Lecture免疫学概述

1、The Origin of Immune Concept1.The 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“天花天花”又名痘疮又名痘疮 中国从宋朝起用人痘接种预防

2、天花3. The 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 cowpox pus = Protect a young boy from smallpox (Protective immunity)The vaccination again

3、st 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. Edward JennerEradication of smallpox200 yearsafter JennerWHO announcesmallpox eradicated1965197019751980Countries withmore than onesmallpox caseper mon

4、th301504. The concept of “Immunity” developed gradually over time through many scientific 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

5、“Protection of Infectious Diseases”= The development of “Immunology” 5. Advances in technology (e.g., Cell culture, Monoclonal Ab, Flow cytometry, Genetic engineeringetc) have facilitated our understanding of the immune system and its functions. “Descriptive Science” = “Experimental Science”免疫（免疫（im

6、munity)immunity)传统概念指免除疫病、免除感染，指机体抗感染的防御能力。现代概念指机体对“自己”或“非己”的识别并排除“非己”的功能。免疫的基本功能免疫的基本功能功能功能正常表现（有利）正常表现（有利）异常表现（有害）异常表现（有害）免疫防御免疫防御immune defenceimmune defence抗病原微生物抗病原微生物的侵袭的侵袭超敏反应超敏反应易受感染或免疫缺陷病易受感染或免疫缺陷病免疫稳定免疫稳定immune homeostasisimmune homeostasis清除损伤、衰老、死亡细清除损伤、衰老、死亡细胞胞 自身免疫性疾病自身免疫性疾病免疫监视免疫监视imm

7、une surveillanceimmune surveillance清除突变或畸变的恶性细清除突变或畸变的恶性细胞胞 恶性肿瘤恶性肿瘤 免疫系统免疫系统 (immune system)(immune system)：机体执行免疫功能的组织、器官、细胞和分子构成免疫系统。The four kinds of pathogens that cause human diseaseOverview of immune responses固有免疫固有免疫（innate immunity）是机体抵御病原微生物入侵的第一道防线，并启动和参与适应性免疫应答。是机体抵御病原微生物入侵的第一道防线，并启动和参与适

8、应性免疫应答。天然免疫（natural immunity)或非特异性免疫(nonspecific immunity)，是个体出生时就具有的免疫力，通过遗传获得，是生物在长期进化过程中逐渐形成的，其针对外来异物的范围广，反应迅速，其应答模式和强度不因与病原微生物的反复接触而改变。固有免疫应答的作用时相：瞬时固有免疫应答阶段、早期固有免疫应答阶段、适应性免疫应答诱导阶段固有免疫系统的组成固有免疫系统的组成屏障屏障细胞细胞分子分子皮肤黏膜屏障：皮肤黏膜屏障：物理、化学、微生物物理、化学、微生物血血-脑屏障、血脑屏障、血-胸腺屏障胸腺屏障血血-胎屏障、气胎屏障、气-血屏障血屏障巨噬细胞、中性粒细胞、树

9、突状细胞、巨噬细胞、中性粒细胞、树突状细胞、T 细胞、细胞、NK细胞、细胞、NKT细胞、细胞、B1细胞、肥大细胞、嗜碱细胞、肥大细胞、嗜碱性粒细胞和嗜酸性粒细胞等。性粒细胞和嗜酸性粒细胞等。抗菌肽、溶菌酶、急性期蛋抗菌肽、溶菌酶、急性期蛋白、补体、细胞因子和黏附白、补体、细胞因子和黏附分子、分子、Epithelial barriers prevent the entry of microbes固有免疫细胞固有免疫细胞 PhagocyteNKILLs（固有样淋巴细胞）（固有样淋巴细胞）DC MCBasophil Eosinophil T细胞 NKT细胞 B1细胞Monocyte-macropha

