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  • 机译 口服免疫疗法:通过肠道免疫系统靶向全身免疫系统治疗炎性肠病
    • 作者:Yaron Ilan
    • 刊名:Clinical Translational Immunology
    • 2016年第1期
    摘要:Inflammatory bowel diseases (IBD) are associated with an altered systemic immune response leading to inflammation-mediated damage to the gut and other organs. Oral immune therapy is a method of systemic immune modulation via alteration of the gut immune system. It uses the inherit ability of the innate system of the gut to redirect the systemic innate and adaptive immune responses. Oral immune therapy is an attractive clinical approach to treat autoimmune and inflammatory disorders. It can induce immune modulation without immune suppression, has minimal toxicity and is easily administered. Targeting the systemic immune system via the gut immune system can serve as an attractive novel therapeutic method for IBD. This review summarizes the current data and discusses several examples of oral immune therapeutic methods for using the gut immune system to generate signals to reset systemic immunity as a treatment for IBD.
  • 机译 单核细胞/巨噬细胞发育,活化和代谢中的组蛋白脱乙酰基酶:改善炎症和传染性疾病的HDAC靶标
    摘要:Macrophages have central roles in danger detection, inflammation and host defense, and consequently, these cells are intimately linked to most disease processes. Major advances in our understanding of the development and function of macrophages have recently come to light. For example, it is now clear that tissue-resident macrophages can be derived from either blood monocytes or through local proliferation of phagocytes that are originally seeded during embryonic development. Metabolic state has also emerged as a major control point for macrophage activation phenotypes. Herein, we review recent literature linking the histone deacetylase (HDAC) family of enzymes to macrophage development and activation, particularly in relation to these recent developments. There has been considerable interest in potential therapeutic applications for small molecule inhibitors of HDACs (HDACi), not only for cancer, but also for inflammatory and infectious diseases. However, the enormous range of molecular and cellular processes that are controlled by different HDAC enzymes presents a potential stumbling block to clinical development. We therefore present examples of how classical HDACs control macrophage functions, roles of specific HDACs in these processes and approaches for selective targeting of drugs, such as HDACi, to macrophages. Development of selective inhibitors of macrophage-expressed HDACs and/or selective delivery of pan HDACi to macrophages may provide avenues for enhancing efficacy of HDACi in therapeutic applications, while limiting unwanted side effects.
  • 机译 人类树突状细胞群体表型的新见解
    摘要:HLDA10 is the Tenth Human Leukocyte Differentiation Antigen (HLDA) Workshop. The HLDA Workshops provide a mechanism to allocate cluster of differentiation (CD) nomenclature by engaging in interlaboratory studies. As the host laboratory, we invited researchers from national and international academic and commercial institutions to submit monoclonal antibodies (mAbs) to human leukocyte surface membrane molecules, particularly those that recognised molecules on human myeloid cell populations and dendritic cells (DCs). These mAbs were tested for activity and then distributed as a blinded panel to 15 international laboratories to test on different leukocyte populations. These populations included blood DCs, skin-derived DCs, tonsil leukocytes, monocyte-derived DCs, CD34-derived DCs, macrophage populations and diagnostic acute myeloid leukaemia and lymphoma samples. Each laboratory was provided with enough mAb to perform five repeat experiments. Here, we summarise the reactivity of different mAb to 68 different cell-surface molecules expressed by human myeloid and DC populations. Submitted mAbs to some of the molecules were further validated to collate data required to designate a formal CD number. This collaborative process provides the broader scientific community with an invaluable data set validating mAbs to leukocyte-surface molecules.
