Lecture免疫學概述培訓課件

1、Lecture免疫學概述Lecture免疫學概述The Origin of Immune ConceptThe term “Immunity” = Latin word “Immunitas” = Protection from legal prosecution (Roman senators)Biological definition = Protection from infectious diseases2.The concept of immunity = existed in ancient Greek & Chinese = the experienced view“天花”又名痘

2、瘡 十六世紀下半葉（明代隆慶年間1567-1572）正式發(fā)明了人痘接種術，十七世紀普遍推廣。2Lecture免疫學概述The Origin of Immune ConceptThThe medical view of immunity = Edward Jenner (1796)Observation = Milkmaids generally get No SmallpoxHypothesis = Pus from vaccinia (cowpox) = Protect milkmaids from smallpox Test = Inoculate materials from cowpo

3、x pus = Protect a young boy from smallpox (Protective immunity)The vaccination against smallpoxExudate from a cowpox pustule on the hand of milkmaid Sarah Nelmes was inserted into scratches on the arms of James Phipps, May 14, 1796. 1796年，英國人Edward Jenner發(fā)明牛痘苗預防天花（cowpox vaccine）。3Lecture免疫學概述The va

4、ccination against smallpEdward JennerEradication of smallpox200 yearsafter JennerWHO announcesmallpox eradicated1965197019751980Countries withmore than onesmallpox caseper month301504Lecture免疫學概述Edward JennerEradication of sm4.The concept of “Immunity” developed gradually over time through many scie

5、ntific findings: = Robert Koch (1905 Nobel Laureate) = Infectious diseases caused by microorganisms= Louis Pasteur = Vaccines against cholera & rabies= These clinical successes = The search of underlying mechanism of “Protection of Infectious Diseases”研制出多種減毒疫苗（attenuated vaccine）,用于預防雞霍亂,炭疽桿菌,狂犬病等疾

6、病。Louis Pasteur1880年，雞霍亂弧菌減毒疫苗5Lecture免疫學概述4.The concept of “Immunity” dVaccines for common infectious diseasesb型流感嗜血桿菌 破傷風 百日咳 風疹 腮腺炎 麻疹 脊髓灰質炎 乙肝 白喉 Still no effective vaccines for many infectious microbes, e.g., HCV, HIV, Dengue virus.etc6Lecture免疫學概述Vaccines for common infectious細胞免疫和體液免疫學派的形成： (

7、19世紀后葉-20世紀中葉) 免疫學重大學說和理論：克隆選擇學說(1957)；免疫網(wǎng)絡學說(1974) 對免疫系統(tǒng)的全面認識：發(fā)現(xiàn)各種免疫器官及免疫細胞Descriptive Science” = “Experimental Science”7Lecture免疫學概述細胞免疫和體液免疫學派的形成： (19世紀后葉-20世紀中葉(1) 細胞免疫學說 (cellular immunity) Neutrophil梅契尼可夫1880s- Metchnikoff discovered phagocytic cells that ingest microbes and particlescells con

8、ferred immunity免疫應答機制的研究:8Lecture免疫學概述(1) 細胞免疫學說 (cellular immunity1. The Discovery of antibody functions in 18972. The Nobel Laureate in Medicine 1908Adopted from Nature Immunology, July 2008 liquid of blood conferred immunity 發(fā)現(xiàn)抗體能清除各種病原微生物或者能中和細菌毒素。(2) 體液免疫學說 (humoral immunity)Paul Ehrlich: One o

9、f the fathers of humoral adaptive immunity9Lecture免疫學概述1. The Discovery of antibody fQ: Which confers immunity cells or serum?A: Both cells and serum contribute to immunity!10Lecture免疫學概述Q: Which confers immunity celMacFarlane Burnet （1899-1985） 克隆選擇學說clonal selection theory 體內事先就存有能識別各種抗原的細胞克隆(clon

