Microsoft PowerPoint - 8 The cytokines_ Interferons and Interleukins.pptx

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1 Pharmaceutical Biotechnology The cytokines: the interferon family By Yuqiong Xia 4/14/2017

2 生物技术制药 2 技术基础生物技术药物生物技术制药概念药物的开发药物的生产细胞因子生长因子激素类药物血液制品和治疗性酶抗体疫苗和佐剂核酸药物药物的发现专利的申请临床前试验临床试验生物药物的来源生物药物的生产和纯化生物药物的分析干扰素白介素造血生长因子

3 概念干扰素白介素细胞因子干扰素分类细胞因子受体白细胞概念和分类信号传导生物活性生产医疗应用生长因子趋化因子其它细胞因子结合区信号传导区单核巨噬细胞淋巴细胞粒细胞 α,β,ϒ JAK-STAT 通路抗病毒机制重组 DNA 技术治疗白血病, 多发性硬化等 3

4 Outline Cytokines Concept Classification Cytokine receptor Leukocytes Interferons 4

5 Cytokines They are regulatory proteins or glycoproteins Normally produced in minute quantities by the body Act as chemical communicators between various cells 5

6 The action of cytokines Endocrine: affect different and distant tissues Paracrine: act near cytokine s secretion Autocrine: act on the cell that secretes it 6

7 Cytokines Most cytokines act upon or are produced by leukocytes (white blood cells) Regulate both immune and inflammatory function and related processes The production of blood cells from haematopoietic stem cells in the adult bone marrow Wound healing 7

8 Outline Cytokines Concept Leukocytes Classification Cytokine receptor Interferons 8

9 Classification of cytokines Interferons (IFNs) Interleukin(ILs) Growth factors (GFs) Chemokines (CKs) Others 9

10 IFNs Proteins produced by eukaryotic cells in response to viral infections, tumors and other biological inducers Promote an antiviral state in other neighboring cells 10

11 Interleukins (ILs) Mainly secreted by leukocytes Primarily affect growth and differentiation of hematopoietic and immune cells. E.g. IL-11 is a key regulator in stimulation of megakaryocyte maturation 11

12 GFs Activate cellular proliferation and/or differentiation Promote proliferation of connective tissue( 结缔组织 ), glial ( 神经胶质的 ) and smooth muscle cells, enhance normal wound healing Hematopoietic growth factors belong to GFs 12

13 Chemokines (CKs) Induce directed chemotaxis ( 趋药性 ) in nearby responsive cells Cells CKs 13

14 CKs 1. Tumor cell produces CKs 2. Macrophage with CK receptor binds to CK 3. Macrophage migrate to tumor cells 14

15 Others: Tumor necrosis factors (TNF) TNF α Produced by monocyte Induce tumor regression( 肿瘤消退 ) Induce cachexia ( 恶病质 ) TNF β Also named lymphotoxin α Produced by lymphocytes Can cause destruction of cancer cells Inhibited by interleukin 10 15

16 夏玉琼 Others: Transforming GF (TGF) 转化生长因子 Function 西安电子科技大学 Induce oncogenic transformation in a specific cell culture system TGF α is upregulated in some human cancers. TGF β is upregulated in Marfan s syndrome( 马方氏综合征 ) and some human cancers. 16

17 Outline Cytokines Concept Classification Cytokine receptor Leukocytes Interferons 17

18 Cytokine receptor Cytokine receptor on the surface of target cells binds to cytokine and triggers corresponding effect Cytokine Cytokine receptor 18

19 Cytokine receptor Different Same 19 Each type of cytokine displays a unique cytokine ( ligand )-binding domain, but different types of cytokines share additional receptor components, which are normally responsible for signal transduction

20 Outline Cytokines Concept Classification Cytokine receptor Leukocytes Interferons 20

suppressor cells NK cells Granulocytes Neutrophiles 嗜中性粒细胞 Eosinphiles

21 Leukocytes Mononuclear phagocytes Monocytes Macrophages Lymphocytes B lymphocytes T lymphocytes: T helper cells, T cytotoxic cells, T suppressor cells NK cells Granulocytes Neutrophiles 嗜中性粒细胞 Eosinphiles 嗜酸性粒细胞 Basophiles 嗜碱性粒细胞 21

22 Mononuclear phagocytes Execute their defense function primarily by phagocytosis 成单核细胞 22 Hepatic macrophages: Kupffer cells CNS macrophages: microglia 小神经胶质细胞 Lung macrophages: alveolar ( 肺泡 ) macrophages

23 Lymphocytes responsible for the specificity of the immune response recognize and respond to specific antigens Distribute in blood, spleen and thymus Classification B-cells: produce antibody T-cells: cell-mediated immunity 23