  • 机译 与染色体1q42.1-q42.3的微缺失和肌醇1,4,5-三磷酸激酶B(ITPKB)缺乏相关的常见可变免疫缺陷
    摘要:Common variable immunodeficiency (CVID) is a heterogenous disorder characterized by hypogammaglobulinemia and impaired specific antibody response and increased susceptibility to infections, autoimmunity and malignancies. A number of gene mutations, including ICOS, TACI and BAFF-R, and CD19, CD20, CD21, CD81, MSH5 and LRBA have been described; however, they account for approximately 20–25% of total cases of CVID. In this study, we report a patient with CVID with an intrinsic microdeletion of chromosome 1q42.1-42.3, where gene for inositol 1,3,4, trisphosphate kinase β (ITPKB) is localized. ITPKB has an important role in the development, survival and function of B cells. In this subject, the expression of ITPKB mRNA as well as ITKPB protein was significantly reduced. The sequencing of ITPKB gene revealed three variants, two of them were missense variants and third was a synonymous variant; the significance of each of them in relation to CVID is discussed. This case suggests that a deficiency of ITPKB may have a role in CVID.
  • 机译 1型糖尿病的Treg激活缺陷:TNFR2激动剂的校正
    摘要:Activated T-regulatory cells (aTregs) prevent or halt various forms of autoimmunity. We show that type 1 diabetics (T1D) have a Treg activation defect through an increase in resting Tregs (rTregs, CD4+CD25+Foxp3+CD45RA) and decrease in aTregs (CD4+CD25+Foxp3+CD45RO) (n= 55 T1D, n=45 controls, P=0.01). The activation defect persists life long in T1D subjects (T1D=45, controls=45, P=0.01, P=0.04). Lower numbers of aTregs had clinical significance because they were associated with a trend for less residual C-peptide secretion from the pancreas (P=0.08), and poorer HbA1C control (P=0.03). In humans, the tumor necrosis factor receptor 2 (TNFR2) is obligatory for Treg induction, maintenance and expansion of aTregs. TNFR2 agonism is a method for stimulating Treg conversion from resting to activated. Using two separate in vitro expansion protocols, TNFR2 agonism corrected the T1D activation defect by triggering conversion of rTregs into aTregs (n=54 T1D, P<0.001). TNFR2 agonism was superior to standard protocols and TNF in proliferating Tregs. In T1D, TNFR2 agonist-expanded Tregs were homogeneous and functionally potent by virtue of suppressing autologous cytotoxic T cells in a dose-dependent manner comparable to controls. Targeting the TNFR2 receptor for Treg expansion in vitro demonstrates a means to correct the activation defect in T1D.
  • 机译 HLDA10单克隆抗体组对人单核细胞及其衍生的巨噬细胞和树突状细胞亚群的分化
    摘要:The mononuclear phagocyte system, consisting of monocytes, macrophages and dendritic cells (DCs), has an important role in tissue homeostasis as well as in eliciting immune responses against invading pathogens. Blood monocytes have been viewed for decades as precursors of tissue macrophages. Although the newest data show that in the steady state resident macrophages of many organs are monocyte independent, blood monocytes critically contribute to tissue macrophage and DC pools upon inflammation. To better understand the relationship between these populations and their phenotype, we isolated and differentiated human blood CD14+ monocytes in vitro into immature and mature monocyte-derived dendritic cells (MoDCs) as well as into seven different monocyte-derived macrophage subsets. We used the panel of 70 monoclonal antibodies (mAbs) submitted to the 10th Human Leukocyte Differentiation Antigen Workshop to determine the expression profiles of these 10 populations by flow cytometry. We now can compile subpanels of mAbs to differentiate the 10 monocyte/macrophage/MoDC subsets, providing the basis for novel diagnostic and therapeutic tools.