10、geNeutrophil肺部巨噬细胞吞噬大肠杆菌Phagocytosis by innate immunityLeukocyte recruitment to sites of inflammationor DC固有性免疫分子固有性免疫分子指体表分泌液以及血浆和其它体液中能够识别或攻击病原体的可溶性分子。指体表分泌液以及血浆和其它体液中能够识别或攻击病原体的可溶性分子。抗菌肽抗菌肽 antimicrobial peptides溶菌酶溶菌酶 lysozyme急性期蛋白急性期蛋白(acute phase proteins, APP)脂多糖结合蛋白（脂多糖结合蛋白（LBP）血清淀粉样蛋白（血清淀粉样

11、蛋白（SAP）甘露糖结合蛋白（甘露糖结合蛋白（MBP）C反应蛋白等（反应蛋白等（CRP）补体补体 细胞因子和黏附分子细胞因子和黏附分子Complement activation pathways Elie 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 Immun

12、ology in 20th century mainly centers on understanding the Adaptive Immune System.Charles A. Janeway, M.D.Yale Univ. In 1989, Janeway = Immune recognition of microbes = Detection of conserved molecular patterns, referred to PAMPs (Pathogen-Associated Molecular Patterns) with features:1. Invariant amo

13、ng 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 immunity Julie A. Hoffmann, Ph.D.Strasbourg, FranceIn 1996, Hoffmanns group Toll fu

14、nctions as a PRR in DrosophilaKey concepts in innate immunity1. The innate immune system mainly recognizes common structures shared by classes of microbes, = Pathogen Associated Molecular Patterns (PAMPs), e.g., LPS, Peptidoglycan, Microbial DNA & RNA. 2. Host receptors that recognize PAMPs are call

15、ed Pattern- Recognition Receptors (PRRs), which are encoded in “Germline” DNA= limited Diversity. 3. Innate immunity 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 diseasesPat

16、tern Lipopolysaccharide (LPS) Lipoteichoic acid Bacterial lipopeptides Peptidoglycan Yeast and gram+ bacteria 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）表面存在一些人体所没有的，但可为许多相关微生物所共享、结构恒定、进化保守的分子结构。损伤相关分子模式损伤

17、相关分子模式（damage-associated molecular patterns，DAMPs）机体自身细胞所释放的内源性分子，即内源性危险信号，来源于受损或坏死组织和某些激活的免疫细胞。主要有HMGB1、热体克蛋白等。PAMP vs DAMPSterile inflammationconserved microbial motifs VS non-microbial signals Toll-like ReceptorsLocations of Different PRRsBody fluids-Soluble PRRsCellular PRRs- Cell surface- Endos

18、omes- CytosolSurface receptors of macrophagesMac-1、CR3PRR甘露聚糖凝集素（MBL）C反应蛋白（CRP）脂多糖结合蛋白（LBP）可溶性：体液和血液细胞吞噬型：细胞膜甘露糖受体（MR）清道夫受体（SR）补体受体（CR）Fc受体（FcR）甲酰甲硫氨酰肽受体（fMLPR）信号转导型细胞膜内体、溶酶体细胞质TLR1、2、4、5、6、10、11TLR3、7、8、9NLRs、RLRs、ALRs固有免疫细胞表面、内体、溶酶体、细胞质中、可识别一种或多种PAMPs或DAMPs的识别分子。Diversity of pattern recognition re

19、ceptorsToll-Like Receptors (TLRs)MyD88-Dependent and independent SignalingNLRs are cytoplasmic bacterial sensors that activate inflammasomes1Viral Pattern Recognition Receptors: Signaling and ConsequencesInteraction between innate and& adaptive immunity1. Innate immunity = Ag presentation (by Dendri

20、tic cells)2. Adaptive immunity = Ag recognition (by T & B lymphocytes)适应性免疫（adaptive immunity）是机体获得性、抗原特异性、抵抗病原微生物感染的高效防御机制。获得性免疫（acquired immunity)或特异性免疫(specific immunity)，是个体出生后，在环境中受抗原刺激所产生的免疫力，针对特定抗原，有特异性、多样性、记忆性和耐受性。1) 特异性，对某个特定的异物性抗原能引起特异性免疫应答；指抗原特异性。2) 多样性，机体可针对环境中多种多样的抗原，分别建立起不同的特异性免疫应答；多样性