24 T-cells T helper cells Produce various cytokines, which stimulate and regulate the immune response Express a membrane protein termed CD4 on their surface T cytotoxic cells Induce the lysis of cells exhibiting foreign antigen on their surfaces. Their major target cells are body cells infected by viruses or other intracellular pathogens (e.g. some protozoa) Express a membrane protein termed CD8 on their surface T suppressor cells Suppress an activated immune response, an off switch Express a membrane protein termed CD8 on their surface 24

25 NK cells Directly lysing cancer cells and virally infected cells 25

26 Granulocytes Presence of large granules in their cytoplasm Activated by cytokines, play a direct role in immunity and inflammation 26

27 Granulocytes Neutrophiles 嗜中性粒细胞 Most abundant, display IgG Fc receptor Mediate acute inflammation and phagocytose opsonized antigen Eosinphiles 嗜酸性粒细胞 Display a cell surface IgE receptor Destroy foreign substances that specifically elicit an IgE response (e.g. parasite) Basophiles 嗜碱性粒细胞 Display a cell surface IgE receptor Binding of antigen IgE complex can secrete the granule contents, and mediate hypersensitivity reactions 27

28 Outline Cytokines Concept Classification Cytokine receptor Leukocytes Interferons Concept Signal pathway Biological effects Production Application 28

29 Interferon (IFN) Interferons are named after their ability to "interfere" with viral replication within host cells. 29

30 Classification of IFNs IFN-I IFN-α and IFN- β, 166AA, α-helical structure Bind to type I interferon receptor Exhibit anti-virus and anti-propogation effect IFN-II IFN-ϒ, 143AA, α-helical structure Weak anti-virus and anti-propogation effect Control the effect of IFN α/β, modulating immune response and inflammation 30

IFN belongs to Class-1 helical cytokines 31 http://maptest.rutgers.

31 IFN belongs to Class-1 helical cytokines 31

32 Outline Cytokines Concept Classification Cytokine receptor Leukocytes Interferons Concept Signal pathway Biological effects Production Application 32

33 IFN signaling pathway By interacting with their specific receptors, IFNs activate signal transducer and activator of transcription (STAT) complexes; STATs are a family of transcription factors that regulate the expression of certain immune system genes IFN IFN receptor STATs 33

34 34

35 IFN signaling pathway STAT: signal transducer and activator of transcription ISGF3: interferonstimulated gene factor 3 ISRE: interferonstimulated response element 35

36 Outline Cytokines Concept Classification Cytokine receptor Leukocytes Interferons Concept Signal pathway Biological effects Production Application 36

37 2-5 An synthase pathway 2-5 -phosphodiesterase 37

38 A n 3-5 A n

39 39 eif-2α synthase pathway

40 Outline Cytokines Concept Classification Cytokine receptor Leukocytes Interferons Concept Signal pathway Biological effects Production Application 40

41 Production of IFN-α2B Upstream processing Purification Formulation Phosphate buffer, containing glycine and human albumin as excipients Freezee-dried. The PEGylated product Prolonged plasma half-life (13 25 h as compared to 4 h for unpegylated species). 41

42 Production of Infergen An engineered IFN recently approved for the treatment of hepatitis C The product s amino acid sequence contains the most frequently occurring amino acid residue in native IFNs. Produced in E. coli Accumulates intracellularly as inclusion bodies, need solubilization and refolding Formulation Phosphate buffer and sodium chloride 42

43 Outline Cytokines Concept Classification Cytokine receptor Leukocytes Interferons Concept Signal pathway Biological effects Production Application 43

44 Therapeutical use of IFN 44 IFNα2, -β and -γ are the most extensively studied IFN-α2A and α2b is used to treat hairy cell leukaemia (B lymphocyte neoplasm) IFN β1a is used to treat multiple sclerosis ( 多发性硬化症 ) Interferon-γ 1b is approved by FDA to treat chronic granulomatous disease ( 慢性肉芽肿病 ) and osteopetrosis( 骨硬化病 ) The most frequent adverse effects are flu-like symptoms

45 概念干扰素白介素细胞因子干扰素分类细胞因子受体白细胞概念和分类信号传导生物活性生产医疗应用生长因子趋化因子其它细胞因子结合区信号传导区单核巨噬细胞淋巴细胞粒细胞 α,β,ϒ JAK-STAT 通路抗病毒机制重组 DNA 技术治疗白血病, 多发性硬化等 45

Chapter 20

Chapter 20 Chapter 18 Defense Mechanisms of the Body Immunology: Defenses Against Foreign Matter Immune defenses may be nonspecific, in which the identity of the target is not recognized, or it may be specific, in