  • 机译 重新思考胆红素在病毒性肝炎中的免疫特性:从板凳到床边
    摘要:Communication between the immune system and metabolic components can be exemplified by the process of heme catabolism. The immunomodulatory functions of the enzymes, substrates and active products related to catabolism of the heme group have been extensively studied. Bilirubin (BR), the final breakdown product of heme, is primarily considered to be a toxic waste product but has recently been considered to be an immunomodulatory metabolite. Through mechanisms that include intracellular signaling and transcriptional control, BR affects those immune cell functions that regulate cell proliferation, differentiation and apoptosis. During the pathogenesis of viral hepatitis, the heme degradation pathway is disrupted, resulting in changes to normal BR concentrations. These alterations have been previously studied mainly as a consequence of the infection. However, little is known about the potential immunomodulatory role played by BR in the development of infectious hepatocellular diseases. Differences in BR levels in the context of viral hepatitis are likely to provide important insights into the metabolite-mediated mechanisms controlling the immune responses underlying both the long-term persistence of hepatitis C virus (HCV) infection and the resolution of hepatitis A virus (HAV) infection during the acute phase. In this review, the cross-talk between heme catabolism and immune function is described in detail. Special emphasis is given to discoveries that hold promise for identifying immunologic features of metabolic products in the resolution of viral diseases.
  • 机译 HIV阳性妇女的免疫细胞中的α7烟碱受体上调:对胆碱能抗炎反应的影响
    摘要:Antiretroviral therapy partially restores the immune system and markedly increases life expectancy of HIV-infected patients. However, antiretroviral therapy does not restore full health. These patients suffer from poorly understood chronic inflammation that causes a number of AIDS and non-AIDS complications. Here we show that chronic inflammation in HIV+ patients may be due to the disruption of the cholinergic anti-inflammatory pathway by HIV envelope protein gp120IIIB. Our results demonstrate that HIV gp120IIIB induces α7 nicotinic acetylcholine receptor (α7) upregulation and a paradoxical proinflammatory phenotype in macrophages, as activation of the upregulated α7 is no longer capable of inhibiting the release of proinflammatory cytokines. Our results demonstrate that disruption of the cholinergic-mediated anti-inflammatory response can result from an HIV protein. Collectively, these findings suggest that HIV tampering with a natural strategy to control inflammation could contribute to a crucial, unresolved problem of HIV infection: chronic inflammation.
  • 机译 透明质酸在肿瘤血管生成中的免疫学作用
    摘要:The relationship between the immune system and angiogenesis has been described in several contexts, both in physiological and pathological conditions, as pregnancy and cancer. In fact, different types of immune cells, such as myeloid, macrophages and denditric cells, are able to modulate tumor neovascularization. On the other hand, tumor microenvironment also includes extracellular matrix components like hyaluronan, which has a deregulated synthesis in different tumors. Hyaluronan is a glycosaminoglycan, normally present in the extracellular matrix of tissues in continuous remodeling (embryogenesis or wound healing processes) and acts as an important modulator of cell behavior by different mechanisms, including angiogenesis. In this review, we discuss hyaluronan as a modulator of tumor angiogenesis, focusing in intracellular signaling mediated by its receptors expressed on different immune cells. Recent observations suggest that the immune system is an important component in tumoural angiogenesis. Therefore, immune modulation could have an impact in anti-angiogenic therapy as a new therapeutic strategy, which in turn might improve effectiveness of treatment in cancer patients.
  • 机译 合成抗环状瓜氨酸肽抗体的研制及其致关节炎作用
    摘要:This study was undertaken to develop a novel anti-citrullinated peptide antibody (ACPA) and to investigate its arthritogenicity in a collagen-induced arthritis (CIA) model. The novel ACPA, 12G1, was developed by injecting cyclic citrullinated antigen in mice and subsequently hybridizing the B cells producing citrullinated peptide-specific antibodies with a myeloma cell line. The arthritic joints of mice with CIA and collagen antibody-induced arthritis (CAIA) as well as interleukin-1 receptor antagonist (IL-1Ra) knockout (KO) mice were stained immunohistochemically using the 12G1 antibody. Confocal immunostaining was used to identify colocalization of 12G1 with various citrullinated proteins. 12G1 in the presence or absence of chelating beads was administered to CIA mice on days 21 and 28 after type II collagen (CII) immunization to investigate 12G1 arthritogenecity. 12G1 detected citrullinated proteins in the arthritic joints of all the experimental arthritis models used. Confocal immunostaining showed that 12G1 was colocalized with well-known citrullinated proteins, including vimentin, collagen, anti-immunoglobulin binding protein and fibronectin. Staining of citrullinated proteins using 12G1 was more diffuse in CIA mice compared with CAIA and IL-1Ra KO mice. 12G1 injection apparently acted as a booster of immunization in CIA mice in combination with a single CII immunization, with this effect being abolished when 12G1 was injected with chelating beads. The novel ACPA, 12G1, identified various citrullinated proteins in the arthritic joints of three experimental arthritis models. 12G1-treated mice developed arthritis following a single CII immunization, suggesting an arthritogenic potential for ACPA in CIA mice.
