第六章 细胞因子
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第六章 细胞因子 Chapter 6 Cytokines. Objectives and Requirements Master the concept of the cytokines; 2. Familiar with the common properties. 3. Comprehend the functions of cytokines and the cytokine receptor. 目的、要求 1、掌握细胞因子的概念和细胞因子的命   名与分类 ; 2、熟悉细胞因子的共同特点 ; 3、了解细胞因子及其受体的功能。.

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第六章 细胞因子 Chapter 6 Cytokines

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Chapter cytokines

第六章 细胞因子

Chapter 6 Cytokines


Chapter cytokines

  • Objectives and Requirements

  • Master the concept of the cytokines;

  • 2. Familiar with the common properties.

  • 3. Comprehend the functions of cytokines and the cytokine receptor.


Chapter cytokines

目的、要求

1、掌握细胞因子的概念和细胞因子的命

  名与分类;

2、熟悉细胞因子的共同特点;

3、了解细胞因子及其受体的功能。


Chapter cytokines

1. History for the research of the cytokines

细胞因子研究简史

 In 1957,Interferon (IFN ) was first found

 In 1969, termed lymphokine

 In1974,denominated cytokine

 cytokinology created;

international cytokine society

founded

《 Cytokine 》journal

 Companies for developing

cytokines in many countries


Chapter cytokines

细胞因子研究简史

 1957年,发现干扰素(Interferon, IFN);

1969年,提出淋巴因子(lymphokine)的概念 ;

1974年,定名细胞因子(cytokine);

 近二十年来, 细胞因子发展迅猛, 现已发现一百

  多种细胞因子;

形成专门学说——细胞因子学(cytokinology);

成立专门学会,如国际细胞因子学会

(international cytokine society);

创办专门杂志,如《Cytokines》等;

 开办了众多细胞因子的研制公司;


Chapter cytokines

Mj

IL-1

2. 细胞因子的概念 Concept of Cytokine

细胞因子是由免疫细胞和某些非免疫细胞(如血管内皮细胞、表皮细胞和成纤维细胞等)经刺激而合成分泌的一类小分子量可溶性糖蛋白或蛋白多肽。

Cytokines are low-molecular-weight regulatory proteins or glycoproteins secreted by white blood cells and various cells (vascular endothelial cell, epidermic cell and fibroblast ) in body in response to a number of stimuli.

Activated Th1 cell

macrophage

a

A

B’

D

C

P56

B

C58

IL-2

105

COOH

NH2


Chapter cytokines

Cytokine-producing cell

Cytokine

gene

Cytokine

Receptor

signal

Gene activation

Biological effects

Inducing stimulus

Overview of the induction and function of Cytokine

细胞因子诱导与功能概观


Chapter cytokines

3. Production of cytokines

细胞因子的产生

  • Normal cells(正常细胞)

  • Activated lymphocyte, activated monocyte / macrophage, NK cell, fibroblast, epithelial cell, endothelial cell.


  • Chapter cytokines

    • Tumor cells(肿瘤细胞)

    • Jurkat cell, WEHI-3, myeloma cell(骨髓瘤细胞)

    • Genetic engineering technique

    • 基因工程技术

    • Engineering cells, such as E.coli , yeast produce the recombinant cytokines.

    Cytokine gene

    E.coli expresses the cytokine protein

    purification

    Cytokine (product)

    E.coli


    Chapter cytokines

    4. 细胞因子分类 Cytokine classification

      按细胞因子的结构和功能分6类:

    Classified based on the structure and function

    1. interleukins, ILs (白细胞介素)

    2. colony stimulating factor,CSF(集落刺激因子)

    3. interferon, IFN(干扰素)

    4. tumor necrosis factor, TNF (肿瘤坏死因子)

    5. chemokine (趋化因子)

    6. growth factor, GF (生长因子)


    Chapter cytokines

    Interleukin, IL 白细胞介素

    Interleukins (ILs) are secreted by some leukocytes and act upon other leukocytes, until now, IL-1~IL-35 have been identified.

