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1.
Tumour necrosis factor alpha stimulates resorption and inhibits synthesis of proteoglycan in cartilage 总被引:55,自引:0,他引:55
J Saklatvala 《Nature》1986,322(6079):547-549
During inflammatory reactions, activated leukocytes are thought to produce a variety of small proteins (cytokines) that influence the behaviour of other cells (including other leukocytes). Of these substances, which include the interleukins, interferons and tumour necrosis factors (TNFs), interleukin-1 (IL-1) has been considered potentially a most important inflammatory mediator because of its wide range of effects. In vivo it is pyrogenic and promotes the acute phase response; in vitro it activates lymphocytes and stimulates resorption of cartilage and bone. Cartilage resorption is a major feature of inflammatory diseases such as rheumatoid arthritis, and IL-1 is the only cytokine hitherto known to promote it. TNFs are characterized by their effects on tumours and cytotoxicity to transformed cells, but share some actions with IL-1. I report here that recombinant human TNF alpha stimulates resorption and inhibits synthesis of proteoglycan in explants of cartilage. Its action is similar to and additive with IL-1, and it is a second macrophage-derived cytokine whose production in rheumatoid arthritis, or inflammation generally, could contribute to tissue destruction. 相似文献
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Tumour necrosis factor alpha restores granulomas and induces parasite egg-laying in schistosome-infected SCID mice. 总被引:38,自引:0,他引:38
P Amiri R M Locksley T G Parslow M Sadick E Rector D Ritter J H McKerrow 《Nature》1992,356(6370):604-607
Schistosomiasis (bilharzia) is a parasitic disease caused by several species of schistosome worms (blood flukes). The key pathogenic event in this disease is the formation of granulomas around schistosome eggs trapped in portal venules of the liver. Granulomas are a distinctive form of chronic inflammation characterized by localized aggregation of activated macrophages around an inciting stimulus. Each granuloma evolves to form a fibrous scar; in schistosomiasis, the result is widespread hepatic fibrosis and portal hypertension. To identify the specific immune signal molecules necessary for granuloma formation, we studied schistosome infections in severe combined immunodeficient (SCID) mice, which have normal macrophages but lack functional B or T lymphocytes. Here we report that the immunoregulatory cytokine tumour necrosis factor alpha is necessary and sufficient to reconstitute granuloma formation in schistosome-infected SCID mice. Moreover, we find that the parasitic worms require tumour necrosis factor alpha for egg-laying and for excretion of eggs from the host. The implication of this latter result is that the parasite has adapted so successfully to its host that it uses a host-derived immunoregulatory protein as a signal for replication and transmission. 相似文献
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A unique set of polypeptides is induced by gamma interferon in addition to those induced in common with alpha and beta interferons 总被引:41,自引:0,他引:41
Human immune interferon (IFN-gamma) differs from leukocyte interferon (IFN-alpha) and fibroblast interferon (IFN-beta) in cell origin, inducing agents, physical and biological properties and amino acid sequence. These differences have led to interest in possible differences in the biological properties of IFN-gamma compared with IFN-alpha and IFN-beta. IFN-gamma has the same broad range of biochemical and biological actions as do IFN-alpha and IFN-beta, although relative potencies vary depending on the cell type and function investigated. There has so far been no direct evidence that IFN-gamma alters normal cell functions differently from other interferons. We report here striking qualitative and quantitative differences in the intracellular response of human fibroblasts to IFN-gamma compared with IFN-alpha and IFN-beta. Two-dimensional gel electrophoresis demonstrates, in addition to the induction of a common group of polypeptides, the existence of a set of polypeptides whose synthesis is uniquely induced by IFN-gamma. 相似文献
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Monoclonal antibodies inhibit prion replication and delay the development of prion disease 总被引:19,自引:0,他引:19
White AR Enever P Tayebi M Mushens R Linehan J Brandner S Anstee D Collinge J Hawke S 《Nature》2003,422(6927):80-83
Prion diseases such as Creutzfeldt-Jakob disease (CJD) are fatal, neuro-degenerative disorders with no known therapy. A proportion of the UK population has been exposed to a bovine spongiform encephalopathy-like prion strain and are at risk of developing variant CJD. A hallmark of prion disease is the transformation of normal cellular prion protein (PrP(C)) into an infectious disease-associated isoform, PrP(Sc). Recent in vitro studies indicate that anti-PrP monoclonal antibodies with little or no affinity for PrP(Sc) can prevent the incorporation of PrP(C) into propagating prions. We therefore investigated in a murine scrapie model whether anti-PrP monoclonal antibodies show similar inhibitory effects on prion replication in vivo. We found that peripheral PrP(Sc) levels and prion infectivity were markedly reduced, even when the antibodies were first administered at the point of near maximal accumulation of PrP(Sc) in the spleen. Furthermore, animals in which the treatment was continued remained healthy for over 300 days after equivalent untreated animals had succumbed to the disease. These findings indicate that immunotherapeutic strategies for human prion diseases are worth pursuing. 相似文献