21、是特异性产生的基础。 3) 记忆性，当异物抗原再次入侵时，可产生快而强的再次免疫应答效应；记忆性淋巴细胞。4) 耐受性，正常情况下，免疫系统对自身成分有保护性的免疫耐受； 抗原决定簇抗原决定簇Antigenic determinant，AD抗原分子表面具有特殊立体构型和免疫活性的化学基团称为抗原分子表面具有特殊立体构型和免疫活性的化学基团称为抗原决抗原决定簇或抗原决定基定簇或抗原决定基。由于抗原决定簇通常位于抗原分子表面，因由于抗原决定簇通常位于抗原分子表面，因而又称为而又称为抗原表位抗原表位( (epitope) )。 抗原决定簇抗原决定簇抗原决定基抗原决定基 抗原表位抗原表位 抗原决定簇决

22、定抗原的特异性，即决定抗原与抗体发生特异性结抗原决定簇决定抗原的特异性，即决定抗原与抗体发生特异性结合的能力合的能力（实际是抗原决定簇与抗体的结合决定簇与抗体的结合）。ADAD的数目、性质和空间构象决定抗原特异性的数目、性质和空间构象决定抗原特异性抗原以抗原以ADAD与相应抗原受体及抗体特异性结合与相应抗原受体及抗体特异性结合 T T细胞表位和细胞表位和B B细胞表位细胞表位 T T细胞表位细胞表位： TCRTCR识别识别 必须经降解加工处理后才能被必须经降解加工处理后才能被T T细胞识别细胞识别 线性决定簇线性决定簇 B B细胞表位细胞表位： BCRBCR识别或抗体识别并结合识别或抗体识别并

23、结合 直接识别直接识别 构象决定簇或线性决定簇构象决定簇或线性决定簇 抗原提呈细胞(antigen-presenting cell, APC) 是指能摄取是指能摄取, 加工处理抗原加工处理抗原, 并将抗原信息提呈给淋巴细胞的一类并将抗原信息提呈给淋巴细胞的一类免疫细胞，在机体免疫应答过程中发挥重要作用。免疫细胞，在机体免疫应答过程中发挥重要作用。 此类细胞能辅助和调节此类细胞能辅助和调节T细胞、细胞、B细胞识别抗原并对其产生应答，细胞识别抗原并对其产生应答，故又称为辅佐细胞故又称为辅佐细胞(accessory cell)，简称，简称A细胞。细胞。APC加工处理的抗原种类加工处理的抗原种类: 外

24、源性抗原外源性抗原(exogenous antigen): 通过吞噬或吞饮等作用被通过吞噬或吞饮等作用被APC从细胞外摄入的抗原，以抗原肽从细胞外摄入的抗原，以抗原肽-MHC I I类分子复合物形式提类分子复合物形式提呈给呈给CD4+T细胞细胞 。 内源性抗原内源性抗原(endogenous antigen): 细胞内合成的抗原，以抗细胞内合成的抗原，以抗原肽原肽-MHC I类分子复合物形式提呈给类分子复合物形式提呈给CD8+T细胞细胞 。 外源性抗原加工，处理及提呈外源性抗原加工，处理及提呈内源性抗原加工，处理及提呈内源性抗原加工，处理及提呈内源性抗原经蛋白酶体降解成肽，通过抗原加工相关转运

