外科学与免疫学

外科学与免疫学Surgery & Immunology,Bing-ya Liu, M.D., Ph. D. , Shanghai Institute of Digestive Surgery,基本概念Basic Principles, 免疫:Immune: protect from pathogens 免疫性 Immunity: Capacity of defense infection 免疫应答 Immune response : response of recognition and elimination antigenicity foreign material 免疫学 Immunology: The science study on the structure & function of the immune systemScience of self-nonself discrimination,概念 Concepts,天然免疫与获得性免疫Adaptive and Innate immunity,天然免疫机体与生具有的抵抗外来病原的防御系统无特异性, 包括,Innate immunity Body defenses come from birthAgainst all kinds of pathogens, Not specificIncluding barriersBasic barrier: skin, mucosaPhysical barrier: body temp, phPhagocytesInflammation,Adaptive or Specific Immune response Highly specific for a particular pathogen Specific Muti-type Remember/ memory Transferable,获得性免疫应答具有高度病原特异性特异性多样性记忆性可转移性,免疫应答的三个时相Three phases of immune response, Recognition: Ag recognized by lymphocytes Activation: lymphocytes activation Response: Lymphocytes coordinate an immune response that eliminates the source of the Ag,识别相激活相效应相,免疫系统Immune System,Organs of the Immune System免疫器官 Cells of the Immune System免疫细胞 Molecule of the Immune System免疫分子,Lymphoid Tissues,Primary lymphoid organsThymusT cell maturefetal liverBone marrowSecondary lymphoid organs and tissuesSpleenlymph nodes and lymphatic systemMucosa-associated lymphoid tissue (MALT),B Cell,Cells of the Innate Immune System,PhagocytesMononuclear phagocytesPolymorphsNeutrophilsEosinophilsBasophils and mast cellsPlateletsNatural killer (NK) cells,Cells of the Adaptive Immune System,Lympho cytesT cellsTTSuppressor TB cells Antigen-presenting cells (APCs),Surface Molecules Expressed on DC,抗原递呈细胞的表面标志,T B 细胞表面标志的主要差别,Molecules of immune sys, immunoglobulin / BCRTCR complement cytokines adhesion molecules MHC,TCR,The TCR heterodimer forms the recognition unit of the receptorCD3 complex associates with the and forms of the TCR,MHC,MHC I molecules consist of an MHC-encoded heavy chain bound to 2-microglobalin2-M is essential for expression of MHC I moleculesHeavy chain1 &2 domains form the Ag-binding grooveVariations in aa sequence change the shape of the binding grooveMHC II blinding groove accommodate longer peptides than class IPeptides are held in the MHC molecules binding cleft by characteristic anchor residues,Antigen presentation抗原递呈,T cells recognize peptide fragments which have been processedT细胞识别的是经过加工过的多肽片段Interaction with APC is essential for T-cell activationAPC-T细胞之间的相互作用是T细胞激活所必须,Antigen Processing and Presentation抗原加工与递呈, Ags are processed before they are presented to T cells抗原递呈给T细胞之前须加工 Ags are partially degraded into peptide before binding to MHC molecules抗原在与MHC分子结合之前被降解成抗原肽 Class I molecules associate with endogenously synthesized peptidesI 类分子与内原性合成多肽相关 Proteasomes are cytoplasmic organelles that degrade cytoplasmic proteins蛋白酶体是胞质细胞器以降解胞内蛋白 Class II molecules are loaded with exogenous peptides in an endosomal compartmentII 类分子在包涵体内负载外原性抗原多肽,Two pathways of protein Ag processing & presentation蛋白质抗原加工递呈的两类途径,Main molecules associated with T cell activation,MHC-Pep-TCR tri-molecular complexTCR-CD3 complexCD4/CD8 co-receptorCD45CD28LFA1 / ICAM1, CD2 / LFA3,T cell Activation,3 signals: recognition, activation, growth3 receptor-ligants: Pep-TCR, B7-CD28, IL2-IL2R3 results: surface molecules expression, cytokines synthesis and secretion, T cell cloning forming and amplification,Specific Signal & Co-stimulator,T