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Cytokines Weilin Chen, Ph. D. Institute of Immunology, ZJU [email protected] History for the research of the cytokines In 1957,Interferon (IFN ) was found In 1969, termed lymphokine In1974,denominated cytokine cytokinology; international cytokine society 《 Cytokine 》 Companies for developing cytokines Introduction to cytokines Categories of CKs Biological function of CKs Cytokines related diseases Medical application of cytokines Introduction to cytokines Cytokine (CK) Cytokines are small proteins (8-80 KD) that are secreted by cells and exert biological activity through specific cell surface receptors. Inducing stimulus Cytokine gene Cytokineproducing cell Cytokine Receptor signal Gene activation Overview of the induction and function of Cytokine Biological effects General properties of CKs Small proteins (MW: approx. 15-80 KD) Extremely potent, acting at pM or fM The production is transient and tightly regulated Autocrine, paracrine or endocrine Non-specific and non-MHC restricted 3 MAJOR ROUTES OF CYTOKINE TRAVEL Cytokine actions 1) Pleiotropy Acts on more than one cell type 2) Redundancy More than one cytokine have the same action 3) Synergy Two or more cytokines cooperate to produce an effect that is different or greater than the combined effect of the two cytokines when functioning separately 4) Antagonism Two or more cytokines work against each other 5 ) The cytokine network Categories of CKs CKs are classified into 6 functional categories Interleukin (IL) Interferon (IFN) Tumor necrosis factor (TNF) Colony stimulating factor (CSF) Chemokine Growth factor (GF) Interleukin, IL IL-2 IL 1~38 IL-1 IL-2 IL-4, IL-5, IL-6, IL-13 (Th2 type) IL-8 (belongs to chemokine family) IL-10 (Tr, Ts type) IL-11 (stimulator of platelets) IL-12 (DC, macrophages, directs Th1) IL-4 IL-13 AUTOCRINE IL-2 DRIVES CLONAL EXPANSION OF T CELLS Ag-specific stimulus IL-2 T cell IL-4 PARACRINE IL-4 DRIVES CLONAL EXPANSION OF B CELLS AUTOCRINE OR PARACRINE IL-4 OR IL-13 DRIVES Ig CLASS SWITCHING TO IgE B cell IgG1 IgE Interferon, IFN IFNs are mediators of the innate immune response and Th1/CTL responses. Groups Type I IFN: IFN-α and IFN-β The major source is leukocytes (PDC), fibroblasts and virus infected cells. Type II IFN: IFN-γ IFN-γ is produced by activated T cells and NK cells. Production of interferon by infected cells Anti-viral effects of interferon a/b © New Science Press Ltd. 2004 Tumor necrosis factor, TNF TNF was originally identified (and was so named) as a substance that can cause the necrosis of tumors in vivo TNF-α and TNF-β TNF-α is produced by LPS-stimulated mononuclear phagocytes and activated T cells. TNF-β is also termed lymphotoxin ( LT), and is produced mainly by activated T cells. 【商 品 名】纳科思 【通 用 名】注射用重组改构人肿瘤坏死因子 【规 格】冻干粉针剂500万IU/瓶 【适 应 症】非小细胞肺癌 【批准文号】国药准字20030065 纳科思联合化疗药物治疗肺癌、头颈部癌、消化道癌、 泌尿系统恶性肿瘤的疗效显著优于单纯化疗。 该产品是上海赛达生物药业股份有限公司与中国人民 解放军第四军医大学合作研究开发的新产品,2003年8 月正式上市,是全球第一个上市的全身用药的肿瘤坏死 因子产品。 Colony-stimulating factors, CSF Stimulates the differentiation and expansion of bone marrow progenitor cells. It is assayed by its ability to stimulate the formation of cell colonies in culture. Includes IL-3, CSF (G-CSF, M-CSF, GM-CSF), SCF, EPO, TPO, etc . GM-CSF G-CSF Chemokines (chemotactic cytokines) Chemokines are a large family of structurally homologous CKs that stimulate movement and regulate the migration of leukocytes from the blood to tissues and within tissues, and includes about 50 different members. Subfamilies: CXC (a), CC (b), C (), CX3C (), based on structural characteristics (cysteine residues). IL-8 CXC MCP-1 CC Lymphotactin C Fractalkine CX3C neutrophils monocyte lymphocyte lymphocyte The Chemokine Fold C N G.M.Clore & A.M.Gronenborn IL8 Growth factors, GF Promote the proliferation and differentiation of cells. Include TGF-b、EGF、VEGF、FGF、NGF, etc. vascular endothelial growth factor (VEGF) VEGF promotes Tumor Angiogenesis Biologic functions of CKs (1) Anti-bacteria: IL-1, TNF, IL-6, IL-8 and IL-12 Anti-virus: type I IFN Mediation and regulation of adaptive immunity: *Stimulating the proliferation of lymphocytes: IFN-, IL-2, IL-7, IL-4, IL-5, IL-15. *Stimulating the development of lymphocytes: IL12, IFN- ,IL-4. *Enhancing the activity of effector cells: IFN-, IL2. *Inhibiting immune response: TGF-b, IL-10 Induction of Inflammation following recognition of pathogens or mast cell Inflammatory mediators: Cytokines, chemokines and lipids TNF © New Science Press Ltd. 2000 Downloaded from: StudentConsult (on 1 June 2006 03:50 PM) © 2005 Elsevier Biologic actions of CKs (2) Stimulation of hemopoiesis SCF → stem cells CSF → granulocytes and monocytes IL-4 and GM-CSF →dendritic cells EPO → erythrocytes IL-11 and TPO →platelets IL-7, IL-15 → formation of Tm Angiogenesis IL-8, VEGF, etc. Cytokine-related diseases Bacterial septic shock Blood pressure drops, clots form, hypoglycemia ensues, patient dies LPS triggers results in TNF release TNF induces IL-1 which induces IL-6 and IL-8 Bacterial toxic shock and related diseases Superantigens trigger large numbers of T cells which release massive amounts of cytokines (Super antigens are bacterial toxins that bridge CD4 T cell receptors and the MHC class II molecules on APC’s, bypassing the need for antigen) Lymphoid and myeloid cancers Some cancer cells secrete cytokines Medical application of cytokines rIFN-a: Intron-A, Referon-A rIFN-b: Prokine rEPO: Epogen rG-CSF rGM-CSF: Acimmune Human TNF McAb: HumiraTM