    IL-4

    IL-13

    IL-2


    Chapter cytokines

    Immune bioactivities of IL-2

    Mj

    Mj

    Th1

    NK

    LAK

    B

    Antigen presentation

    antigen

    APC

    IL-1

    Th1

    Th1

    Activation of T cell ( precursor producing IL-2)

    differentiation

    Th1

    IL-2 reactive cells (Th or TC )

    replication

    g-IFN IL-4 IL-5 IL-6

    antigen

    Th1

    Th1

    proliferation, differentiation Secretion of antibody


    Chapter cytokines

    Colony stimulating factor, CSF

    聚落刺激因子

    The cytokines that stimulate hemopoietic cells to form cell colony, Participate hemopoietic function are called CSF, for example GM-CSF,G-CSF,M-CSF, Epo,Tpo, etc

    G-CSF

    GM-CSF


    Chapter cytokines

    集落刺激因子的作用


    Chapter cytokines

    Interferon, IFN 干扰素

    The cytokines that have anti-viral infection, anti-tumor, and immune regulation, including IFN, IFN ( type I ); IFN ( type II ).

    virus

    infection

    cell

    IFN

    IFN

    IFN-, IFN-


    Chapter cytokines

    The anti-virus mechanism of IFN- a / 

    virus

    viral replication

    Inhibition of viral replication

    IFN-induced protein

    stimulating

    Signal-transduction

    nuclear

    nuclear

    IFN-a / 


    Chapter cytokines

    Type II interferon,

    IFN- g


    Chapter cytokines

    Activated Th1 cell

    NK cell

    IFN-

    NK cell

    B cell

    macrophage

    T cell

    Virus infected cell

    promoting IL-2 production IL-2R expression

    Enhancing

    IV hypersensitivity

    Plantation rejection

    cytotoxicity

    Promoting production of IgG3 and IgG2a

    Inhibiting

    Viral replication,

    proliferation

    Promoting expression of MHC-II and Fc, antimicroorganism and antitumor, synthesis ofTNF-.

    Promoting Activation

    killed

    Inhibitingexpression of CD23 and production of IgE

    Immune biological effects of IFN-


    Chapter cytokines

    Tumor necrosis factor,TNF

    The cytokines that induce directly apoptosis of

    tumor cells, including TNF, TNF (Lymphotoxin),

    FASL, CD70L, CD30L, CD40L, OX40L, TRAIL (TNF related apoptosis-inducing ligand)

    TNF- 


    Chapter cytokines

    Growth factor

    The cytokines that promote growth of various cells, epidermal growth factor,insulin-like growth factor,vascular endothelial growth factor

    vascular endothelial growth factor (VEGF)


    Chapter cytokines

    Chemokine(趋化因子)

    Chemokines, a group of low-molecular-weight cytokines including interleuki 8, that affect chemotaxis and other aspects of leukocyte behavior.

    Solution Structure Of The Cx3C Chemokine Domain Of Fractalkine

    Stromal Derived Factor-1 a


    Chapter cytokines

    趋化因子引起细胞形态的改变

    Chemokines induce cell shape change


    Chapter cytokines

    5.Biological effects of the cytokines

    生物学作用

    • Anti-infection and anti-tumor(抗感染,抗肿瘤)

    • Immune regulation(免疫调节)

    • Apoptosis(凋亡)

    • Stimulating the proliferation and differentiation of hemopoietic stem cells(刺激造血干细胞增殖,分化)

    • Promote the growth and differentiation of various cells

    • Participation and regulation of the inflammatory responses(参与和调节炎症反应)

    • Cytokine abnormalities in the pathogenesis in certain diseases (细胞因子异常与疾病)


    Chapter cytokines

    细胞因子的主要生物学效应

    • 抗感染和抗肿瘤作用

    • 免疫调节作用

    • 参与细胞凋亡

    • 刺激造血细胞增埴分化

    • 促进各种细胞的生长和分化

    • 参与和调节炎症反应

    • 细胞异常可导致疾病的发生


    Chapter cytokines

    Circulation

    6.main properties of the cytokines 主要特点

    (1)action manners 作用方式

    Bind to receptors on the membrane of the same cell that secreted it

    Autocrine 自分泌(自产自销)

    Binding to receptors on a target cell in close proximity to the producer cells

    Paracrine 旁分泌(自产旁销)

    Binding to target cells in distant parts of the body.

    Endocrine 内分泌(自产远销)


    Chapter cytokines

    B

    (2)Pleiotropy(多效性)

    One kind of cytokine may have multiple

    effects.

    Activation proliferation differentiation

    IL-4

    proliferation

    Thymus cell

    proliferation

    Mast cell


    Chapter cytokines

    B

    (3)Redundancy(重叠性)

    Several kinds of cytokines may have the same or similar effect.

