Induction and kinetics of natural killer cells in humans following interferon therapy

Natural killer (NK) cells are non-B, non-T lymphocytes that effect spontaneous cytolysis of both virus-infected and neoplastically transformed target cells. These NK lymphocytes have been detected in several species including man. Interferon is a primary regulator of natural killer activity. Because NK cells have been implicated in the regulation of tumour cell expression and can be induced by interferon in murine models, we have studied patients receiving large doses of interferon to determine (1) whether interferon could induce NK lymphocytes in the peripheral blood of man, and (2) whether there are characteristic kinetics for the appearance, disappearance and reactivation of NK lymphocytes following interferon therapy. We report here the activation of human NK cells by the systemic inoculation of human subjects with interferon. Five patients received interferon as therapy for non-Hodgkin's lymphoma. All showed a marked increase in NK cell activity 12--24 h after inoculation. Peak NK activity occurred 18 h after introducing interferon, and thereafter declined rapidly but remained above pre-interferon levels. Induced NK activity occurred with reintroduction of interferon but at lower levels of activity and with different kinetics.     

博来霉素A5和异博定联合用药对小鼠免疫功能的影响

研究了博来霉素A_5和异博定联合用药对小鼠免疫功能的影响,包括迟发型超敏反应、抗体产生、血液循环系统中~(51)Cr标记的绵羊红细胞的清除、淋巴细胞转化实验、白细胞介素2的产生以及免疫器官的重量等指标。实验证实5mg/kg博来霉素A_5明显抑制迟发型超敏反应、DTH反应、血液循环中~5 Cr标记的绵羊红细胞清除和小鼠胸、脾重量。40mg/kg异博定只明显地抑制DTH反应和降低小鼠胸、脾重量。联合用药更大程度地抑制由5mg/kg博来霉素A_5引起的免疫抑制反应,但联合用药能进一步促进白细胞介素2的产生。     

Preferential effect of gamma interferon on the synthesis of HLA antigens and their mRNAs in human cells

Interferons produce a variety of biological effects on cells. They induce resistance to virus proliferation, inhibit cell growth, modify cell structure and differentiation, stimulate some immune functions and inhibit others. However, the different interferon (IFN) species may vary in their mechanism of action and, hence, in their relative efficiency for inducing each of the effect. IFN-gamma (type II) appears to show stronger immunoregulatory and growth inhibitory effects than antiviral effects, but this conclusion has been challenged in other reports. The aim of the present work is to compare the action of IFN-gamma and other (type I) interferons on the induction of (2'-5') oligo(A) synthetase which is probably part of the antiviral response and the induction of the histocompatibility HLA-A,-B,-C antigens. We have shown previously that the induction of both proteins is regulated by interferons at the mRNA level, but show here that IFN-gamma from stimulated human lymphocytes and from monkey cells transfected by cloned human IFN-gamma cDNA induced the HLA-A,-B,-C and beta 2-microglobulin mRNAs or proteins at concentrations over 100 times lower than those needed to induce the (2'-5')oligo(A) synthetase and the antiviral state. This difference was not found with IFN-alpha and -beta (type I).     

IRF7表达与系统性红斑狼疮的相关性

探讨了干扰素调节因子7(IRF7)的表达与中国汉族人群系统性红斑狼疮(SLE)的相关性.运用实时荧光定量聚合酶链式反应的方法分别测定疾病患者与正常对照组外周血IRF7mRNA的表达水平,并与血清中干扰素水平、干扰素积分以及SLEDAI积分作相关性分析.结果发现,患者外周血IRF7mRNA的表达水平较正常对照组的明显增高,且其与血清中干扰素水平、干扰素积分以及SLEDAI积分均呈正相关.由此可知,IRF7表达的增高可能促使干扰素通路异常激活,从而导致系统性红斑狼疮的发生.     

Interferon inhibits transformation by murine sarcoma viruses before integration of provirus

Neoplastic transformation by C-type retroviruses requires synthesis of a DNA copy (the provirus) of the RNA genome and its integration into the host cell DNA. We have previously shown that interferon (IFN) can stably prevent transformation of murine fibroblasts by the Kirsten strain of murine sarcoma virus (KiMSV), a murine leukaemia virus (MLV). A series of cell clones (IFN clones), isolated in the presence of IFN (10(4) U ml-1) from cultures of NIH-3T3 cells which had been treated with IFN, and then infected with KiMSV (KiMLV) in conditions where every cell was infected, were shown to be phenotypically untransformed. These untransformed cells did not produce virus or contain rescuable KiMSV. However, cells isolated using an identical procedure, but in the absence of IFN, were uniformly transformed and all produced KiMSV (KiMLV) or contained rescuable KiMSV. It was concluded that IFN either prevents synthesis or integration of the provirus, or else that in the presence of IFN the provirus is integrated such that it is not expressed. We now show that five representative clones contain no detectable KiMSV proviral DNA, and also that the initial stages of infection by KiMSV (KiMLV) are inhibited by IFN treatment. IFN seems to act before integration, preventing either the synthesis or the integration of proviral DNA.     

