Biomedical subjects

Taku Okazaki

Publications and source records attributed to Taku Okazaki.

15 recordsLinked to original sources

PubMed2006

The PD-1-PD-L pathway in immunological tolerance.

Since the first observation of spontaneous autoimmune diseases in programmed cell death 1 (PD-1) knockout mice, PD-1 has been postulated to have essential roles in the regulation of autoimmunity but the precise mechanism was largely unknown. Recent studies clearly demonstrated that PD-1 has dual roles in immunological tolerance: induction and maintenance of peripheral tolerance. PD-1 ligands (PD-Ls) on antigen-presenting cells have been shown to switch off autoreactive T cells and induce peripheral tolerance, whereas those on parenchymal cells prevent tissue destruction by suppressing effector T cells to maintain tolerance. In addition, PD-1 and other immuno-inhibitory receptors have been shown to collaborate in the regulation of tolerance. Here, we review recent studies on the role of PD-1 in immunological tolerance and discuss possible clinical applications of PD-1 manipulation.

Animals↗

PubMed2006

Rejuvenating exhausted T cells during chronic viral infection.

In a recent paper in Nature, show that the immunoreceptor PD-1 is upregulated by "exhausted" T cells during the chronic phase of viral infection in mice. Remarkably, blocking the interaction between PD-1 and its ligand, PD-L1, reactivates these T cells and reduces viral load.

Animals↗

PubMed2005

Hydronephrosis associated with antiurothelial and antinuclear autoantibodies in BALB/c-Fcgr2b-/-Pdcd1-/- mice.

Because most autoimmune diseases are polygenic, analysis of the synergistic involvement of various immune regulators is essential for a complete understanding of the molecular pathology of these diseases. We report the regulation of autoimmune diseases by epistatic effects of two immunoinhibitory receptors, low affinity type IIb Fc receptor for IgG (FcgammaRIIB) and programmed cell death 1 (PD-1). Approximately one third of the BALB/c-Fcgr2b(-/-)Pdcd1(-/-) mice developed autoimmune hydronephrosis, which is not observed in either BALB/c-Fcgr2b(-/-) or BALB/c-Pdcd1(-/-) mice. Hydronephrotic mice produced autoantibodies (autoAbs) against urothelial antigens, including uroplakin IIIa, and these antibodies were deposited on the urothelial cells of the urinary bladder. In addition, approximately 15% of the BALB/c-Fcgr2b(-/-)Pdcd1(-/-) mice produced antinuclear autoAbs. In contrast, the frequency of the autoimmune cardiomyopathy and the production of anti-parietal cell autoAb, which were observed in BALB/c-Pdcd1(-/-) mice, were not affected by the additional FcgammaRIIB deficiency. These observations suggest cross talk between two immunoinhibitory receptors, FcgammaRIIB and PD-1, on the regulation of autoimmune diseases.

Animals↗

PubMed2005

Establishment of NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes.

Mice deficient in programmed cell death 1 (PD-1, Pdcd1), an immunoinhibitory receptor belonging to the CD28/cytotoxic T lymphocyte-associated antigen-4 family, spontaneously develop lupus-like autoimmune disease and autoimmune dilated cardiomyopathy on C57BL/6 and BALB/c backgrounds, respectively. However, how PD-1 deficiency induces different forms of autoimmune diseases on these two strains was unknown. Here, we report that PD-1 deficiency specifically accelerates the onset and frequency of type I diabetes in NOD (nonobese diabetic) mice, with strong T helper 1 polarization of T cells infiltrating into islets. These results suggest that PD-1 deficiency accelerates autoimmune predisposition of the background strain, leading to the induction of different forms of autoimmune diseases depending on the genetic background of the strain. Using NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes, we screened diabetes-susceptible loci by genetic linkage analysis. The diabetic incidence of NOD-Pdcd1-/- mice was controlled by five genetic loci, including three known recessive loci [Idd (insulin-dependent diabetes) 1, Idd17, and Idd20] and two previously unidentified dominant loci [Iddp (Idd under PD-1 deficiency) 1 and Iddp2].

Animals↗

PubMed2005

Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4.

T cells recognizing self proteins exist without causing autoimmunity in healthy individuals. These autoreactive T cells are kept in check by peripheral tolerance. Using a model for peripheral CD8(+) T cell tolerance resulting from antigen presentation by resting dendritic cells in vivo, we show here that CD8(+) T cell tolerance operates through T cell-intrinsic mechanisms such as deletion or functional inactivation. Peripheral CD8(+) T cell tolerance depended on signaling via the costimulatory molecule PD-1, as an absence of PD-1 converted tolerance induction into priming. Blocking of the costimulatory molecule CTLA-4 resulted in impaired tolerance and enhanced the effect of the absence of PD-1, suggesting that PD-1 and CTLA-4 act synergistically. Thus PD-1 and CTLA-4 are crucial molecules for peripheral CD8(+) T cell tolerance induced by resting dendritic cells.

Animals↗

PubMed2005

Pathogenic roles of cardiac autoantibodies in dilated cardiomyopathy.

