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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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slide1

第六章 细胞因子

Chapter 6 Cytokines

slide2

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.
slide3

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。

slide4

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

slide5

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;

slide6

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

slide7

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

slide8

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.
slide9

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

slide10

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)

slide11

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

slide12

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

slide13

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

slide15

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-

slide16

The anti-virus mechanism of IFN- a / 

virus

viral replication

Inhibition of viral replication

IFN-induced protein

stimulating

Signal-transduction

nuclear

nuclear

IFN-a / 

slide18

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-

slide19

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- 

slide20

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)

slide21

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

slide22

趋化因子引起细胞形态的改变

Chemokines induce cell shape change

slide23

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)
slide24

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
slide27

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)

slide28

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

slide29

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

slide30

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

slide31

(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.

slide33

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

slide34

(2) Soluble cytokine receptors (sCKR)

Production:

 Most of them break off from the member receptors

 Secretory receptor

Secretory receptor

member receptors

slide35

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 .
slide36

(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)
slide37

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

slide39

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

slide40

细胞因子抑制剂

用于治疗炎症,自身免疫病,移植排斥,休克

slide41

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

slide42

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

slide44

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

slide45

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)

slide46

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

slide47

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)

slide48

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)

slide49

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.

slide50

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.

slide51

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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