  • 机译 使用澳大利亚卧龙岗市HLDA10研讨会的单克隆抗体对原代外周血和单核细胞来源的树突状细胞进行分析
    摘要:Dendritic cells (DCs) arise from hematopoietic stem cells and develop into a discrete cellular lineage distinct from other leucocytes. Mainly three phenotypically and functionally distinct DC subsets are described in the human peripheral blood (PB): plasmacytoid DCs (pDCs), which express the key marker CD303 (BDCA-2), and two myeloid DC subsets (CD1c+ DC (mDC1) and CD141+ DC (mDC2)), which express the key markers CD1c (BDCA-1) and CD141 (BDCA-3), respectively. In addition to these primary cell subsets, DCs can also be generated in vitro from either CD34+ stem/progenitor cells in the presence of Flt3 (Fms-related tyrosine kinase 3) ligand or from CD14+ monocytes (monocyte-derived DCs (mo-DCs)) in the presence of granulocyte–macrophage colony-stimulating factor+interleukin-4 (GM-CSF+IL-4). Here we compare the reactivity patterns of HLDA10 antibodies (monoclonal antibody (mAb)) with pDCs, CD1c+ DCs and CD141+ DCs, as well as with CD14+-derived mo-DCs cultured for 7 days in the presence of 100 ng/ml GM-CSF plus 20 ng/ml IL-4. A detailed profiling of these DC subsets based on immunophenotyping and multicolour flow cytometry analysis is presented. Using the panel of HLDA10 Workshop mAb, we could verify known targets selectively expressed on discrete DC subsets including CD370 as a selective marker for CD141+ DCs and CD366 as a marker for both myeloid subsets. In addition, vimentin and other markers are heterogeneously expressed on all three subsets, suggesting the existence of so far not identified DC subsets.
  • 机译 在严重恶性疟疾中,GATA3和T-bet的低表达与IL-10的下调相关
    摘要:Interleukin (IL)-10, a non-redundant anti-inflammatory cytokine is produced by different cells and its production involves activation of cell-specific transcriptional regulatory machinery in response to specific pathogen. We have previously demonstrated downregulated levels of IL-10 in severe falciparum malaria. The present study investigated transcriptional regulation of IL-10 in severe malaria. Comparative expression analysis of cell-specific signalling proteins and transcription factors for IL-10 production during the stage of active infection and with resolution of parasitaemia was performed. Interestingly, T-bet and GATA3, the Th1 and Th2 transcription factors, respectively, were downregulated in severe malaria with fold change values of 0.59 and 0.86. Increase in the levels of both the factors with resolution of parasitaemia implicated a role for parasite in depressed levels of these factors. Further support for probable parasite manipulation of GATA3 was obtained from negative correlation of GATA3 with parasitaemia. In addition, a role for interferon-α in suppressing IL-10 transcription was evident from its negative correlation with GATA3 and IL-10 levels. In summary, IL-10 transcription in Th1 and Th2 is defective and appears to have major contribution to low levels in severe malaria.
  • 机译 鼻病毒刺激IFN-α产生:浆细胞样DC,单核细胞和内体pH值有多重要?