Whether autoimmunity could cause dilated cardiomyopathy (DCM) was disputed for more than half a century. Autoantibodies against various cardiac antigens have been found in the sera of patients with DCM but none of these autoantibodies has been shown to have a substantial role in the development of DCM. It was recently reported that the injection of autoantibodies against cardiac troponin I (cTnI) can induce DCM in normal mice. This observation showed that autoantibodies can cause DCM and put an end to the controversy. Clinical trials of immunoglobulin-adsorption therapy for DCM have already started in Germany and the results seem promising. Here, we discuss the recent findings and possibilities of immunoglobulin-adsorption therapy for this deadly disease.

Animals↗

PubMed2005

PD-1/PD-L pathway and autoimmunity.

Programmed cell death 1 (PD-1) was isolated in 1992 by subtractive-hybridization technique, as a molecule whose expression is enhanced by apoptotic stimuli. Since then we have been analyzing the function of PD-1 in the regulation of immune responses. Generation of PD-1 deficient mice, pathophysiological analyses of autoimmune diseases in PD-1 deficient mice, identification of two ligands, and analyses of downstream events of PD-1 revealed that PD-1 prevents autoimmunity by inhibiting activation of self-reactive lymphocytes. These findings were further applied on human autoimmune diseases and single nucleotide polymorphisms (SNPs) on human PD-1 gene have been reported to link with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and type I diabetes.

Animals↗

PubMed2005

Enhanced expression of programmed death-1 (PD-1)/PD-L1 in salivary glands of patients with Sjögren's syndrome.

OBJECTIVE: Programmed death-1 (PD-1) mediates a negative signal and introduces tolerance for lymphocytes. Dysfunction of the PD-1 pathway is thought to result in autoimmune diseases such as rheumatoid arthritis (RA). To investigate the role of the PD-1/PD-L system in the pathology of Sjögren's syndrome (SS), we examined the expression of PD-1 and its ligand PD-L1 in salivary lymphocytes and salivary glands from patients with SS. METHODS: Flow cytometry analysis was used to determine expression of PD-1 in SS salivary lymphocytes. Intracellular staining of interleukin 10 (IL-10) was performed after stimulation with PMA and ionomycin. Indirect immunohistochemistry was used to investigate the expression of PD-1 and PD-L1. RESULTS: The mean fluorescence intensity of PD-1 expression in SS salivary lymphocytes was significantly higher than that from healthy controls and patients with RA or systemic lupus erythematosus. PD-1-positive SS salivary lymphocytes expressed IL-10 intracellularly upon PMA/ionomycin stimulation. Immunohistochemical analysis showed that PD-1 was expressed on infiltrating lymphocytes in salivary gland from 52% of SS patients, and PD-L1 was expressed on ductal and acinar epithelial cells from 68% of SS patients. In vitro analysis using HSG cells revealed that PD-L1 was induced by interferon-gamma but not by tumor necrosis factor-alpha and IL-1beta. CONCLUSION: PD-1 is expressed on T lymphocytes and PD-L1 on epithelial cells from inflamed salivary glands of patients with SS, which suggests that dysfunction of the PD-1/PD-L1 pathway may be related to tolerance for lymphocytes, which causes SS.

Antigens, CD↗

PubMed2003

Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice.

We recently reported that mice deficient in the programmed cell death-1 (PD-1) immunoinhibitory coreceptor develop autoimmune dilated cardiomyopathy (DCM), with production of high-titer autoantibodies against a heart-specific, 30-kDa protein. In this study, we purified the 30-kDa protein from heart extract and identified it as cardiac troponin I (cTnI), encoded by a gene in which mutations can cause familial hypertrophic cardiomyopathy (HCM). Administration of monoclonal antibodies to cTnI induced dilatation and dysfunction of hearts in wild-type mice. Monoclonal antibodies to cTnI stained the surface of cardiomyocytes and augmented the voltage-dependent L-type Ca2+ current of normal cardiomyocytes. These findings suggest that antibodies to cTnI induce heart dysfunction and dilatation by chronic stimulation of Ca2+ influx in cardiomyocytes.

Animals↗

PubMed2003

PD-1 inhibits antiviral immunity at the effector phase in the liver.

Unlike naive T cells, effector T cells can be activated by either T cell receptor signal or costimulatory signal alone and therefore the absence of costimulatory molecules on tissue cells cannot explain the tolerance mechanism at the effector phase. Here we report that PD-L1, the ligand for the immunoinhibitory receptor PD-1, was expressed on vascular endothelium in peripheral tissues. Liver nonparenchymal cells including sinusoidal endothelial cells and Kupffer cells constitutively expressed PD-L1 and inhibited proliferation and cell division of activated T cells expressing PD-1. The absence of PD-1 induced proliferation of effector T cells in the adenovirus-infected liver and resulted in rapid clearance of the virus. These results indicate that PD-1 plays an important role in T cell tolerance at the effector phase and the blockade of the PD-1 pathway can augment antiviral immunity.

