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Cytokines Online Pathfinder Encyclopaedia http://www.copewithcytokines.de/cope.cgi The term cytokine, or Immunocytokines , was used initially to separate a group of immunomodulatory proteins, called also Immunotransmitters , from other Growth factors that modulate the proliferation and bioactivities of non-immune cells. Some cytokines are produced by a rather limited number of different cell types while others are produced by almost the entire spectrum of known cell types. For lecture only; BC Yang Cyto: cell -kines: kinesis, 可移動, 分裂 In the more restricted sense cytokines comprise Interleukins , initially thought to be produced exclusively by leukocytes, Lymphokines , initially thought to be produced exclusively by lymphocytes, Monokines , initially thought to be produced exclusively by monocytes, interferons, initially thought to be involved in antiviral responses, colony stimulating factors, initially thought to support the growth of cells in semi-solid media, Chemokines , thought to be involved in Chemotaxis , and a variety of other proteins. For lecture only; BC Yang Established cell lines that entirely depend for their survival and proliferation on the continuous presence of one or more of growth factors . Factor-dependent cell lines are capable of continuous growth in the presence of the growth factors and cytokines they require For lecture only; BC Yang Hematopoiesis: Greek haima for blood and poiein, to make Hematopoiesis is the dynamic and complex developmental process of the formation of new blood cells. An early intra-embryonic site of hematopoiesis is found in the Paraaortic splanchnopleura and in a structure termed AGM ( abbr. for aorta, gonads, and mesonephros) ( Nishikawa et al). mice and birds Hematopoiesis taking place prior to the development of the fetal liver is referred to as primitive hematopoiesis . The fetal liver is the site of definitive hematopoiesis early during embryonal development. The bone marrow with its intersinusoidal spaces is the site responsible for the generation of blood cells in the post-natal phase. For lecture only; BC Yang www.wsu.edu/~ms523/ ms523s198.html Hematopoesis Sites of blood cell formation Embryo: yolk sac Fetus: spleen and liver Adult: “bone marrow” sternum, ribs, pelvis, cranium, vertebrae, long bones (tibia and femur) For lecture only; BC Yang The high proliferative potential colony assay Bone marrow cells 25000 cells of Balb/c, after 150 mg/kg of 5Fu. Culture s are incubated under low oxygen tension for 12 days and scored for HPP-CFU. For lecture only; BC Yang Moore, 10:2719 The development of neutrophils from the stem cell stage For lecture only; BC Yang http://www.whfreeman.com/immunology/CH03/hematopoiesis.htm For lecture only; BC Yang http://www.whfreeman.com/immunology/CH03/hematopoiesis.htm In the presence of infection, cytokines produced by activated macrophages and T-helper cells induce additional hematopoietic activity, resulting in rapid expansion of white blood cells that participate in fighting infection. For lecture only; BC Yang Mosmann TR et al , J Immunol (1986) 136:2348-2357 This is underscored by the uniform phenotype of our anti-CRBC T cell lines, which were all Th1. Only when we examined T cell clones specific for FGG or alloantigens did we discover antigen-specific T cells of the Th2 cells Th2 cells produce activities that strongly enhance IgE/IgG1 production....., whereas Th1 cells produce interferon-g, which strongly inhibits the enhancing activities in Th2 supernatants ..... For lecture only; BC Yang Two types of murine helper T cell clone Mosmann TR et al , J Immunol (1986) 136:2348-2357 For lecture only; BC Yang Cytokine secretion phenotypes of mouse T cells For lecture only; BC Yang Immunosuppresive cytokines For lecture only; BC Yang Th1 and Th2 cell generation is regulated by the equilibrium between different groups of cytokines, with dominant effects of IL-12 and IL-4 (with feed back mechanisms) For lecture only; BC Yang The commitment of TH0 cells to become TH1 or TH2 is influenced by cytokines secreted by the 2 subtypes themselves and by macrophages , NK cells and mast cells. http://www.brown.edu/Courses/Bio_160/Projects1999/ies/cytok.html For lecture only; BC Yang Cytokine soup during disease For lecture only; BC Yang A Th1 to Th2 switch ia a critical step in the etiology of HIV infection Clerici M and Shearer GM, Immunol Today 14:107-111 (1993) For lecture only; BC Yang Becoming a paradigm for disease management Susceptibility to Leishmania major infection in interleukin-4deficient mice. Noben-Trauth et al 1996, Science 271:987-989 For lecture only; BC Yang Induction of Th1 and Th2 responses: a key role for the natural immune respones? Immunol Today 