10、e)，每一細胞表面均有對特定抗原的受體，能與相應抗原結合而識別它們?？乖淖饔迷谟谶x擇與其相應的細胞克隆與其受體結合后，引起細胞的增殖分化，產生免疫應答，產生大量抗體（即免疫球蛋白）。抗體形成理論 -克隆選擇學說 體內存在無數(shù)抗原特異性淋巴細胞克隆胚胎期與自身成分反應的淋巴細胞被“禁忌”形成耐受出生后淋巴細胞遇到相應抗原發(fā)生特異應答，并形成記憶禁忌細胞突變可導致自身免疫11Lecture免疫學概述MacFarlane Burnet克隆選擇學說 體內事Advances in technology (e.g., Cell culture, Monoclonal Ab, Flow cytometry

11、, Genetic engineeringetc) have facilitated our understanding of the immune system and its functions. “(1)免疫學理論研究抗體多樣性和特異性的遺傳學基礎 T細胞抗原受體的基因克隆免疫遺傳學和MHC限制性的發(fā)現(xiàn)細胞因子及其受體信號轉導的研究危險信號學說(2)免疫學應用研究：基因工程疫苗基因工程制備重組細胞因子免疫細胞治療治療性抗體12Lecture免疫學概述(1)免疫學理論研究(2)免疫學應用研究：12Lecture免疫（immunity)傳統(tǒng)概念指免除疫病、免除感染，指機體抗感染的防御能力。現(xiàn)

12、代概念指機體對“自己”或“非己”的識別并排除“非己”的功能。13Lecture免疫學概述免疫（immunity)13Lecture免疫學概述免疫的基本功能功能正常表現(xiàn)（有利）異常表現(xiàn)（有害）免疫防御immune defence抗病原微生物的侵襲超敏反應易受感染或免疫缺陷病免疫穩(wěn)定immune homeostasis清除損傷、衰老、死亡細胞 自身免疫性疾病免疫監(jiān)視immune surveillance清除突變或畸變的惡性細胞 惡性腫瘤 14Lecture免疫學概述免疫的基本功能功能正常表現(xiàn)（有利）異常表現(xiàn)（有害）免疫防御抗免疫系統(tǒng) (immune system)：機體執(zhí)行免疫功能的組織、器官、細

13、胞和分子構成免疫系統(tǒng)。15Lecture免疫學概述免疫系統(tǒng) (immune system)：機體執(zhí)行免疫功能的The four kinds of pathogens that cause human disease常見的病原微生物16Lecture免疫學概述The four kinds of pathogens thOverview of immune responses17Lecture免疫學概述Overview of immune responses17固有免疫（innate immunity）是機體抵御病原微生物入侵的第一道防線，并啟動和參與適應性免疫應答。天然免疫（natural im

14、munity)或非特異性免疫(nonspecific immunity)，是個體出生時就具有的免疫力，通過遺傳獲得，是生物在長期進化過程中逐漸形成的，其針對外來異物的范圍廣，反應迅速，其應答模式和強度不因與病原微生物的反復接觸而改變。18Lecture免疫學概述固有免疫18Lecture免疫學概述固有免疫系統(tǒng)的組成屏障細胞分子皮膚黏膜屏障：物理、化學、微生物血-腦屏障、血-胸腺屏障血-胎屏障、氣-血屏障巨噬細胞、中性粒細胞、樹突狀細胞、T 細胞、NK細胞、NKT細胞、B1細胞、肥大細胞、嗜堿性粒細胞和嗜酸性粒細胞等?？咕?、溶菌酶、急性期蛋白、補體、細胞因子和黏附分子、19Lecture免疫學

15、概述固有免疫系統(tǒng)的組成屏障皮膚黏膜屏障：物理、化學、微生物巨噬細Epithelial barriers prevent the entry of microbes20Lecture免疫學概述Epithelial barriers prevent th固有免疫細胞 PhagocyteNKILLs（固有樣淋巴細胞）DC MCBasophil Eosinophil T細胞 NKT細胞 B1細胞Monocyte-macrophageNeutrophil21Lecture免疫學概述固有免疫細胞 Phagocyte T細胞Monocyt肺部巨噬細胞吞噬大腸桿菌22Lecture免疫學概述肺部巨噬細胞吞噬大