    Stimulating the proliferation of the B cells

    IL-2、 IL-4、 IL-5

    B

    (4)synergy(协同性)

    Cytokines can also act synergistically (two or more cytokines

    acting together)。

    More effectively inducing the exchange of IgE

    IL-4 + IL-5


    Chapter cytokines

    B

    (5)Antagonism(拮抗性)

    Two or more cytokines show opposing activities.

    _

    IL-4

    +

    IFN-

    IL-4 interdicts the action that IFN-  induces Ig exchanges


    Chapter cytokines

    (6)Rapidity (作用迅速)

    On stimulation, rapid synthesis , release , action and degragation. Cytokine secretion is a brief, self-limited event.

    (7)high potency(高活性)

    Low-concentration cytokines perform remarkable biological effects(pM,10-12 M).

    (8) Non-specificity(非特异性)

    perform in the non-specific manner, and not restricted by MHC.


    Chapter cytokines

    (9)binding to specific receptors(结合受体)


    Chapter cytokines

    7. 细胞因子受体 Cytokine receptors

    TNF-R

    免疫球蛋白超家族受体

    I类细胞因子受体

    II类细胞因子受体

    趋化因子受体

    C1C3C2

    -S-S-

    C1C3C2

    -S-S-

    C1C3C2

    CC

    C

    C

    -S-S-

    C1C3C2

    G 蛋白

    IL-2 IL-3 IL-4 IL-5 IL-6 IL-7

    IL-9 IL-11 IL-12 IL-13 IL-15 OSM

    GM-CSF G-CSF LIF CNTF 生长激素催乳素

    IFN-a IFN-b IFN-g

    TNF-a TNF-bCD40 神经生长因子(NGF) FAS

    IL-8 RANTES MIP-1 PF4 MCAF NAP-2

    IL-1 M-CSF C-kit


    Chapter cytokines

    (2) Soluble cytokine receptors (sCKR)

    Production:

     Most of them break off from the member receptors

     Secretory receptor

    Secretory receptor

    member receptors


    Chapter cytokines

    8. Clinical application of Cytokine

    细胞因子的临床应用

    • Cytokine changes related to diseases

    •  (与疾病相关的细胞因子改变):

    • deficiency of cytokines and receptors ;

    • overexpression of cytokines;

    • high lever of soluble cytokine receptors.

    • Therapeutic use of cytokines and their receptors(疾病治疗):

    • supply and addition;

    • blockage and antagonist .


    Chapter cytokines

    (1) Common diseases related to cytokines

    • Infectious diseases(传染病)

    • tumor

    • Transplantation rejection(移植排斥反应)

    • Hematocytopenia(血细胞减少)

    • Hypersensitivity(超敏反应)

    • Autoimmune diseases (自身免疫病)


    Chapter cytokines

    细胞因子引起的病理反应

    细胞因子

    病理反应

    拮抗剂适应症

    IL-1

    发热,炎症,休克,低血压,-胰岛细胞毒性

    炎症性疾病,休克,类风湿关节炎,糖尿病,白血病等

    IL-2

    发热,渗漏综合征,贫血,低血压

    移植排斥,自身免疫病

    IL-3

    发热,流感样症状,刺激肥大细胞和嗜硷性粒细胞,刺激白血病细胞

    IL-4

    发热,促进IgE产生,I型变态反应

    哮喘等I型变态反应

    IL-6

    发热,炎症,刺激骨髓瘤细胞

    骨髓瘤,炎症性疾病

    IL-8

    炎症

    炎症性疾病

    IL-9

    哮喘

    哮喘

    GM-CSF

    发热, 流感样症状, 刺激白血病细胞

    白血病

    TNF

    发热,炎症,恶液质,休克

    休克, 炎症性疾病,恶液质,类风湿关节炎

    IFN

    发热, 流感样症状,炎症

    炎症性疾病

    TPO

    骨髓纤维化,微血栓形成

    EGF

    刺激某些肿瘤细胞增殖

    肿瘤

    bFGF

    刺激某些肿瘤增殖、转移

    肿瘤


    Chapter cytokines

    大剂量TNF注射造成恶液质的小鼠模型


    Chapter cytokines

    • 细胞因子与临床治疗

    • Clinical use of cytkine inhibitors

    ① 细胞因子抑制剂的临床应用

    IL-1受体拮抗剂(IL-1ra)治疗类风湿关节炎


    Chapter cytokines

    • 细胞因子抑制剂

      用于治疗炎症,自身免疫病,移植排斥,休克


    Chapter cytokines

    进入临床实验的细胞因子抑制剂

    名称

    公司

    适应症

    临床阶段

    可溶性IL-1受体

    (干粉吸入剂)