13:379-381 (1992) For lecture only; BC Yang Role of IL-12 in the generation of Th1 cells For lecture only; BC Yang Cytokine responsiveness in a human volunteer injected with LPS. TNF-a rises almost immediately and peaks at 1.5 hours; the sharp decline of TNF-a may be due to modulation by its soluble receptor sTNF-R. A second wave of cytokines that peaks at 3 hours activates the acute phase response in the liver and the systemic pituitary response (both via IL-6) and the activation and chemotaxis of neutrophils (via IL-6, IL8 and G-CSF). Pituitary-derived adrenocorticotropic hormone (ACTH) and migration inhibition factor (MIF) peak at 5 hours and coincide with peak levels of the regulatory cytokines IL-Ra and IL-10 that counteract the release or activity of proinflammatory cytokines. For lecture only; BC Yang As usual, things may not be so simple IL-4 instructs TH1 responses and resistance to Leishmania major in susceptible BALB/c mice Biedermann T et al. 2001, Nature Immunol 2:11 • When present during the initial activation of dendritic cells (DCs) by infectious agents, IL-4 instructed DCs to produce IL-12 and promote TH1 development. This TH1 response established resistance to Leishmania major in susceptible BALB/c mice. When present later, during the period of T cell priming, IL-4 induced TH2 differentiation and progressive leishmaniasis in resistant mice. Because immune responses developed via the consecutive activation of DCs and then T cells, the contrasting effects of IL-4 on DC development and T cell differentiation led to immune responses that had opposing functional phenotypes. For lecture only; BC Yang IL-4 instructs DCs to produce increased amounts of IL12 and to promote TH1 development in vitro. For lecture only; BC Yang IL-4 instructs resistance to L. major in susceptible BALB/c mice. Groups of five BALB/c mice or more were inoculated in one hind footpad with 2×105 stationary phase L. major promastigotes either of strain LV39, MRHO/Sv/59/P (a) or strain MHOM/IL/81/FE/BNI (b). For lecture only; BC Yang IL-4 instructs parasite containment in susceptible BALB/c mice. BALB/c mice were infected with L. major and treated twice with the indicated doses of IL-4 or NMS during the first 8 h of infection. After 9 weeks, the number of viable parasites in infected tissues was estimated using a parasite-limiting dilution assay. For lecture only; BC Yang IL-4 treatment during the first 8 h of L. major infection instructs IL-12– producing DC1s and suppresses IL-4 expression. Control mice (Control and IL-4) or mice infected with L. major promastigotes (3×106) were treated either with NMS or twice with 1.0 μg of IL-4 at 0 and 8 h of infection. For lecture only; BC Yang Induction of TH1 responses with IL-4 depends on IL-12. BALB/c mice were infected with L. major and treated twice with IL-4 (at 0 and 8 h) and either NMS or anti–IL-12. After 8 weeks, popliteal lymph node cells were isolated, RNA extracted and expression of IL-4 and IFN-γ mRNA determined by semiquantitative RT-PCR. (a) The relative changes in IL-4 and IFN-γ mRNA were normalized to the values in control infected BALB/c mice, arbitrarily fixed as 100. (b) The ratio of IL-4:IFN-γ mRNA for each experimental group was determined. L. major infection, cytokine treatment and mRNA analysis were done. For lecture only; BC Yang Treatment with anti–IL-12 abrogates IL-4–induced resistance to L. major in BALB/c mice. Mice were infected with L. major promastigotes and treated with either NMS (open circles) or twice with 1.0 μg of IL-4 (at 0 and 8 h) and either NMS (filled squares) or the IL-12 mAbs C17.8 and C17.15 (open triangles) 12 and 3 h before infection. One of two similar experiments is shown. Infection, cytokine treatment and weekly monitoring of footpad lesions were done . For lecture only; BC Yang Extension of IL-4 treatment into the period of T cell priming reverses IL-4–induced resistance to L. major. Three groups of mice were infected and treated with either 1.0 μg of IL-4 or NMS. The first L. major–infected group received NMS (open circles), the second 1.0 μg of IL-4 at 0 and 8 h (filled squares) and the third 1.0 μg of IL-4 at 0, 8, 16 and 24 h (crosses). Infection, cytokine treatment and weekly monitoring of footpad lesions were done . For lecture only; BC Yang Timing determines whether IL-4 treatment instructs a TH1 phenotype and resistance or a TH2 phenotype and susceptibility to L. major in TCR Vβ4-deficient mice. (a,b) After parasite inoculation,Vβ4-deficient BALB/c mice were treated during the first 64 h with either eight injections of PBS–1% NMS or eight injections of 0.1 μg of IL-4 (total amount: 0.8 μg). Alternatively, mice were treated twice during the first 8 h of infection with 1.0 μg of IL-4 as in Fig. 2. Eight weeks after