16、腸桿菌22Lecture免疫學概述Phagocytosis by innate immunity23Lecture免疫學概述Phagocytosis by innate immunit固有性免疫分子指體表分泌液以及血漿和其它體液中能夠識別或攻擊病原體的可溶性分子?？咕?antimicrobial peptides溶菌酶 lysozyme急性期蛋白(acute phase proteins, APP)脂多糖結合蛋白（LBP）血清淀粉樣蛋白（SAP）甘露糖結合蛋白（MBP）C反應蛋白等（CRP）補體 細胞因子和黏附分子24Lecture免疫學概述固有性免疫分子指體表分泌液以及血漿和其它體液中能夠

17、識別或攻擊Complement activation pathways 25Lecture免疫學概述Complement activation pathwaysElie Mechnikoff:The Pioneer of Innate Immunity1. The Discovery of Phagocytes & Phagocytosis2. The Nobel Laureate in Medicine 1908Adopted from Nature Immunology, July 2008 The development of modern Immunology in 20th cent

18、ury mainly centers on understanding the Adaptive Immune System.26Lecture免疫學概述Elie Mechnikoff:The Pioneer ofCharles A. Janeway, M.D.Yale Univ. The “Renaissance” of innate immunityIn 1989, Janeway = Immune recognition of microbes = Detection of conserved molecular patterns, referred to PAMPs (Pathogen

19、-Associated Molecular Patterns) with features:1. Invariant among a given class of microbes.2. Have essential roles in microbial physiology. 3. Recognized by receptors of the innate immune system, called PRRs (Pattern-Recognition Receptors). 4. Innate immunity regulates adaptive immunity27Lecture免疫學概

20、述Charles A. Janeway, M.D.The “R Julie A. Hoffmann, Ph.D.Strasbourg, FranceThe “Renaissance” of innate immunityIn 1996, Hoffmanns group Toll functions as a PRR in Drosophila28Lecture免疫學概述 Julie A. Hoffmann, Ph.D.The Key concepts in innate immunity1. The innate immune system mainly recognizes common s

21、tructures shared by classes of microbes, = Pathogen Associated Molecular Patterns (PAMPs), e.g., LPS, Peptidoglycan, Microbial DNA & RNA. 2. Host receptors that recognize PAMPs are called Pattern- Recognition Receptors (PRRs), which are encoded in “Germline” DNA= limited Diversity. 3. Innate immunit

22、y not only provide the first line of defenses but link to the program of adaptive immunity.4. PRRs may also recognize components from injured or dead host cells = Autoimmune diseases29Lecture免疫學概述Key concepts in innate immunitPattern Lipopolysaccharide (LPS) Lipoteichoic acid Bacterial lipopeptides

23、Peptidoglycan Bacterial DNA (CpG) Flagellin Terminal mannose/fucose Viral DNA (CpG) ssRNA dsRNAPathogen-AssociatedMolecularPatterns(PAMP)是病原微生物（尤其是原核生物）表面存在一些人體所沒有的，但可為許多相關微生物所共享、結構恒定、進化保守的分子結構。30Lecture免疫學概述Pattern Lipopolysaccharide (L損傷相關分子模式（damage-associated molecular patterns，DAMPs）機體自身細胞所釋放的內

24、源性分子，即內源性危險信號，來源于受損或壞死組織和某些激活的免疫細胞。主要有HMGB1、熱體克蛋白等。31Lecture免疫學概述損傷相關分子模式機體自身細胞所釋放的內源性分子，即內源性危險PAMP vs DAMPSterile inflammationconserved microbial motifs VS non-microbial signals 32Lecture免疫學概述PAMP vs DAMPSterile inflammat33Lecture免疫學概述33Lecture免疫學概述Locations of Different PRRsBody fluids-Soluble PRR

25、sCellular PRRs- Cell surface- Endosomes- Cytosol34Lecture免疫學概述Locations of Different PRRsBodToll-like Receptors35Lecture免疫學概述Toll-like Receptors35Lecture免疫MyD88-Dependent and independent Signaling36Lecture免疫學概述MyD88-Dependent and independenNLRs are cytoplasmic bacterial sensors that activate inflamm