25、体(TAP1、TAP2)转运进入内质网，与 MHC类分子(在内质网合成)结合成肽-MHCI类复合物，通过高尔基体表达于细胞表面。TAP是内质网上的异源性二聚体，由TAP-1及TAP-2基因编码胞浆中蛋白酶体（proteasomes, 核心成分为低分子量多肽LMP细胞被病毒感染后出现的病毒蛋白，基因突变后产生的肿瘤抗原 脂类抗原的CD1分子提呈 CD1分子：非经典分子：非经典MHC I类分子，类分子，30%同源性。同源性。 提呈抗原：提呈糖脂或脂类抗原，供提呈抗原：提呈糖脂或脂类抗原，供CD1限制性限制性T细胞识别细胞识别CD1分子提呈微生物的分子提呈微生物的脂质抗原，脂质抗原，脂质抗原由脂质抗

26、原由CD1分子提呈后激活分子提呈后激活CD1限制性限制性T细胞。细胞。Adaptive immunity Main effectors: Antibody T cell receptorsBBCRTTCRTHE ADAPTIVE IMMUNE RESPONSE Antibody-Mediated Immunity (AMI) Involves B lymphocytes, plasma cells and antibodies Humoral immunity Name derives from antibodies found in body fluids (humors - old med

27、ical term) Cell-Mediated Immunity (CMI) Involves T lymphocytes, antigen-presenting cells and MHC (major histocompatibility complex) molecules Cellular immunityTypes of adaptive immunity1. Humoral immunity = Molecules in body fluid, e.g. Antibody (Ab) = Key player = B cells = Target extracellular mic

28、robes & toxins2. Cell-mediated immunity = Key player = T cells = regulate other immune cells = Target intracellular microbes, e.g. viruses, bacteriaFor innate immunity, it also includes Humoral & Cellular components for immune defense1 1、抗原提呈与识别阶段（感应阶段）：2 2、活化、增殖、分化阶段（反应阶段）： T T细胞活化、增殖分化为效应T T细胞； B

29、B细胞活化、增殖分化为浆细胞； 部分细胞发育为记忆细胞。3 3、效应阶段： 效应T T细胞对抗原的清除； 浆细胞分泌抗体清除抗原。免疫应答的三个阶段Overview of adaptive immune responsesCELL-MEDIATED IMMUNITY (CMI) Directed against intracellular microorganisms Non-phagocytic cells and phagocytic cells T-lymphocytes (T cells) Differentiate into effector cells following anti

30、gen presentation by antigen presenting cells (APCs) Functional types of T cells Helper (CD4 T cells) TH1 and TH2 cells Cytotoxic (CD8 T cells)T cells develop in the thymus T cells develop in bone marrow, but in order to mature, they need to migrate to thymus = thymus-(T)-dependent lymphocytes Thymus

31、 is a primary lymphoid organ located in the upper thorax (chest), just above the heart. Progenitor (precursor) T cells enter the thymus, where they mature (= produce T cell receptors). Mature T cells leave the thymus and enter the secondary lymphoid tissues, where they become activated after exposur

32、e to antigen.T cells develop in bone marrow and then migrate to thymus where they matureMature T cells enter the blood stream, and after infection accumulate in the secondary lymphoid tissues where they are activated. T cell developmentTSCCD4 RTEDNPre-TCRDPTCRCD4CD8TCRTCRCD8CD4 SPTCRCD4CD4b b-select

33、ionPositiveselectionNegative selectionFunctional maturationTCR-b b rearrangementTCR-a a rearrangementTCRCD8CD8 SPCD8 RTEDevelopment of ThymocytesDoublenegativeDoublepositiveSinglepositiveNotch Signal and T-lineage Commitment受体受体: Notch 1-4；胸腺细胞表达；胸腺细胞表达Notch1-3；全部效应由；全部效应由Notch 1介导介导 配体：配体：Dll1，3，4，

34、 Jagged 1，2；胸腺上皮细胞表达全部配体；胸腺上皮细胞表达全部配体；Dll4 可能为生理性配体可能为生理性配体 T系定向：系定向：始于始于DN1，完成于，完成于DN3；绝对依赖；绝对依赖Notch1信号信号T cells undergo further differentiation in secondary lymphoid tissues after encounter with antigen Only a small fraction of naive T cells (mature T cells before they encounter antigen) survives