    摘要:Human rhinovirus (HRV) infection is a major cause of asthma exacerbations, which appears to be linked to a defective innate immune response to infection. Although the type I interferons (IFN-α and IFN-β) have a critical role in protecting against most viral infections, the cells responsible for IFN production in response to HRV and the relative importance of pattern recognition receptors located in endosomes has not been fully elucidated. In the current study we demonstrate that, using intracellular flow cytometry, >90% of the IFN-α-producing cells in human blood mononuclear cells following HRV16 exposure are plasmacytoid dendritic cells, whereas monocytes and myeloid dendritic cells contribute only 10% and <1%, respectively, of the IFN-α production. Bafilomycin and chloroquine, agents that inhibit the function of endosomal toll-like receptors (TLRs), significantly reduced the capacity of TLR3-, TLR7- and TLR-9-stimulated cells to produce IFN-α and the IFN-induced chemokine CXCL10 (IP-10). In contrast, only bafilomycin (but not chloroquine) effectively suppressed HRV16-stimulated IFN-α and IP-10 production, whereas neither bafilomycin or chloroquine inhibited HRV16-stimulated interleukin-6 release. Attempts to block IFN-α production with commercially available TLR-specific oligonucleotides were unsuccessful due to major ‘off-target' effects. These findings suggest that among circulating haemopoietic cells, plasmacytoid dendritic cells and TLRs located within endosomes are critical for inducing efficient IFN-I production in response to HRVs.
  • 机译 第十届HLDA Workshop抗体小组对人胸腺树突状细胞表面分子的表达分析
    摘要:Dendritic cells (DC) in the thymus have an important role in the establishment of central tolerance by promoting negative selection of autoreactive T cells and regulatory T-cell differentiation. Whereas human DC have recently been studied in various tissues in more detail, thymic DC subsets are still ill-defined. In the present work, we studied the binding of 71 monoclonal antibodies (mAb) submitted to the HLDA10 workshop to human CD123+ plasmacytoid DC and the two subsets of conventional DC (cDC, CD141+ and CD11b+) isolated from thymus tissue of infants undergoing corrective heart surgery. Within the panel, we found mAb binding to thymic pDC and both cDC subsets (for example, anti-Clec12A, TIM-3, Clec4A, CCR5, Axl, FLT3), but most of them additionally reacted with other thymic cell types. MAb directed to CD85h (ILT1) and the C-type lectin Clec7A (now CD369) reacted selectively with both cDC subsets, but not with other cells. Only one mAb directed to CD85g (ILT7) stained thymic pDC in a highly specific manner. Clec9A (DNGR1, now CD370) was the only tested HLDA10 antigen exclusively expressed on thymic CD141+ cDC. The present report summarizes all data obtained.
  • 机译 基因组医学时代的医学病例报告
    • 作者:Matthew C Cook
    • 刊名:Clinical Translational Immunology
    • 2015年第10期
    摘要:The case report has been a pillar of medical literature but has been displaced recently because of inherent risks of bias. As we move towards precision medicine, however, the case report format could provide an important method for describing disease mechanisms based on rare genetic variants. Empirical evidence reveals that many previously unexplained Mendelian diseases are accounted for by rare heterozygous alleles, de novo mutations or compound heterozygous mutations, and that disease-associated variants are often confined to the kindred of the affected individual. Elucidation of the phenotypes of these rare genetic variants will necessarily offer unique insights into disease mechanisms. Even when the association between variants in a specific gene and a disease has already been identified, individual cases are valuable. Allelic series extend both the clinical and laboratory phenotypes. Finally, the prevalence of a disease is not a reliable indicator of the therapeutic importance of the underlying mechanism, so resolving extreme phenotypes even in single cases has the potential to identify new treatment strategies relevant to more common disease.
  • 机译 阻止HIV-1在女性生殖道中的传播:从杀菌剂的开发到探索局部抗病毒反应
    摘要:The majority of new HIV-1 infections are transmitted sexually by penetrating the mucosal barrier to infect target cells. The development of microbicides to restrain heterosexual HIV-1 transmission in the past two decades has proven to be a challenging endeavor. Therefore, better understanding of the tissue environment in the female reproductive tract may assist in the development of the next generation of microbicides to prevent HIV-1 transmission. In this review, we highlight the important factors involved in the heterosexual transmission of HIV-1, provide an update on microbicides' clinical trials, and discuss how different delivery platforms and local immunity may empower the development of next generation of microbicide to block HIV-1 transmission in the female reproductive tract.