cell Activated & Proliferation,Cell-mediated cytotoxicity,Cytotoxic T cells recognize Ag presented on MHC moleculesNK cells react against cells which do not express MHC-INK cells express two major classes of inhibitory receptors for MHC moleculesCytotoxicity is mediated by combinations of direct cell-cell interactions, cytokines and the release of granule proteinsLigation of Fas or the type-1 TNF-R on the target cell leads to the activation of caspasesMyeloid cells induce damage in targets principally by the release of toxic molecules,Mechanisms of cytotoxicity,Cytotoxicity is effected by direct cellular interaction, cytokines and granule exocytosisCytotoxic T cells and NK cells induce apoptosis in their targetsCaspases mediate cell death by apoptosisCytotoxicity may be signalled via Fas or a TNF receptor on a target cellGranules of cytotoxic T cells contain perforin and granzymes,Immune Response,Antibody,NeutralizationComplement dependent cytotoxicity (CDC)IgG, IgMAb dependent cell mediated cytotoxicity (ADCC) IgG,T cell,Granule exocytosis: profin, granzymeApoptosis: Fas-FasL,NK and M,NK: same as CTL: Granule exocytosis, ApoptosisNK & M: ADCCM: direct kill: release lysomal enzymes inhibit DNA, RNA, and Pro. synthesis,Cytokine,Lymphocytes differentiation and maturationEnhance molecules expression on lymphocytesDirect toxicityAnti-viruses,Immunity to viruses病毒免疫,Viruses are obligate intracellular parasites病毒是专性胞内寄生物Viruses have evolved strategies to avoid recognition by the host病毒通过进化以逃避宿主识别Viruses may directly disrupt the function of the immune system病毒可以直接破坏免疫系统功能,Innate immune response to viruses天然免疫,Initial defence: Integrity of the body surface初始抵御：机体表面的完整性IFN stimulates inhibition of viral replicationIFN刺激抑制病毒复制NK cells are cytotoxic for virally infected cellsNK细胞对被感染细胞的细胞毒作用Macrophages become active巨嗜细胞的活化,Adaptive immune response获得性免疫应答,Antibody and complement can limit viral spread or re-infectionAb和补体限制病毒播散或再感染Antibody can neutralize the infectivity of viruses Ab中和病毒complements in involved in the neutralization of some free viruses补体中和一些游离病毒Abs mobilize complement &/ or effect cells to destroy virus-infected cellsAb动员补体和/或效应性细胞杀伤病毒感染的细胞,Adaptive immune response获得性免疫应答,T cell mediate viral immunity in several waysT细胞介导的抗病毒免疫Most of the Ab response is thymus dependent, requiring the presence of CD4+ T cells for class switching and affinity maturation.抗体应答须要有CD4+ T 的辅助CD4+ T cells also help in the induction of CD8+ CTL CD4+ T还可以辅助诱导CD8+ CTL CD4+ T in the recruitment and activation of macrophages at sites of virus infectionCD4+ T在病毒感染部位可募集和激活巨嗜细胞CD8+ T cells are also effective in prevention of re-infection.CD8+ T可有效地防止再感染,Tumor Immunology,Immune surveillance免疫监视,Immune surveillance is a concept that envisages prevention of the development of most tumors through early destruction of abnormal cells by the hosts immune sys机体免疫系统可以发挥免疫监视作用，识别并消灭任何表达新抗原的“异己”成分或突变细胞，以保持机体内环境的稳定Surveillance is most effective against viruses not tumor cells,Immune surveillance免疫监视的证据,Postmortem data suggest that there may be more tumors than become clinically apparent尸检资料显示肿瘤实际发生率高于临床发现Many tumors contain lymphoid infiltrates and in some tumors this may be favorable sign许多肿瘤有淋巴细胞浸润，在某些肿瘤是预后好的征象Spontaneous regression of tumor occurred有肿瘤自行消退的现象Tumors occurred more frequently in the neonatal period and in old age, when the immune sys functions less effectively免疫功能低下状态肿瘤更易发生Tumors arise frequently