector cell markers and are mostly CD45RA(+) When isolated and put into culture, they are unable to proliferate, but produce IFN-gamma (but no IL-5) upon stimulation with anti-CD3 or autoantigen These autoreactive CD8(+) type 1 effector cells seem to trigger a Th1 polarization, as CD4(+) T cells from elderly persons without in vivo Ab production produce Th1, but only low amounts of Th2 cytokines upon in vitro stimulation with PHA Therefore, the increased occurrence of CD8(+)CD28(-) clonal expansions may be decisive for the development of immune deficiency in the elderly

IgG4 breaking the rules.

Abstract: Immunoglobulin G4 (IgG4) antibodies have been known for some time to be functionally monovalent. Recently, the structural basis for this monovalency has been elucidated: the in vivo exchange of IgG half-molecules (one H-plus one L-chain) among IgG4. This process results in bispecific antibodies that in most situations will behave as functionally monovalent antibodies. The structural basis for the abnormal behaviour of IgG4 seems to be largely the result of a single amino acid change relative to human IgG1: the change of a proline in core hinge of IgG1 to serine. This results in a marked shift in the equilibrium between interchain disulphide bridges and intrachain disulphide bridges, which for IgG4 results in 25-75% absence of a covalent interaction between the H-chains. Because of strong non-covalent interactions between the CH3 domains (and possibly also between the CH1 domain and the trans-CH2 domain) IgG4 is a stable four-chain molecule and does not easily exchange half-molecules under standard physiological conditions in vitro. We postulate that the exchange is catalysed in vivo by protein disulphide isomerase (PDI) and/or FcRn (the major histocompatibility complex (MHC)-related Fc receptor) during transit of IgG4 in the endosomal pathway in endothelial cells. Because IgG4 is predominantly expressed under conditions of chronic antigen exposure, the biological relevance of this exchange of half-molecules is that it generates antibodies that are unable to form large immune complexes and therefore have a low potential for inducing immune inflammation. In contrast to monovalent immunoglobulin fragments, these scrambled immunoglobulins have a normal half-life. The significance of the ensuing bispecificity needs further evaluation, because this will be relevant only in situations where high IgG4 responses are found to two unrelated antigens that happen to be present in the body at the same time and place. In this context the significance of IgG4 autoreactivity might have to be re-evaluated. The main function of IgG4, however, is presumably to interfere with immune inflammation induced by complement-fixing antibodies, or, in the case of helminth infection or allergy, by IgE antibodies.

Critical Role for Tumor Necrosis Factor–related Apoptosis-inducing Ligand in Immune Surveillance Against Tumor Development

Abstract: Natural killer (NK) cells and interferon (IFN)-γ have been implicated in immune surveillance against tumor development. Here we show that tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) plays a critical role in the NK cell–mediated and IFN-γ–dependent tumor surveillance. Administration of neutralizing monoclonal antibody against TRAIL promoted tumor development in mice subcutaneously inoculated with a chemical carcinogen methylcholanthrene (MCA). This protective effect of TRAIL was at least partly mediated by NK cells and totally dependent on IFN-γ. In the absence of TRAIL, NK cells, or IFN-γ, TRAIL-sensitive sarcomas preferentially emerged in MCA-inoculated mice. Moreover, development of spontaneous tumors in p53+/− mice was also promoted by neutralization of TRAIL. These results indicated a substantial role of TRAIL as an effector molecule that eliminates developing tumors.

Identification of Neutralizing and Nonneutralizing Epitopes in the Porcine Reproductive and Respiratory Syndrome Virus GP5 Ectodomain

Abstract: After infection of swine with porcine reproductive and respiratory syndrome virus (PRRSV), there is a rapid rise of PRRSV-specific nonneutralizing antibodies (NNA), while neutralizing antibodies (NA) are detectable not sooner than 3 weeks later. To characterize neutralizing epitopes, we selected phages from a 12-mer phage display library using anti-PRRSV neutralizing monoclonal antibody (MAb) ISU25-C1. In addition, phages carrying peptides recognized by swine antibodies with high seroneutralizing titer were isolated after subtracting from the library those clones binding to swine anti-PRRSV serum with no neutralizing activity. Two epitopes located in the ectodomain of PRRSV GP5 were identified. One of these epitopes, which we named epitope B, was recognized both by neutralizing MAb ISU25-C1 and swine neutralizing serum (NS) but not by swine nonneutralizing serum (NNS), indicating that it is a neutralizing epitope. Epitope B is sequential, conserved among isolates, and not immunodominant. Antibodies directed against it are detected in serum late after infection. In contrast, the other epitope, which we named epitope A, is hypervariable and immunodominant. Antibodies against it appear early after infection with PRRSV. This epitope is recognized by swine NNA but is not recognized by either neutralizing MAb ISU25-C1 or swine NA, indicating that it is not involved in PRRSV neutralization. During infection with PRRSV, epitope A may act as a decoy, eliciting most of the antibodies directed to GP5 and delaying the induction of NA against epitope B for at least 3 weeks. These results are relevant to the design of vaccines against PRRSV.