26、asomes37Lecture免疫學概述NLRs are cytoplasmic bacterial1Viral Pattern Recognition Receptors: Signaling and Consequences38Lecture免疫學概述1Viral Pattern Recognition RecInteraction between innate and& adaptive immunity1. Innate immunity = Ag presentation (by Dendritic cells)2. Adaptive immunity = Ag recognitio

27、n (by T & B lymphocytes)39Lecture免疫學概述Interaction between innate and適應性免疫（adaptive immunity）是機體獲得性、抗原特異性、抵抗病原微生物感染的高效防御機制。獲得性免疫（acquired immunity)或特異性免疫(specific immunity)，是個體出生后，在環(huán)境中受抗原刺激所產生的免疫力，針對特定抗原，有特異性、多樣性、記憶性和耐受性。1) 特異性，對某個特定的異物性抗原能引起特異性免疫應答；指抗原特異性。2) 多樣性，機體可針對環(huán)境中多種多樣的抗原，分別建立起不同的特異性免疫應答；多樣性是特

28、異性產生的基礎。 3) 記憶性，當異物抗原再次入侵時，可產生快而強的再次免疫應答效應；記憶性淋巴細胞。4) 耐受性，正常情況下，免疫系統(tǒng)對自身成分有保護性的免疫耐受； 40Lecture免疫學概述適應性免疫是機體獲得性、抗原特異性、抵抗病原微生物感染的高效抗原決定簇Antigenic determinant，AD抗原分子表面具有特殊立體構型和免疫活性的化學基團稱為抗原決定簇或抗原決定基。由于抗原決定簇通常位于抗原分子表面，因而又稱為抗原表位(epitope)。 抗原決定簇抗原決定基 抗原表位 抗原決定簇決定抗原的特異性，即決定抗原與抗體發(fā)生特異性結合的能力（實際是抗原決定簇與抗體的結合）。AD

29、的數(shù)目、性質和空間構象決定抗原特異性抗原以AD與相應抗原受體及抗體特異性結合41Lecture免疫學概述抗原決定簇Antigenic determinant，AAPC加工處理的抗原種類: 外源性抗原(exogenous antigen): 通過吞噬或吞飲等作用被APC從細胞外攝入的抗原，以抗原肽-MHC I I類分子復合物形式提呈給CD4+T細胞 。 內源性抗原(endogenous antigen): 細胞內合成的抗原，以抗原肽-MHC I類分子復合物形式提呈給CD8+T細胞 。 42Lecture免疫學概述APC加工處理的抗原種類:42Lecture免疫學概述外源性抗原加工，處理及提呈AP

30、C 攝取的外源性抗原在內體中降解成肽，與 MHC類分子(在內質網(wǎng)合成) 結合后表達于細胞表面。外源性抗原加工中需要 Ii 鏈和 HLA-DM 分子的參與。Ii 鏈 與 MHC類分子的轉運有關，并通過 CLIP 封閉 MHC類分子的肽結合部位，阻止 MHC-類分子在內質網(wǎng)中與內源性抗原肽結合。HLA-DM 分子促使 CLIP 從 MHC類分子肽結合區(qū)解離，有利抗原肽與 MHC類分子結合。 43Lecture免疫學概述外源性抗原加工，處理及提呈APC 攝取的外源性抗原在內體中降內源性抗原加工，處理及提呈內源性抗原經(jīng)蛋白酶體降解成肽，通過抗原加工相關轉運體(TAP1、TAP2)轉運進入內質網(wǎng)，與 M

31、HC類分子(在內質網(wǎng)合成)結合成肽-MHCI類復合物，通過高爾基體表達于細胞表面。TAP是內質網(wǎng)上的異源性二聚體，由TAP-1及TAP-2基因編碼胞漿中蛋白酶體（proteasomes, 核心成分為低分子量多肽LMP細胞被病毒感染后出現(xiàn)的病毒蛋白，基因突變后產生的腫瘤抗原 44Lecture免疫學概述內源性抗原加工，處理及提呈內源性抗原經(jīng)蛋白酶體降解成肽，通過THE ADAPTIVE IMMUNE RESPONSEAntibody-Mediated Immunity (AMI)Involves B lymphocytes, plasma cells and antibodiesHumoral