  • 机译 静脉免疫球蛋白中穿透细胞的抗体的免疫学证据和调节潜力
    摘要:Anti-DNA cell-penetrating autoantibodies have been extensively studied in autoimmune but not in normal sera. We investigated herein the presence and properties of cell-penetrating antibodies (CPAbs) in intravenous immunoglobulin (IVIg), a blood product of pooled normal human IgG. IVIg cell penetration was observed into various cell lines, as well as cells from several organs of mice injected intravenously with IVIg therapeutic dose. In all cell types examined in vitro and in vivo, intracellular IgG localized in the cytoplasm, in contrast to the nuclear accumulation of disease-related CPAbs. IVIg was found to rapidly enter cells via an energy-independent mode. The CPAb-fraction was isolated and found to be polyreactive to nuclear and cytoplasmic components; although it corresponded to ~2% of IVIg, it accounted for its inhibitory effect on splenocyte activation. Investigation of IVIg cell penetration capacity provides insight into its mechanisms of action and may account for some of its beneficial effects in numerous diseases.
  • 机译 对糖尿病前期小鼠进行基因表达谱分析以发现可用于1型糖尿病的临床药物
    摘要:In the NOD mouse model of type 1 diabetes (T1D), genetically identical mice in the same environment develop diabetes at different rates. Similar heterogeneity in the rate of progression to T1D exists in humans, but the underlying mechanisms are unclear. Here, we aimed to discover peripheral blood (PB) genes in NOD mice predicting insulitis severity and rate of progression to diabetes. We then wished to use these genes to mine existing databases to identify drugs effective in diabetes. In a longitudinal study, we analyzed gene expression in PB samples from NOD.CD45.2 mice at 10 weeks of age, then scored pancreatic insulitis at 14 weeks or determined age of diabetes onset. In a multilinear regression model, Tnf and Tgfb mRNA expression in PB predicted insulitis score (R2=0.56, P=0.01). Expression of these genes did not predict age of diabetes onset. However, by expression-profiling PB genes in 10-week-old NOD.CD45.2 mice, we found a signature of upregulated genes that predicted delayed or no diabetes. Major associated pathways included chromatin organization, cellular protein location and regulation of nitrogen compounds and RNA. In a clinical cohort, three of these genes were differentially expressed between first-degree relatives, T1D patients and controls. Bioinformatic analysis of differentially expressed genes in NOD.CD45.2 PB identified drugs that are predicted to delay or prevent diabetes. Of these drugs, 11 overlapped with drugs predicted to induce a human ‘non-progressor' expression profile. These data demonstrate that disease heterogeneity in diabetes-prone mice can be exploited to mine novel clinical T1D biomarkers and drug targets.
  • 机译 血液病患者真菌感染的过继T细胞疗法
    摘要:The prolonged immune deficiency resulting from haematopoietic stem cell transplant and chemotherapy predisposes to a high risk of invasive fungal infections. Despite the recent advances in molecular diagnostic testing, early initiation of pre-emptive antifungal therapy and the use of combination pharmacotherapy, mortality from invasive mould infections remain high among recipients of allogeneic stem cell transplant. The increasing incidences of previously rare and drug-resistant strains of fungi present a further clinical challenge. Therefore, there is a need for novel strategies to combat fungal infections in the immunocompromised. Adoptive therapy using in vitro-expanded fungus-specific CD4 cells of the Th-1 type has shown clinical efficacy in murine studies and in a small human clinical study. Several techniques for the isolation and expansion of fungus-specific T cells have been successfully applied. Here we discuss the incidence and changing patterns of invasive fungal diseases, clinical evidence supporting the role of T cells in fungal immunity, methods to expand fungus-specific T cells in the laboratory and considerations surrounding the use of T cells for fungal immunotherapy.

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