35、 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, T cells accumulate in T cell areas, where they become activated

36、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 site of infection (CD8 and CD4-TH1 cells).T细胞受体复合物由TCR和CD3组成。前者识别

37、和结合抗原肽, 后者将TCR获得的抗原信号传递至细胞内。T细胞对抗原的识别 APCT细胞细胞 MHC- MHC-B7 CD40 CD58 CD2 信信 号号第一信号第一信号第二信号第二信号T细胞细胞TCR和和CD4/CD8 CD28APCMHC-肽肽复合物复合物B7(B7.1、B7.2)T细胞活化的双信号刺激 第一信号：TCR对MHCII抗原肽复合物的识别，CD3分子将第一信号传递到细胞内。 第二信号：CD28识别专职APC上的B7分子,又称协同刺激信号。 Effector T cells In contrast to terminally differentiated B cells (pl

38、asma cells), there are several types of terminally differentiated effector T cells.CD8 T cells Cytotoxic T cells (recognize 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)Activ

39、ation (cytokines)(recognize MHC II molecules)The immune system is maintained in a carefully regulated balance between the two polarised control arms, Th1 (cellular immunity) and Th2 (humoral immunity).In disease states the balance is skewed. multiple sclerosis, rheumatoid arthritis and type I diabet

40、es, have a Th1 bias, whereas cancer patients have a Th2 bias. More T helper subsetsTh3: TGF-producing CD4 T cellsTr1: IL-10-producing CD4 T cellsTh9: IL-9-producing CD4 T cellsTfh: follicular helper T cells, located in the follicular regions of lymph nodes and spleen,follicular Th1/Th2/Th17 cellsANT

41、IBODY-MEDIATED (HUMORAL) IMMUNITY Directed against extracellular microorganisms and toxins B-lymphocytes (B cells) Differentiate into plasma cells which produce antibodies Function as antigen-presenting cells (APCs) Classification of Antibodies (Immunoglobulins) Immunoglobulin M (IgM) Immunoglobulin

42、 G (IgG) Immunoglobulin A (IgA) Immunoglobulin D (IgD) Immunoglobulin E (IgE)Paul Ehrlich: One of the fathers of humoral adaptive immunity1. The Discovery of Antibody functions2. The Nobel Laureate in Medicine 1908Adopted from Nature Immunology, July 2008 抗体的功能V区的功能 识别并特异性结合抗原 单体（IgG, IgE) 2价 二聚体(分泌

43、型IgA) 4价 五聚体(IgM) 10价 中和效应 中和毒素和病毒 与Ag结合 促吞噬细胞吞噬C区的功能区的功能 1.1.激活补体系统激活补体系统 Ab(IgM、IgG) + Ag C1q 补体经典途径补体经典途径 IgG4、IgA和和 IgE的凝聚物的凝聚物 补体旁路途径补体旁路途径 2.2.介导免疫细胞活性介导免疫细胞活性 (1)(1)调理作用（调理作用（opsonization）：IgG + + 抗原抗原( (颗粒性颗粒性) ) FcR（单（单核、巨噬细胞及中性粒细胞）核、巨噬细胞及中性粒细胞） 促吞噬细胞吞噬；促吞噬细胞吞噬； (2)(2)ADCC：IgG + + 抗原抗原( (靶细

44、胞靶细胞) ) Fc R（NK 细胞）细胞） 杀伤杀伤靶靶细胞；细胞； (3)(3)介导超敏反应介导超敏反应：型型、型型和和型超敏反应。型超敏反应。 3.3.穿越胎盘和粘膜穿越胎盘和粘膜Antibody-Dependent Cellular Cytotoxicity (ADCC) Th2与与B细胞的相互作用，获得第二信号：协同刺激信号细胞的相互作用，获得第二信号：协同刺激信号胸腺依赖性抗原（TD-Ag）活化的活化的B B细胞增殖与分化细胞增殖与分化 活化B细胞 浆细胞 产生抗体 原始淋巴滤泡分裂增殖，形成生发中心（一周左右）Specificity, Memory, and Homeostasi