infection, cells from draining lymph nodes were stimulated in vitro with ultravioletirradiated parasites and cytokines were determined in the supernatants as described (see Methods). The IL4:IFN-γ ratio was 3.71 in mice that received IL-4 over 64 h and 0.37 in mice that received two injections of IL4 at 0 h and 8 h. (c). For lecture only; BC Yang How Th1/2 cytokines are regulated? • Transcriptional regulation of Th1/Th2 polarization, Jyothi Rengarajan J et al 2000, Immunol Today 21:479 The two polarized T helper (Th) subsets Th1 and Th2 are identified by their signature cytokines, interferon-g (IFN-g) and interleukin 4 (IL-4) respectively. Understanding the transcriptional regulation of cytokine expression is therefore critical for elucidating the process of Th cell differentiation. Ubiquitous and tissue-specific transcription factors, as well as chromatin remodeling of genomic loci have been implicated in IL-4 and IFN-g regulation. For lecture only; BC Yang Class I cytokine receptor family (Hematopoietin recetor) this family includes receptors for growth hormone and prolactin. There are conserved amino acid sequence motifs in the extracellular domain - 4 positionally conserved cysteine residues (CCCC) and a conserved sequence of TrpSer-X-Trp-Ser (WSXWS) where X is a nonconserved amino acid. The receptors consist of 2 polypeptide chains: a cytokine-specific subunit and a signaltransducing subunit which is usually not specific for the cytokine. http://www.umdnj.edu/pathnweb/genpath/lec_1/Class_I_Cytokin e_Receptors/class_i_cytokine_receptors.htm For lecture only; BC Yang Class II cytokine receptor family (Interferon receptor family) The ligands for these receptors are the three interferons a, ß, and g. These receptors possess the conserved cysteine motifs, but lack the WSXWS motif present in class I cytokine receptors. For lecture only; BC Yang Overview of Th cell differentiation. A naive CD4 T cell is activated via the TCR when it encounters antigen presented by an antigen presenting cell. For lecture only; BC Yang Regulation at transcriptional level GATA3, a zinc finger protein that was originally identified as binding the TCRa gene enhancer via a WGATAR sequence. T-bet (T-box expressed in T cells) is a member of the T-box family of transcription factors that regulate several developmental processes. T-bet expression strongly correlates with IFNg expression. For lecture only; BC Yang (a) IL-4 regulatory regions: the IL-4 proximal promoter with cis and trans elements and map of IL-4 locus showing DNAse I HSs. (b) IFN-g regulatory region and map of locus with DNAse I HS sites. For lecture only; BC Yang Striking a balance: GATA3 and T-bet – model for Th1/Th2 polarization. Signals through the TCR and cytokine receptors can lead to the initiation of a Th1 program (via Stat4 activation) and the induction of T-bet, which promotes Th1 lineage commitment. Signals that favor the activation of Stat6 induce GATA3 leading to Th2 differentiation. cMaf is then upregulated leading to increased IL4 production and Th2 polarization. For lecture only; BC Yang More than immunoregulatroy actions Cytokine regulation of neuronal differentiation of hippocampal progenitor cells (Mehler MF et al. 1993, Nature 362:62-65.) The signalling mechanisms governing haematolymphopoiesis and those regulating neural development may be closely related, as indicated by similarities of higher-order structure and function of the cytokines involved, of the regional and temporal regulation of their transcription and translation, and of their bioactivity. The mechanisms regulating lineage commitment and cellular differentiation in the neural and haematopoietic systems are similar. For lecture only; BC Yang Electrophysiological analysis of the effects of growth factor treatment on neuronal maturation For lecture only; BC Yang Morphological and immunocytochemical indices of progressive neuronal maturation For lecture only; BC Yang Immune System and the Brain Estrogen, microglia and the IBB The microglial-cytokine--estrogen mediated network is described as a major player in the brain including the Immune Brain Barrier. One of the functional areas involved maybe the role that microglia could play in synaptic plasticity. http://info.med.yale.edu/obgyn/reproimmuno/projects/immune.html For lecture only; BC Yang Combinatorial signal by inflammatory cytokines and chemokines mediate leukocyte interactions with extracellular matrix Vaday GG et al. 2001, J leukoc Biol 69:885-892 For lecture only; BC Yang limitations of cytokines for therapeutic use High local concentrations of cytokines during immune response cannot be mimicked clinically Short half-life of cytokines Pleiotropic effects can cause unpredictable side-effects For lecture only; BC Yang