    Immunex

    哮喘

    I/II期

    可溶性IL-1受体

    (注射剂)

    急性髓样白血病

    I期

    IL-1受体拮抗剂

    Amegen

    败血性休克(试验中止),类风湿关节炎

    完成III期

    可溶性IL-4受体

    Immunex

    哮喘

    I/II期

    抗IL-4人源化抗体

    SmithKline

    哮喘

    I/II期

    抗IL-5人源化抗体

    SmithKline

    哮喘

    II期

    可溶性TNF受体II-Fc融合蛋白

    Immunex

    类风湿关节炎,慢性心衰

    上市,I期

    可溶性TNF受体I-Fc融合蛋白

    Hoffmann-La Roch

    休克,类风湿关节炎,多发性硬化症

    II/III期

    Centocor

    Crohn's Disease

    上市

    抗TNF单抗

    (infliximab)

    Genentech

    乳腺癌转移

    上市

    人源化抗HER2 (EGFR2)单抗

    DAB389-IL-2

    (IL-2免疫毒素)

    Seragen

    上市 

    I/II期

    T细胞淋巴瘤, I型糖尿病,严重类风湿关节炎,牛皮癣,HIV感染


    Chapter cytokines

    DAB389-EGF

    Seragen

    肿瘤

    I/II期

    人源化抗VEGF单抗

    Genentech Inc.

    晚期肺癌,肠癌

    III期

    抗VEGFR2(KDR)嵌合抗体

    Albert LoBuglio

    转移性肠癌

    I期

    人源化抗IL-8抗体(ABX-IL8)

    Abgenix

    Severe psoriasis

    I/II期临床

    IL13-PE38QQR(IL-13免疫毒素)

    NeoPharm, Inc

    肾癌

    I期临床

    TNF反义寡核苷酸

    Isis

    类风湿关节炎,牛皮癣

    I期临床

    抗eotaxin抗体

    (CAT-213)

    Cambridge Antibody

    变态反应

    I期临床


    Chapter cytokines

    ② 细胞因子的临床应用(Clinical use of cytokines)


    Chapter cytokines

    名称

    适应症

    IFNα

    白血病、Kaposi肉瘤、肝炎、癌症、AIDS

    IFNγ

    慢性肉芽肿、生殖器疣、过敏性皮炎、感染性疾病、类风湿关节炎

    G-CSF

    自身骨髓移植、化疗导致的粒细胞减少症、 AIDS、白血病、再生障碍性贫血

    GM-CSF

    自身骨髓移植、化疗导致的血细胞减少症、 AIDS、再生障碍性贫血、

    Epo

    慢性肾衰导致的贫血、癌症或癌症化疗导致的贫血、失血后贫血

    IL-2

    癌症、免疫缺陷、疫苗佐剂

    IFNβ

    多发性硬化症

    IL-11

    放化疗所致血小板减少症

    干细胞因子(SCF)

    与G-CSF联合应用于外周血干细胞移植

    EGF

    外用药治疗烧伤、溃疡

    bFGF

    外用药治疗烧伤、外周神经炎

    已批准上市的细胞因子基因工程药物


    Chapter cytokines

    正进行临床试验的细胞因子基因工程药物

    细胞因子名称

    适应症

    公司

    Immunex,Schering-Plough

    IL-10

    炎症,银屑病,Crohn’s 病,类风湿关节炎

    IL-12

    肿瘤,HIV感染,I型变态反应

    GI

    Tpo

    血小板减少症

    GI,沈阳三生

    TNF变异体

    肿瘤

    国内多家企业

    Flt3/flk3 Ligand(FL)

    肿瘤

    Immunex

    Myeloid Progenitor Inhibitory Factor-1 (MPIF-1)

    HGS

    肿瘤大剂量化疗

    TGF-

    慢性皮肤溃疡,多发性硬化症

    Genzyme

    促进烧伤、慢性溃疡的伤口愈合;抗癌药物引起的粘膜损伤;炎症性肠道疾病

    Keratinocyte Growth Factor-2 (KGF-2)

    HGS

    MIP-1变异体

    肿瘤化疗的骨髓保护作用

    British Biotech

    OPG(osteoprotegerin)