Interferon-neutralizing antibodies in a patient treated with human fibroblast interferon

During recent years clinical trials have shown that human leukocyte interferon (HuIFN-alpha) may be useful in the treatment of cancer, but very little has been done concerning the possible use of human fibroblast interferon (HuIFN-beta). Treuner et al. recently reported the successful treatment of a nasopharyngeal carcinoma with HuIFN-beta: in the course of IFN-therapy a HuIFN-beta neutralizing activity appeared in the serum of this patient. We report here that such activity is due to IgG antibodies--this study is the first to present evidence for antigenicity of IFN in a homologous system.     

Interferon-dependent induction of mRNA activity for (2'-5')oligo-isoadenylate synthetase

At least three different enzymes involved in the regulation of protein synthesis are induced in a variety of cells by interferon (IFN). Sensitive assays for these enzymes have been developed and used to establish the specificity, dose dependence and time course of their induction by IFN. One of these enzymes, the oligo-isoadenylate synthetase E, whose product (2'-5')pppApApA activates the latent ribonuclease F, is increased over 50-fold after IFN treatment. We describe here the assay for an mRNA from IFN-treated mouse L cells, that produces oligo-isoadenylate synthetase activity when injected into Xenopus oocytes. This mRNA is found in the cells only after exposure to IFN. The mRNA increases in mouse L cells with the same time course as the enzyme activity itself. In particular, there is a 3-h lag period between IFN addition and the onset of enzyme and mRNA accumulation. Using anti-IFN antibodies, we show that during this lag period the continued interaction of IFN with the cells is necessary for the full induction of the oligo-isoadenylate synthetase.     

Effect of human interferon preparations on lymphoblastogenesis in Down's syndrome

The best characterised properties of human interferon, its antiviral (AV) and cell multiplication inhibitory (CMI) activities, are controlled, in an unexplained manner, by genes on chromosomes 21 (refs 1-4; 14-16). Human and animal interferons have various immunosuppressive effects, among them the inhibition in vitro of DNA synthesis in activated lymphocytes. Using mitogen- and antigen-stimulated lymphocytes from normal subjects (disomic 21) and others with Down's syndrome (trisomic 21), we have found that DNA synthesis is inhibited to a greater degree in the latter by both fibroblastoid and leukocyte interferons. We suggest that this property is also regulated by genes on chromosome 21.     

Lymphokine-induced IgM secretion by clones of neoplastic B cells

The induction of antibody secretion by B cells requires T-cell-derived factors1-5. Such factors have been described1,2,6-12 but the precise relationship among these various factors is not clear, and it has been difficult to demonstrate that these factors act directly on the B cell and do not exert their effect via T cells or macrophages. In this report we describe the direct induction of IgM synthesis and secretion in cloned lines of long-term tissue culture adapted neoplastic B cells (BCL1) by T-cell supernatants from phorbol-12-myristate 13-acetate (PMA)-induced EL-4 cells or concanavalin A (Con A)-induced 7.1.1a cells5,9. We have termed this activity BCDFmu (B-cell differentiation factor for IgM). The supernatants containing BCDFmu induce activated and neoplastic B cells to secrete IgM5 and the factor responsible is distinct from BCGF13, interleukin-2 (IL-2)5, the classical T-cell replacing factor (TRF) described by Schimpl and Wecker5, and immune interferon (IFN gamma)5.     

展示肿瘤特异性抗原表位的噬菌体在小鼠体内引起的细胞免疫变化

以含有肿瘤特异性抗原表位的杂合型噬菌体(TSPA-M-A1)作为抗原,免疫C57BL/ 6J小鼠,观察免疫4周后小鼠的细胞免疫变化.结果表明:抗原TSPA-M-A1在小鼠体内能够提高T淋巴细胞对ConA刺激的反应性,使NK细胞杀伤活性明显增高,产生了特异性T淋巴细胞(CTL)反应,引起了较强的迟发型超敏反应.这些结果为肿瘤的免疫治疗提供了实验依据.     

Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response

Type I interferon (IFN) production is a critical component of the innate defence against viral infections. Viral products induce strong type I IFN responses through the activation of Toll-like receptors (TLRs) and intracellular cytoplasmic receptors such as protein kinase R (PKR). Here we demonstrate that cells lacking TRAF3, a member of the TNF receptor-associated factor family, are defective in type I IFN responses activated by several different TLRs. Furthermore, we show that TRAF3 associates with the TLR adaptors TRIF and IRAK1, as well as downstream IRF3/7 kinases TBK1 and IKK-epsilon, suggesting that TRAF3 serves as a critical link between TLR adaptors and downstream regulatory kinases important for IRF activation. In addition to TLR stimulation, we also show that TRAF3-deficient fibroblasts are defective in their type I IFN response to direct infection with vesicular stomatitis virus, indicating that TRAF3 is also an important component of TLR-independent viral recognition pathways. Our data demonstrate that TRAF3 is a major regulator of type I IFN production and the innate antiviral response.     