32、immunityName derives from antibodies found in body fluids (humors - old medical term)Cell-Mediated Immunity (CMI)Involves T lymphocytes, antigen-presenting cells and MHC (major histocompatibility complex) moleculesCellular immunity45Lecture免疫學概述THE ADAPTIVE IMMUNE RESPONSEAnTypes of adaptive immunit

33、y1. Humoral immunity = Molecules in body fluid, e.g. Antibody (Ab) = Key player = B cells = Target extracellular microbes & toxins2. Cell-mediated immunity = Key player = T cells = regulate other immune cells = Target intracellular microbes, e.g. viruses, bacteriaFor innate immunity, it also include

34、s Humoral & Cellular components for immune defense46Lecture免疫學概述Types of adaptive immunity1. H1、抗原提呈與識別階段（感應階段）：2、活化、增殖、分化階段（反應階段）： T細胞活化、增殖分化為效應T細胞； B細胞活化、增殖分化為漿細胞； 部分細胞發(fā)育為記憶細胞。3、效應階段： 效應T細胞對抗原的清除； 漿細胞分泌抗體清除抗原。免疫應答的三個階段47Lecture免疫學概述1、抗原提呈與識別階段（感應階段）：免疫應答的三個階段47LOverview of adaptive immune response

35、s48Lecture免疫學概述Overview of adaptive immune reCELL-MEDIATED IMMUNITY (CMI)Directed against intracellular microorganisms Non-phagocytic cells and phagocytic cellsT-lymphocytes (T cells)Differentiate into effector cells following antigen presentation by antigen presenting cells (APCs)Functional types o

36、f T cellsHelper (CD4 T cells)TH1 and TH2 cellsCytotoxic (CD8 T cells)49Lecture免疫學概述CELL-MEDIATED IMMUNITY (CMI)DiT cells develop in the thymus50Lecture免疫學概述T cells develop in the thymus5TSCCD4 RTEDNPre-TCRDPTCRCD4CD8TCRTCRCD8CD4 SPTCRCD4CD4b-selectionPositiveselectionNegative selectionFunctional mat

37、urationTCR-b rearrangementTCR-a rearrangementTCRCD8CD8 SPCD8 RTEDevelopment of ThymocytesDoublenegativeDoublepositiveSinglepositive51Lecture免疫學概述TSCCD4 RTEDNPre-TCRDPTCRCD4CD8T cells undergo further differentiation in secondary lymphoid tissues after encounter with antigenOnly a small fraction of na

38、ive T cells (mature T cells before they encounter antigen) survives the positive and negative selection, and leaves the thymus.Mature naive T cells can re-circulate between blood and lymphoid tissues for many years (in contrast to B cells, which have shorter life span).In secondary lymphoid tissues,

39、 T cells accumulate in T cell areas, where they become activated by their specific antigens.Encounter with antigen induces the final stage of T cell development: their differentiation into effector T cells. Some effector T cells stay in the lymphoid tissues (CD4-TH2 cells), while others migrate to s

40、ite of infection (CD8 and CD4-TH1 cells).52Lecture免疫學概述T cells undergo further differT細胞受體復合物由TCR和CD3組成。前者識別和結合抗原肽, 后者將TCR獲得的抗原信號傳遞至細胞內。T細胞對抗原的識別 APCT細胞53Lecture免疫學概述T細胞受體復合物T細胞對抗原的識別 APCT細胞53Lect信 號第一信號第二信號T細胞TCR和CD4/CD8 CD28APCMHC-肽復合物B7(B7.1、B7.2)T細胞活化的雙信號刺激 第一信號：TCR對MHCII抗原肽復合物的識別，CD3分子將第一信號傳遞到細

41、胞內。 第二信號：CD28識別專職APC上的B7分子,又稱協(xié)同刺激信號。 54Lecture免疫學概述信 號第一信號第二信號T細胞TCR和CD28APCMHC-肽55Lecture免疫學概述55Lecture免疫學概述Effector T cells In contrast to terminally differentiated B cells (plasma cells), there are several types of terminally differentiated effector T cells.CD8 T cells Cytotoxic T cells (recogniz