45、s of Adaptive Immunity体液免疫应答一般规律体液免疫应答一般规律多克隆抗体(polyclonal antibody(polyclonal antibody，PcAb )PcAb )：采用传统的免疫方法，将抗原物质经不同的途径进入动物体内，经数次免疫后采取动物血液，分离出血清，由此获得的抗血清即为多克隆抗体。用天然的抗原物质免疫动物，刺激多个B B细胞克隆所获得的免疫血清（含多种特异性抗体）。单克隆抗体(Monoclonal Antibody(Monoclonal Antibody，McAb):McAb):由一个B B细胞分化增殖的子代细胞产生的针对单一抗原决定簇的抗体，称单

46、克隆抗体。由一个B B细胞克隆产生。识别一种抗原表位。高度均一（结构、特异性）。杂交瘤技术制备。基因工程抗体：利用基因工程技术来制备的抗体分子称为基因工程抗体，是分子水平的抗体。抗体针对的靶分子抗体针对的靶分子作用机制作用机制治疗疾病治疗疾病CD3阻断阻断T细胞功能细胞功能预防肾移植排斥反应预防肾移植排斥反应CD25阻断阻断IL-2受体受体预防肾移植排斥反应预防肾移植排斥反应CD20(或偶联核素或偶联核素)诱导肿瘤细胞凋亡诱导肿瘤细胞凋亡non-Hidgkins淋巴瘤和淋巴瘤和RACD33(免疫毒素免疫毒素)诱导肿瘤细胞凋亡诱导肿瘤细胞凋亡急性髓样白血病急性髓样白血病CD52诱导肿瘤细胞凋亡诱

47、导肿瘤细胞凋亡慢性慢性B淋巴细胞白血病，淋巴细胞白血病，T细胞瘤细胞瘤Her2(CD340)抑制和杀伤肿瘤细胞抑制和杀伤肿瘤细胞转移性乳腺癌转移性乳腺癌EGFR抑制肿瘤血管形成抑制肿瘤血管形成转移性结肠直肠癌和头颈部肿瘤，非鳞癌、非转移性结肠直肠癌和头颈部肿瘤，非鳞癌、非小细胞肺癌，对化疗反应差的多形性胶质细胞小细胞肺癌，对化疗反应差的多形性胶质细胞瘤瘤CD41/CD61 (gpIIbIIIa)抑制血小板凝聚抑制血小板凝聚预防冠状动脉血管形成术中预防冠状动脉血管形成术中 血栓形成血栓形成US和和EU所批准的治疗性抗体所批准的治疗性抗体抗体针对的靶分子抗体针对的靶分子作用机制作用机制治疗疾病治疗

48、疾病TNFa a阻断阻断TNFa a与受体结合与受体结合RA、银屑病性关节炎、银屑病性关节炎、克隆氏病、强直性脊椎炎克隆氏病、强直性脊椎炎CD11a抑制白细胞黏附抑制白细胞黏附斑状牛皮癣斑状牛皮癣VEGF抑制血管形成抑制血管形成年龄相关性黄斑变性年龄相关性黄斑变性a a4整合蛋白整合蛋白抑制白细胞黏附抑制白细胞黏附多发性硬化症多发性硬化症IgE阻断阻断IgE与与 IgE受体结合，抑制受体结合，抑制肥大细胞、肥大细胞、嗜碱性粒细胞释放介质嗜碱性粒细胞释放介质持续性哮喘持续性哮喘RSVgpF中和病毒中和病毒预防儿童高危期预防儿童高危期RSV感染感染US和和EU所批准的治疗性抗体所批准的治疗性抗体