The structure of one of the eight or more distinct chromosomal genes for human interferon-alpha

The 12 interferon (IFN)-related sequences detected in a human gene bank fall into not less than eight distinct classes, indicating that there are at least eight IFN-related genes. Most, if not all, of these direct the synthesis of an IFN in Escherichia coli. The sequence of one chromosomal gene and its flanking regions was identical to that deduced for the cDNA corresponding to IFN-alpha l mRNA. No evidence was found for the existence of an intron, in either the coding or the non-coding segments of the gene.     

Interferon amplifies complement activation by Burkitt's lymphoma cells

Interferon was originally described as an antiviral agent produced shortly after onset of infection with most viruses. However, in addition to inducing an antiviral state, interferon inhibits cell division, increases the expression of cell-surface antigens, boosts the cytotoxic activity of natural killer (NK) cells and modulates several immune functions of lymphocytes and macrophages. Moreover, a special class of interferon (immune interferon or IFN-gamma) is produced by T cells following stimulation with antigen or interaction with mitogens. The different methods by which interferon is induced and its multiple effects suggest that it may be part of a first-line defence system controlling the spread of virus infections and the proliferation of modified 'self' cells that have been affected by virus infection or neoplastic transformation. The ability of certain human lymphoma cells to activate the alternative pathway of complement is well established. Here we show that monoclonal antibody-purified interferon can amplify the ability of certain tumour cells to activate complement via the alternative pathway. This demonstration may reflect an additional, as yet unknown, role of interferon in inducing non-specific anti-tumour immunity.     

A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity

Natural killer (NK) cells are classically viewed as lymphocytes that provide innate surveillance against virally infected cells and tumour cells through the release of cytolytic mediators and interferon (IFN)-gamma. In humans, blood CD56(dim) NK cells specialize in the lysis of cell targets. In the lymph nodes, CD56(bright) NK cells secrete IFN-gamma cooperating with dendritic cells and T cells in the generation of adaptive responses. Here we report the characterization of a human NK cell subset located in mucosa-associated lymphoid tissues, such as tonsils and Peyer's patches, which is hard-wired to secrete interleukin (IL)-22, IL-26 and leukaemia inhibitory factor. These NK cells, which we refer to as NK-22 cells, are triggered by acute exposure to IL-23. In vitro, NK-22-secreted cytokines stimulate epithelial cells to secrete IL-10, proliferate and express a variety of mitogenic and anti-apoptotic molecules. NK-22 cells are also found in mouse mucosa-associated lymphoid tissues and appear in the small intestine lamina propria during bacterial infection, suggesting that NK-22 cells provide an innate source of IL-22 that may help constrain inflammation and protect mucosal sites.     

Constitutive expression of (2'-5') oligo A synthetase confers resistance to picornavirus infection

Study of the mechanisms by which interferon (IFN) treatment of cells induces resistance to virus infections has been complicated by the multiple biochemical changes induced. Over 20 proteins are increased by IFN, including the double-stranded (ds) RNA-activated protein kinase, (2'-5') oligo A synthetase, surface proteins such as the major histocompatibility complex (MHC) proteins, and various proteins with unknown functions. The availability of cloned complementary DNAs for several IFN-induced proteins now allows us to probe their roles in IFN action. For instance, the murine Mx protein has been shown to confer resistance, to influenza virus. We studied chinese hamster ovary (CHO) cell clones expressing high constitutive levels of (2'-5') A synthetase as a result of transfection with the cDNA encoding the enzyme form which has a relative molecular mass (Mr) of 40K. Elevated enzyme correlates directly with resistance to infection by a picornavirus such as Mengo, but does not make the cells resistant to vesicular stomatitis virus (VSV).     

基于多源资料的中国星载闪电探测数据质量控制技术

静止卫星轨道星载闪电探测,因独特的平台优势,可以连续获取较大视场范围内全部闪电活动的观测信息,是未来闪电探测技术发展的新方向。闪电成像仪LMI（Lightning Mapping Imager）是我国首次星载的闪电光学成像观测仪器,在较少先验知识的基础上,自主研发,各项技术指标处于国际前列。然而,LMI独特的数据聚类处理方案,使得其在数据质量控制与真实性检验等方面依然面临着诸多挑战。本文针对其广泛应用的L2 级 1 分钟定量Group数据（LMIG）,基于闪电活动与强天气过程间的耦合关系,提出了基于多源气象资料的多层次数据质量控制技术,并通过与第三方数据的比对,对质控效果评估与优化,有效剔除了误差数据,提升了LMI数据的质量。本文的工作,为LMI数据的应用奠定了更加坚实的基础,同时也有助于促进我国星载闪电观测技术的探索和仪器性能的提升。