Animals↗

PubMed2002

Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues.

PD-1 is a member of the immunoglobulin superfamily expressed on immune cells, including T and B cells, and is involved in the delivery of inhibitory signal upon engagement of its ligands, PD-L1 and PD-L2. While the expression profile of PD-1 has been well documented, the analysis of PD-L1 and PD-L2 distributions on a protein basis has not been carried out because of the lack of available monoclonal antibodies specific for the molecules. In this study, we established two monoclonal antibodies, 1-111A and 122, specific for murine PD-L1 and PD-L2, respectively, and examined their expression profiles. Based on flow cytometric analyses, the expression of PD-L1 was detected in a variety of lymphohematopoietic cell types, including a minor proportion of T and B cells in the spleen, majority of pre-B cells and myeloid cells in bone marrow and subsets of thymocytes, while the expression of PD-L2 was not observed in the lymphohematopoietic cells at all. Notably, a significant proportion of the most immature lineage-marker-negative and c-Kit-positive bone marrow cells containing stem cells did express PD-L1. Following mitogenic stimulation, essentially all lymphocytes expressed PD-L1. Furthermore, a variety of leukemic lines also expressed PD-L1, while none of them did PD-L2. Thus, present results demonstrate the distinct expression patterns of PD-L1 and PD-L2 with the cells of lymphohematopoietic tissues exclusively expressing the former.

Animals↗

PubMed2002

Microanatomical localization of PD-1 in human tonsils.

PD-1 is an immunoinhibitory receptor, which belongs structurally to the CD28 family. PD-1-deficient mice show breakdown of peripheral tolerance and manifest multiple autoimmune symptoms. We previously described expression of PD-1 on activated T and B lymphocytes and myeloid cells. However, little is known about the microanatomical distribution of PD-1 in lymphoid organs. In this study, we performed immunohistochemistry using monoclonal antibodies against human PD-1. In human tonsils, PD-1 was expressed on most of T cells and a small subset of centrocytes in the light zone of germinal centers (GCs), where clonal selection of centrocytes takes place. These results suggest that PD-1 may play an important role in GC reaction.

Adolescent↗

PubMed2002

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

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.

Animals↗

PubMed2002

New regulatory co-receptors: inducible co-stimulator and PD-1.

Autoreactive lymphocytes are suppressed in healthy individuals by so-called peripheral tolerance. Accumulating evidence indicates that co-receptor signaling plays a pivotal role in the regulation of autoreactive lymphocytes. The positive regulatory co-receptors CD28 and inducible co-stimulator (ICOS) transduce stimulatory cosignals, whereas the negative regulatory co-stimulators CTLA-4 and PD-1 are critical for the regulation of peripheral tolerance and autoimmunity. PD-1 deficient mice develop lupus-like glomerulonephritis and arthritis on a C57Bl/6 background and autoimmune-dilated cardiomyopathy on a BALB/c background.

Abatacept↗

PubMed2002

DCIR acts as an inhibitory receptor depending on its immunoreceptor tyrosine-based inhibitory motif.

Major histocompatibility complex class II positive cells, namely dendritic cells, monocytes/macrophages, and B cells, are categorized as antigen-presenting cells. Dendritic cells, so-called professional antigen-presenting cells, use distinct sets of surface receptors before and after maturation: those to capture antigens and those to interact with T cells, respectively. But there remain many surface molecules whose functions are still unknown. In this study, we isolated dendritic cell immunoreceptor from mouse bone-marrow-derived mature dendritic cells. Dendritic cell immunoreceptor is a recently reported C-type lectin receptor characteristic with cytoplasmic immunoreceptor tyrosine-based inhibitory motif. Expression of mouse dendritic cell immunoreceptor mRNA was observed specifically in spleen and lymph node, slightly increased with dendritic cell maturation during in vitro culture of bone marrow cells, and was not detected in cultured natural killer cells. Surface expression of mouse dendritic cell immunoreceptor protein was observed in splenic antigen-presenting cells including B cells, monocytes/macrophages, and dendritic cells, but not in T cells. To reveal the downregulating capacity of dendritic cell immunoreceptor in antigen-presenting cells, the change of B-cell-receptor-mediated signals after coligation with a chimeric Fcgamma receptor IIB containing the cytoplasmic portion of mouse dendritic cell immunoreceptor was examined. As a result, we detected two distinct inhibitory effects of cytoplasmic dendritic cell immunoreceptor minus sign inhibition of B-cell-receptor-mediated Ca2+ mobilization and protein tyrosine phosphorylation minus sign and both of these effects required the tyrosine residue inside the immunoreceptor tyrosine-based inhibitory motif. This report presents immunoreceptor tyrosine-based inhibitory motif-dependent negative regulatory function of dendritic cell immunoreceptors. In conclusion, mouse dendritic cell immunoreceptor expressed on antigen-presenting cells can exert two distinct inhibitory signals depending on its immunoreceptor tyrosine-based inhibitory motif tyrosine residue.

Amino Acid Motifs↗