42、e MHC class I molecules)CD4 T cellsTH1 helper cells (activate macrophages)TH2 helper cells (induce differentiation of B cells into plasma cells and production of antibodies)Activation (cytokines)(recognize MHC II molecules)56Lecture免疫學概述Effector T cells In57Lecture免疫學概述57Lecture免疫學概述The immune syste

43、m is maintained in a carefully regulated balance between the two polarised control arms, Th1 (cellular immunity) and Th2 (humoral immunity).58Lecture免疫學概述The immune system is maintaineIn disease states the balance is skewed. multiple sclerosis, rheumatoid arthritis and type I diabetes, have a Th1 bi

44、as, whereas cancer patients have a Th2 bias. 59Lecture免疫學概述In disease states the balance Th1 and Th2 Cells Do not Represent All CD4+ Cells60Lecture免疫學概述60Lecture免疫學概述More T helper subsetsTh3: TGF-producing CD4 T cellsTr1: IL-10-producing CD4 T cellsTh9: IL-9-producing CD4 T cellsTfh: follicular help

45、er T cells, located in the follicular regions of lymph nodes and spleen,follicular Th1/Th2/Th17 cells61Lecture免疫學概述More T helper subsetsTh3: TGFANTIBODY-MEDIATED (HUMORAL) IMMUNITYDirected against extracellular microorganisms and toxinsB-lymphocytes (B cells)Differentiate into plasma cells which pro

46、duce antibodiesFunction as antigen-presenting cells (APCs)Classification of Antibodies (Immunoglobulins)Immunoglobulin M (IgM)Immunoglobulin G (IgG)Immunoglobulin A (IgA)Immunoglobulin D (IgD)Immunoglobulin E (IgE)62Lecture免疫學概述ANTIBODY-MEDIATED (HUMORAL) IM 抗體的功能V區(qū)的功能 識別并特異性結合抗原 單體（IgG, IgE) 2價 二聚體

47、(分泌型IgA) 4價 五聚體(IgM) 10價 中和效應 中和毒素和病毒 與Ag結合 促吞噬細胞吞噬 抗體的結合價 實際意義63Lecture免疫學概述 抗體的功能 抗體的結合價 實際意義63LeC區(qū)的功能 1.激活補體系統(tǒng) Ab(IgM、IgG) + Ag C1q 補體經(jīng)典途徑 IgG4、IgA和 IgE的凝聚物 補體旁路途徑 2.介導免疫細胞活性 (1)調理作用（opsonization）：IgG + 抗原(顆粒性) FcR（單核、巨噬細胞及中性粒細胞） 促吞噬細胞吞噬； (2)ADCC：IgG + 抗原(靶細胞) Fc R（NK 細胞） 殺傷靶細胞； (3)介導超敏反應：型、型和型超敏

48、反應。 3.穿越胎盤和粘膜64Lecture免疫學概述C區(qū)的功能64Lecture免疫學概述Antibody-Dependent Cellular Cytotoxicity (ADCC) 65Lecture免疫學概述Antibody-Dependent Cellular CyTh2與B細胞的相互作用，獲得第二信號：協(xié)同刺激信號CD40-CD40L活化的Th2細胞分泌細胞因子及表達CD40L，輔助B細胞活化CD79/2第二信號（Th細胞信號） 有二種方式 （1）Th細胞-B細胞間接觸作用：CD40L-CD40等 （2）Th細胞分泌細胞因子：IL-4、5、6等 胸腺依賴性抗原（TD-Ag）66Le

49、cture免疫學概述Th2與B細胞的相互作用，獲得第二信號：協(xié)同刺激信號CD40Specificity, Memory, and Homeostasis of Adaptive Immunity67Lecture免疫學概述Specificity, Memory, and HomeoLecture免疫學概述培訓課件多克隆抗體(polyclonal antibody，PcAb )：采用傳統(tǒng)的免疫方法，將抗原物質經(jīng)不同的途徑進入動物體內，經(jīng)數(shù)次免疫后采取動物血液，分離出血清，由此獲得的抗血清即為多克隆抗體。用天然的抗原物質免疫動物，刺激多個B細胞克隆所獲得的免疫血清（含多種特異性抗體）。單克隆抗體(