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Tumour prevention and rejection with recombinant vaccinia 总被引:2,自引:0,他引:2
Tumour-specific antigens (TSA; ref. 1) have been exploited in the diagnosis and imaging of human cancer and anti-TSA antibodies have therapeutic potential. Vaccination with TSA or anti-idiotypic (TSA) antibodies has also been used to control tumour growth in model systems. An effective immune response nevertheless demands copresentation of antigen with host histocompatibility determinants. We therefore examined whether live vaccinia virus recombinants expressing TSA in cells of the vaccinated host might better elicit tumour immunity. Polyoma virus (PY) is tumorigenic in rodents; because killed PY-transformed cells can elicit tumour immunity, a PY-specific TSA has been postulated. Tumorigenesis involves expression of three early PY proteins, large-T (LT), middle-T (MT) and small-T (ST), but their role as TSAs is unclear. We therefore expressed the three T proteins in separate vaccinia recombinants. Rejection of PY tumours was observed in rats immunized with recombinants expressing either LT or MT. Further, tumour-bearing animals could be induced to reject their tumours by inoculation of recombinants. 相似文献
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Transfer of specificity by murine alpha and beta T-cell receptor genes 总被引:51,自引:0,他引:51
Z Dembi? W Haas S Weiss J McCubrey H Kiefer H von Boehmer M Steinmetz 《Nature》1986,320(6059):232-238
T-cell receptor alpha- and beta-chain genes were isolated from a class I major histocompatibility complex-restricted cytotoxic T-cell clone and transferred by protoplast fusion into another cytolytic T-cell clone of different specificity. Expression of the transfected alpha and beta genes endowed the recipient cell with the specificity of the donor cell. 相似文献
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The worm Caenorhabditis elegans is a model system for studying many aspects of biology, including host responses to bacterial pathogens, but it is not known to support replication of any virus. Plants and insects encode multiple Dicer enzymes that recognize distinct precursors of small RNAs and may act cooperatively. However, it is not known whether the single Dicer of worms and mammals is able to initiate the small RNA-guided RNA interference (RNAi) antiviral immunity as occurs in plants and insects. Here we show complete replication of the Flock house virus (FHV) bipartite, plus-strand RNA genome in C. elegans. We show that FHV replication in C. elegans triggers potent antiviral silencing that requires RDE-1, an Argonaute protein essential for RNAi mediated by small interfering RNAs (siRNAs) but not by microRNAs. This immunity system is capable of rapid virus clearance in the absence of FHV B2 protein, which acts as a broad-spectrum RNAi inhibitor upstream of rde-1 by targeting the siRNA precursor. This work establishes a C. elegans model for genetic studies of animal virus-host interactions and indicates that mammals might use a siRNA pathway as an antiviral response. 相似文献
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Tumour necrosis factor as immunomodulator and mediator of monocyte cytotoxicity induced by itself, gamma-interferon and interleukin-1 总被引:62,自引:0,他引:62
Activated monocytes or macrophages can release soluble cytotoxic molecules capable of lysing tumour cells in vitro and thus represent an important component of the host defence mechanisms against malignancy. The recent availability of pure recombinant or natural human lymphokines and monokines and their respective polyclonal or monoclonal antibodies now makes it possible to dissect the interactions of these factors in the induction and performance of the cytotoxic event by the monocytes. Our studies indicate that pretreatment of monocytes with alpha-IFN or gamma-IFN, and also interleukin (IL)-1 or tumour necrosis factor (TNF) results in enhanced monocyte cytotoxicity. Although all these substances induce the production of IL-1 by monocytes, TNF mediates the enhanced cytotoxicity induced in monocytes by gamma-IFN, IL-1 and, in an autocrine manner, by TNF itself. Neither TNF, IL-1, gamma-IFN nor alpha-IFN mediate spontaneous monocyte cytotoxicity or that induced by alpha-IFN. Our studies thus reveal new interactions between the two monokines IL-1 and TNF and provide a dual role for TNF, as immunomodulator and mediator of monocyte cytotoxicity induced by certain specific lymphokine and monokine molecules. 相似文献
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Tumour necrosis factor and lymphotoxin genes map close to H-2D in the mouse major histocompatibility complex 总被引:3,自引:0,他引:3
Tumour necrosis factor (TNF-alpha) and lymphotoxin (TNF-beta) are related proteins, secreted by macrophages and lymphocytes respectively, which play a role in destruction of tumour cells and virally infected cells (for reviews see refs 1,2). TNF-alpha is a non-glycosylated protein of relative molecular mass 17,000 (Mr 17 K), whereas TNF-beta is a glycoprotein of Mr 25 K. Both TNF-alpha and TNF-beta aggregate into multimers and act through the same receptor molecule on target cells. Genes encoding these two TNF proteins have been cloned from mouse and man and in both are closely linked, being separated by approximately 1 kilobase (kb) of DNA. In the mouse these genes are located on chromosome 17, but in man they are on the short arm of chromosome 6. This segment of chromosome 6 also contains the genes of the major histocompatibility complex (MHC), as does chromosome 17 in the mouse. To find out whether the TNF genes are located within the MHC, we used polymorphic restriction sites to analyse a panel of MHC congeneic and intra-MHC recombinant mouse strains. Initially, we mapped the TNF genes the D or Qa region in the distal half of the mouse MHC. We then studied a gene cluster encompassing part of the D and Qa regions and found the TNF genes are located 70 kb proximal to the D gene. 相似文献