49、鼠源性单克隆抗体将逐渐被人源化抗体所替代：鼠源性单克隆抗体与人补体成分结合能力低，CDC作用相应较弱，对肿瘤细胞的杀伤能力较弱；它与NK等免疫细胞表面Fc受体亲和力弱，介导的 ADCC作用较弱；鼠源抗体在人血循环中的半衰期短，它发挥ADCC与CDC作用的时间较短；鼠单克隆抗体具有免疫原性，宿主易产生抗抗体引起过敏反应。抗体人源化改造及人源抗体制备抗体人源化改造及人源抗体制备1. 人人- -鼠嵌合抗体鼠嵌合抗体：应用基因工程技术将小鼠单克隆抗体的恒定区用人源抗体应用基因工程技术将小鼠单克隆抗体的恒定区用人源抗体恒定区代替而拼接成嵌合抗体。恒定区代替而拼接成嵌合抗体。2.2. 改型抗体如改型抗体如

50、CDRCDR移植、移植、SDRSDR移植移植：用鼠单克隆抗体的用鼠单克隆抗体的CDRCDR、SDRSDR移植到人源移植到人源抗体可变区，替代人源抗体抗体可变区，替代人源抗体CDRCDR、SDRSDR。3.3. 表面氨基酸残基人源化表面氨基酸残基人源化抗体人源化的主要技术抗体人源化的主要技术提高抗体提高抗体效应功能效应功能偶联细胞毒物质偶联细胞毒物质双特异性抗体双特异性抗体抗体抗体Fc突变突变改变抗体糖基化改变抗体糖基化细胞内抗体细胞内抗体抗体融合蛋白抗体融合蛋白提高抗体效应功能MjmacrophagemacrophageIL-8Activated Activated T cellT cella

51、 aADP56BC58BCNH2COOHIL-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. Cytokine Biological effects IL-1TNFa aGM-CSFM-CSFF

52、GFPDGFVEGFIL-12IL-15IL-6LIFOSMChemokinesTGFb bIL-10IL-11IL-13sTNF-RIL-1raPRO-INFLAMMATORYANTI-INFLAMMATORYCytokine imbalance during inflammation 细胞因子的研究热点细胞因子的研究热点1、新细胞因子的基因克隆化、新细胞因子的基因克隆化2、细胞因子受体的基因克隆化、细胞因子受体的基因克隆化3、细胞因子信号转导机制、细胞因子信号转导机制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、新一代细胞因子：高活性，多功能，低毒副作用，长半衰期，高

53、稳定性5、细胞因子作为生物应答调节剂（、细胞因子作为生物应答调节剂（BRM）的临床应用）的临床应用6、细胞因子表达调控、细胞因子表达调控7、细胞因子基因治疗、细胞因子基因治疗Infections occur when the physical barriers of epithelium are breached, or when pathogens adhere to the epithelium1. Pathogen replication2. Recruitment of neutrophils and macrophages 3. InflammationPathogen adhere

54、nce to epitheliumPathogens are carried to the closest lymph node where they stimulate specific T- and B-cells Production of specific antibodies = Adaptive immunityInnate immunityAdaptive immunityActivation of adaptive immunity by innate immunityTime course of primary infection in healthy individuals

55、, and people who lack immune or adaptive immunityIn the absence of innate immunity, there is also no adaptive immunityInfection is cleared from the body by combined actions of innate and adaptive immunityT Cells maitain the homostasis of innate inflammationPathogen Danger signalLymphocyteInflammator

56、y/Innate immune cellINNATE IMMUNITYADAPTIVE IMMUNITYPROTECTIONIMMUNOPATHOLOGYFailure of the immune system1. Ineffective response - Immunodeficiency2. Overactive response - Hypersensitivity 3. Auto-reactive response - Autoimmunity免疫的基本功能免疫的基本功能功能功能正常表现（有利）正常表现（有利）异常表现（有害）异常表现（有害）免疫防御免疫防御immune defenceimmune defence抗病原微生物抗病原微生物的侵袭的侵袭超敏反应超敏反