50、Monoclonal Antibody，McAb):由一個B細胞分化增殖的子代細胞產生的針對單一抗原決定簇的抗體，稱單克隆抗體。由一個B細胞克隆產生。識別一種抗原表位。高度均一（結構、特異性）。雜交瘤技術制備?；蚬こ炭贵w：利用基因工程技術來制備的抗體分子稱為基因工程抗體，是分子水平的抗體。69Lecture免疫學概述多克隆抗體(polyclonal antibody，PcAb抗體針對的靶分子作用機制治療疾病CD3阻斷T細胞功能預防腎移植排斥反應CD25阻斷IL-2受體預防腎移植排斥反應CD20(或偶聯(lián)核素)誘導腫瘤細胞凋亡non-Hidgkins淋巴瘤和RACD33(免疫毒素)誘導腫瘤細胞凋

51、亡急性髓樣白血病CD52誘導腫瘤細胞凋亡慢性B淋巴細胞白血病，T細胞瘤Her2(CD340)抑制和殺傷腫瘤細胞轉移性乳腺癌EGFR抑制腫瘤血管形成轉移性結腸直腸癌和頭頸部腫瘤，非鱗癌、非小細胞肺癌，對化療反應差的多形性膠質細胞瘤CD41/CD61 (gpIIbIIIa)抑制血小板凝聚預防冠狀動脈血管形成術中 血栓形成US和EU所批準的治療性抗體70Lecture免疫學概述抗體針對的靶分子作用機制治療疾病CD3阻斷T細胞功能預防腎移 鼠源性單克隆抗體將逐漸被人源化抗體所替代：鼠源性單克隆抗體與人補體成分結合能力低，CDC作用相應較弱，對腫瘤細胞的殺傷能力較弱；它與NK等免疫細胞表面Fc受體親和力

52、弱，介導的 ADCC作用較弱；鼠源抗體在人血循環(huán)中的半衰期短，它發(fā)揮ADCC與CDC作用的時間較短；鼠單克隆抗體具有免疫原性，宿主易產生抗抗體引起過敏反應。抗體人源化改造及人源抗體制備71Lecture免疫學概述 鼠源性單克隆抗體將逐漸被人源化抗體所替代：鼠源性單克隆 人-鼠嵌合抗體：應用基因工程技術將小鼠單克隆抗體的恒定區(qū)用人源抗體恒定區(qū)代替而拼接成嵌合抗體。改型抗體如CDR移植、SDR移植：用鼠單克隆抗體的CDR、SDR移植到人源抗體可變區(qū)，替代人源抗體CDR、SDR。表面氨基酸殘基人源化抗體人源化的主要技術72Lecture免疫學概述 人-鼠嵌合抗體：應用基因工程技術將小鼠單克隆抗體的恒

53、定區(qū)用MjmacrophageIL-8Activated T cellaADP56BC58BCNH2COOHIL-2 Cytockines 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. Cytokine73Lectur

54、e免疫學概述MjmacrophageIL-8Activated T c Biological effects 74Lecture免疫學概述 Biological effects 74Lecture免IL-1TNFGM-CSFM-CSFFGFPDGFVEGFIL-12IL-15IL-6LIFOSMChemokinesTGFIL-10IL-11IL-13sTNF-RIL-1raPRO-INFLAMMATORYANTI-INFLAMMATORYCytokine imbalance during inflammation75Lecture免疫學概述IL-1GM-CSFFGFIL-12IL-6Chemokin 細胞因子的研究熱點1、新細胞因子的基因克隆化2、細胞因子受體的基因克隆化3、細胞因子信號轉導機制4、新一代細胞因子：高活性，多功能，低毒副作用，長半衰期，高穩(wěn)定性5、細胞因子作為生物應答調節(jié)劑（BRM）的臨床應用6、細胞因子表達調控7、細胞因子基因治療76Lecture免疫學概述 細胞因子的研究熱點76Lecture免疫學概述Activation of adaptive immunity by innate i