in immunosuppressed individuals免疫抑制状态肿瘤发生率高,Cause of common tumour viruses involvedimmunodeficiencytypesInherited lymphoma EBVimmunodeficiencylymphomaEBVcervical cancer papilloma virusesimmunosuppression skin cancer probablyfor organ transplantspapillomaor due to AIDS virusesliver cancerhepatitis B and CvirusesKaposis human herpessarcomavirus 8malariaBurkittsEBVlymphomaautoimmunitylymphomaEBV,Tumour viruses and immunodeficiency,TumourOrganismAdult T-cell leukaemiaHuman T leukaemia virus I(HTLV I)Burkitts lymphoma and EBVLymphoma in immunosuppressionCervical cancerHuman papilloma viruses (HPV 16 and 18 and others)Liver cancerHepatitis B and CNasopharyngeal cancerEBVSkin cancerProbably human papillomavirusesStomach cancerHelicobacter pylori,Micro-organisms and human tumours,Tumor antigens- Classification,Class I HLA-restricted cancer/ testis AgsClass I HLA-restricted differentiation AgsClass I HLA-restricted widely expressed AgsClass I HLA-restricted tumor specific AgsClass II HLA-restricted tumor AgsFusion proteins,Tumor antigens肿瘤抗原特性,Tumor Ags may be detected by immune cells or Abs肿瘤抗原可被T细胞或抗体所检测Shared tumor Ags are viral origin肿瘤共有抗原通常为病毒原性Tumor specific transplantation Ags are due to alterations in tumor genes or gene expression肿瘤特异性抗原通常是肿瘤基因改变后表达产物,Antigen name(s)Tumour typesNormal tissue distributionCancer/testis AgsMAGE 1Some melanomasTestisMAGE3and other tumourBAGEtypesGAGEMelanocyte diff AgsMelanA/MART-1MelanomaNormalTyrosinasemelanocytesgp 100/Pmel 17gp 75/TRP-1Diff Ags of other PSA ProstateProstateCEAColon and otherColoncarcinomasMutated AgsMutated rasMany carcinomasNot presentHer-2/neuBreast and ovaryNot present,Human tumour-associated antigens recognized by T lymphocytes,Name Source cDNA libraryCancer testis Ags HOM-Mel-40MelanomaNY-ESO-1MelanomaMAGE 1MelanomaDiff AgsTyrosinaseMelanomaGalectin-9Hodgkins diseaseCarbonic anhydraseRenal carcinomaHousekeeping genesPCNAMelanomaEndogenous retroviral genesMelanomaHERV-K10Mutated Ags p53 (mutated)Colon carcinoma,Antigens identified by SEREX（Serological analysis of recombinant cDNA expression libraries）,Serological analysis of recombinant cDNA expression libraries（SEREX）,Active non-specificBCG, Corynebacterium parvum,levamisole, cytokinesspecificTherapeutic vaccines of tumour cells,cell extracts, purified or recombinantantigens, peptides, heat shock proteinsor DNA antigen-pulsed dendritic cellsPassivenon-specificLAK cellsspecificAntibodies alone or coupled to ddrugs, pro-drugs, toxins or radioiisotope,bi-specific antibodies T cellsCombinedLAK cells and bi-specific antibody,Immunotherapy of tumours,Immunotherapy免疫治疗策略,Immunization with tumor Ags肿瘤抗原免疫Immunization with dendritic cells树突状细胞免疫Non-specific stimulation of immune responses非特异性免疫Immunotherapy with cytokine can cause tumor regression细胞因子免疫治疗Immunization with oncogenic viruses肿瘤性病毒,Passive Immunotherapy过继性免疫治疗,Therapy with LAK cellsImmunotherapy with T cellsTherapy with antibodies,DC免疫治疗,TumourTarget antigen ImmunizationBreastMUC 1 Sialyl TN Ag-KLH conjugate with adjuvant Recombinant Vaccinia-MUC 1 virus with IL-2CervixHPV E6/E7 Recombinant Vaccinia HPV E6/E7 Recombinant E6/E7 protein Synthetic peptides in adjuvantLymphomaIg Recombinant proteinidiotype ldiotype single chain Fv-toxoid DNA construct DC pulsed with idiotypic proteinMelanomaVarious Allogeneic whole cells,cells trasduced with CK, Peptides, DC/ peptides or DC/ tumor lysateProstatePSA Liposome encapsulated PSA, DC / peptidesGlobo H Synthetic Ag-KLH conjugate with QS21 hexasaccharide adjuvant,Clinical trials of active immunization in man,Type of BRM examplesmajor effectbacterial productsBCG, C. parvum,activate M NKmuramyl dipeptidetrehalose dimycolateSynthetic pyran copolymer,induce IFN prod.molecules MVE, polyI:C,pyrimidinesCytokinesIFN， activate M NKIL-2, TNF Hormones thymosin, thymulin, modulate thymopoietin T-cell functioin,Non-specfic active immunotherapy: biological response modifiers (BRMs),Cytokinetumour typecytokine effects and possibleand resultsanti-tumour mechanismsIFNprolonged remissionspossible cytostaticof hairy-cell leukaemiaeffect on tumourweak effects on increased expression of some carcinomasMHC class I, cytostasisIFNineffective systemically, increased MHC class I and IIremissions of peritoneal macrophage activationcarcinoma of the ovary Tc activation, cytostasisIL-2 remissions in renalT-cell activationcancer and melanomaand proliferationNK-cell activationTNFcan reduce?increased tumourmalignant ascitescell adhesion, macrophage and lymphocyte activation,Cytokine therapy for tmours,肿瘤共刺激分子丢失,肿瘤细胞MHC分子表达缺失,肿瘤逃避免疫识别的机制,Obstacles to tumor immunitySelf-origin of tumor antigensMost proteins that are expressed by tumor cells are recognized by the immune system as self-antigens. The establishment of tumor immunity can therefore be construed as an attempt to induce autoimmunity. Immune mechanisms that have evolved to avoid autoimmunity, such as immunological ignorance, clonal deletion and anergy, therefore hamper the antitumor responseAntigen lossTumor cells can down-regulate the expression of antigens that are recognized by the immune system. This ability to immuno-edit tumor antigen profiles underscores the importance of directing T cells against multiple tumor antigens.Down-regulation of HLA expressionTumor cells can also down-regulate the expression of HLA class IResistance to CTLsT cells express cytolytic and apoptosis-inducing molecules such as FASL, TNF-, perforin and granzyme. Tumous can down-regulate the receptors or the downstream signals that are activated by these molecules to evade CTL induced cell deathEnvironmental suppressionTumors might secrete or express molecules on their cell surface that inhibit the immune response and eventually impair signaling in T cells,The FRESH criteria for expanding antitumor T cellsFunctionThe preservation of antigen specificity and cytolytic activity must be enforced throughout expansion. This can require optimized antigen presentation and/or T-cell purification.RemanenceThe generation of long-lasting immunological memory is an important aspect of cancer immunotherapy. The development of T-cell memory cells requires successful T-cell engraftment and stimulation.ExpansionT-cell number is a crucial parameter in experimental and clinical models of adoptive cell therapy. Therapeutic cell doses might exceed 109 T cells/kg. Prolonged T-cell culture, carries the risk of altering antigen specificity and diminishing T-cell functionality.SurvivalT cells should be expanded in such a way as to avoid passive cell death, as well as activation-induced cell death, following their infusion into the recipient.In vivo cytokine support and T-cell activation conditions during ex vivo T-cell expansion are crucial in determining the survival of adoptively transferred T cells.HomingT cells should have the capacity to home to the tumor a process that is control