    骨质疏松

    Amgen

    Mulitkine(白细胞产生的细胞因子混合制剂)

    转移性肿瘤

    CEL-SCI

    免疫缺陷

    HGS

    B细胞刺激因子(BlyS)


    Chapter cytokines

    9、细胞因子的研究热点

    1) 新细胞因子的基因克隆化 cytokine gene cloning

    2) 细胞因子受体的基因克隆化 cytokine receptor gene cloning

    3) 细胞因子信号转导机制 Signal transduction of cytokines

    4) 新一代细胞因子:高活性,多功能,低毒副作用,长

    半衰期,高稳定性 New-generation cytokines

    5) 细胞因子作为生物应答调节剂(BRM)的临床应用

    Clinical application of cytokines as BRM

    6) 细胞因子表达调控 Regulation of cytokine expression

    7) 细胞因子基因治疗 Gene therapy of cytokines


    Chapter cytokines

    10. Summary

    1. Cytokines are a family of proteins that mediate many of the

    responses of innate and adaptive immunity. (概念)

    2. The same cytokines may be produced by many cell types, and

    individual cytokines often act on diverse cell types. Cytokines

    are synthesized in response to inflammatory or antigenic

    stimuli and usually act locally.(多源性,多效性,协同性)

    3. Cytokines often act in an autocrine or paracrine fashion, and

    may be produced in sufficient quantity to circulate and exert

    endocrine actions. ( 3种作用方式).

    4. Cytokines mediate their actions by binding with high affinity

    to receptors. (与受体结合发挥作用)


    Chapter cytokines

    5.Cytokines serve many functions that are critical to host defense

    against pathogens.(关键的抗感染因子).

    6. Cytokines provide important amplification mechanisms that

    enable small numbers of lymphocytes specific for any one

    antigen to activate a variety of effector mechanisms to eliminate

    the antigen. (放大效应).

    7. Excessive production or actions of cytokines can lead to

    pathologic consequences. The administration of cytokines or

    their inhibitors is a potential approach for modifying biologic

    responses associated with immune and inflammatory diseases.

    (与临床密切相关)


    Chapter cytokines

    11. Practice Quiz

    1. Cytokines may exhibit __________ action, signaling the cells that produce them.

    a. antagonistic b. autocrine c. endocrined. paracrine. e. synergistic

    2. Cytokines are NOT

    a. antigen specific.b. capable of activating more than one cell type.c. made by lymphocytes.d. small protein molecules. e. synthesized de novo in response to antigen or other cytokines.

    3. Several cytokines may have the same effect on the cells they bind. This is an example of

    a. a cascade.b. antagonism.c. pleiotropism.d. redundancy. e. synergy.


    Chapter cytokines

    4. Characterization of cytokine activities is NOT made more difficult by their

    a. gene structure.b. pleiotropism.c. redundancy.d. secretion close to target cell membranes.e. short half-lives.

    5. Interferons

    a. activate B cells to make virus-specific antibodies.b. are Th2 cytokines.c. are virus proteins that interfere with activation of cytotoxic T cells.d. block virus infection of host cells. e. inhibit virus replication by infected cells.

    6. A cytokine can do all of the following EXCEPT

    a. bind to receptors which do not share cytokine-binding subunits.b. bind to its specific receptor on the same cell that produced it.c. bind to receptor antagonists produced by pathogenic viruses.d. compete with other cytokines whose receptors share signal-transducing subunits e. upregulate (increase) synthesis of high affinity subunits for its receptor.


    Chapter cytokines

    7. Members of a cytokine receptor family

    a. all bind the same cytokines. b. are grouped together because they share antigen specificityc. are often found on the same cellsd. are similar in protein structure and sometimes in regions of amino acid sequence. e. are specific for cytokines produced by a single cell type

    8. The ability of a cytokine to change gene expression in the target cell is influenced by all of the following EXCEPT

    a. presence of high-affinity receptors on the target cell.b. presence of soluble cytokine receptors.c. proximity of the producing and target cells.d. rate of transport of cytokine-receptor complexes into the cytoplasm.e. simultaneous production of another cytokine whose receptor uses the same signal transducing subunit.

    9. Cytokines are NOT

    a. able to inhibit the function of other cytokines.b. able to stimulate the synthesis of other cytokines.c. produced by more than one cell type.d. small protein molecules. e. stored in the cell for quick release.


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