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Regulatory properties of LFA-1 alpha and beta chains in human T-lymphocyte activation 总被引:25,自引:0,他引:25
Lymphocyte function-associated antigen-1 (LFA-1) is a heterodimer composed of an alpha and beta chain that is expressed on the surface of most leukocytes and is an essential molecule for adhesion reactions between cells participating in the immune response. A putative ligand for LFA-1 is the intercellular adhesion molecule ICAM-1 (refs 3-5). Leukocyte adhesion abnormality is found in patients with LFA-1 deficiency. It is not clear whether binding of ligand to the LFA-1 molecule merely spatially orientates cells towards each other or can also induce signals that regulate cell activation and differentiation. We have recently developed a T-cell proliferation assay which uses immobilized anti-CD3 monoclonal antibodies as stimulant and is independent of LFA-1-mediated cellular adhesion. As there is no interference by anti-LFA-1 monoclonal antibodies with the adhesion-dependent activation steps, this T-cell activation system allows us to investigate whether transmembrane signals are induced by binding of ligand to LFA-1 on T cells. Our data indicate that binding of ligand to LFA-1 results in the transduction of regulatory signal across the plasma membrane, rather like other molecules (CD2, CD4, CD8) (refs 8-11) with signal-modifying properties involved in the adhesion of T cells to target/stimulator cells. Indeed, adhesion molecules might generally be important in signal transduction, even in cells not belonging to the immune system. 相似文献
15.
Q X Li L S Young G Niedobitek C W Dawson M Birkenbach F Wang A B Rickinson 《Nature》1992,356(6367):347-350
Epstein-Barr virus, a human herpesvirus with oncogenic potential, infects two target tissues in vivo: B lymphocytes, where the infection is largely non-productive, and stratified squamous epithelium in which virus replication occurs. The interaction with B cells, initiated through virus binding to the B-cell surface molecule CR2 (ref. 4), has been studied in vitro and the virus 'latent' genes associated with B-cell growth transformation defined. By comparison, viral infection of epithelium remains poorly understood, reflecting the lack of an appropriate cell-culture model. Here we describe the development of such a model using as targets CR2-expressing transfected cells of two independent human epithelial lines. A high proportion of these cells bind virus and become actively infected, expressing the small EBER RNAs (small non-polyadenylated virus-coded RNAs) and the Epstein-Barr nuclear antigen 1 but not other latent proteins; thereafter, under conditions favouring epithelial differentiation, up to 30% of the cells can be induced to enter virus productive cycle with some progressing to full virus replication. We find significant differences between laboratory virus strains in their ability to infect epithelium that do not correlate with their B-cell growth-transforming activity. 相似文献
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The generation of mature T cells requires interaction of the alpha beta T-cell receptor with major histocompatibility antigens 总被引:17,自引:0,他引:17
THE T-cell repertoire within an individual is biased to recognize antigen in the context of self major histocompatibility complex (MHC) antigens. This is thought to depend on a process of positive selection during development. Support for this notion has recently been obtained in experiments using transgenic mice bearing genes for T-cell receptors (TCR) of defined specificity: T cells expressing the introduced genes form the main part of the mature T-cell population only in mice that express the appropriate MHC product. We have now extended these observations using TCR transgenic mice homozygous for the severe combined immunodeficiency (SCID) mutation which are defective in the rearrangement of both TCR and immunoglobulin genes. In this case mature thymocytes develop only in transgenic mice that express the MHC product which restricts the specificity of the transgenic TCR. This shows that the interaction of the alpha beta TCR with thymic MHC antigen is essential for the development of mature T cells. Furthermore, the peripheral lymph nodes of such mice are underdeveloped, suggesting that the peripheral expansion of mature T cells may require interactions with other lymphocytes expressing a range of receptors. 相似文献
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Mutations in T-cell antigen receptor genes alpha and beta block thymocyte development at different stages. 总被引:83,自引:0,他引:83
P Mombaerts A R Clarke M A Rudnicki J Iacomini S Itohara J J Lafaille L Wang Y Ichikawa R Jaenisch M L Hooper 《Nature》1992,360(6401):225-231
Analysis of mice carrying mutant T-cell antigen receptor (TCR) genes indicates that TCR-beta gene rearrangement or expression is critical for the differentiation of CD4-CD8- thymocytes to CD4+CD8+ thymocytes, as well as for the expansion of the pool of CD4+CD8+ cells. TCR-alpha is irrelevant in these developmental processes. The development of gamma delta T cells does not depend on either TCR-alpha or TCR-beta. 相似文献