上海交大外科學(xué)16-外科學(xué)與免疫學(xué)

1、外科學(xué)與免疫學(xué)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

2、疫應(yīng)答 Immune response : response of recognition and elimination antigenicity foreign material● 免疫學(xué) Immunology: The science study on the structure & function of the immune systemScience of self-nonself discriminat

3、ion,概念 Concepts,天然免疫與獲得性免疫Adaptive and Innate immunity,天然免疫●機(jī)體與生具有的抵抗外來病原的防御系統(tǒng)無特異性, 包括,Innate immunity Body defenses come from birthAgainst all kinds of pathogens, Not specificIncluding barriersBasic barrier: s

4、kin, mucosaPhysical barrier: body temp, phPhagocytesInflammation,Adaptive or Specific Immune response Highly specific for a particular pathogen ● Specific ● Muti-type ● Remember/ memory ● Transferable,獲得性免疫應(yīng)答

5、具有高度病原特異性特異性多樣性記憶性可轉(zhuǎn)移性,免疫應(yīng)答的三個時相Three phases of immune response,● Recognition: Ag recognized by lymphocytes● Activation: lymphocytes activation● Response: Lymphocytes coordinate an immune response that eliminates

6、the source of the Ag,識別相激活相效應(yīng)相,免疫系統(tǒng)Immune System,●Organs of the Immune System免疫器官● Cells of the Immune System免疫細(xì)胞● Molecule of the Immune System免疫分子,Lymphoid Tissues,Primary lymphoid organsThymus——T cell ma

7、turefetal liverBone marrowSecondary lymphoid organs and tissuesSpleenlymph nodes and lymphatic systemMucosa-associated lymphoid tissue (MALT),B Cell,,Cells of the Innate Immune System,PhagocytesMononuclear

8、phagocytesPolymorphsNeutrophilsEosinophilsBasophils and mast cellsPlateletsNatural killer (NK) cells,Cells of the Adaptive Immune System,Lympho cytesT cellsαβTγδTSuppressor TB cells Antigen-presenti

9、ng cells (APCs),Surface Molecules Expressed on DC,抗原遞呈細(xì)胞的表面標(biāo)志,T B 細(xì)胞表面標(biāo)志的主要差別,Molecules of immune sys,● immunoglobulin / BCR●TCR● complement● cytokines● adhesion molecules● MHC,TCR,The αβ TCR heterodimer forms the

10、recognition unit of the receptorCD3 complex associates with the αβand γδforms of the TCR,MHC,MHC I molecules consist of an MHC-encoded heavy chain bound to β2-microglobalinβ2-M is essential for expression of MHC I mole

11、culesHeavy chainα1 &α2 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

12、 molecules binding cleft by characteristic anchor residues,Antigen presentation抗原遞呈,T cells recognize peptide fragments which have been processedT細(xì)胞識別的是經(jīng)過加工過的多肽片段Interaction with APC is essential for T-cell activation

13、APC-T細(xì)胞之間的相互作用是T細(xì)胞激活所必須,Antigen Processing and Presentation抗原加工與遞呈,● Ags are processed before they are presented to T cells抗原遞呈給T細(xì)胞之前須加工● Ags are partially degraded into peptide before binding to MHC molecules抗原在與MH

14、C分子結(jié)合之前被降解成抗原肽● Class I molecules associate with endogenously synthesized peptidesI 類分子與內(nèi)原性合成多肽相關(guān)● Proteasomes are cytoplasmic organelles that degrade cytoplasmic proteins蛋白酶體是胞質(zhì)細(xì)胞器以降解胞內(nèi)蛋白● Class II molecules are lo

15、aded with exogenous peptides in an endosomal compartmentII 類分子在包涵體內(nèi)負(fù)載外原性抗原多肽,Two pathways of protein Ag processing & presentation蛋白質(zhì)抗原加工遞呈的兩類途徑,Main molecules associated with T cell activation,MHC-Pep-TCR tri-molec

16、ular 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

17、 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 recogni

18、ze 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 cel

19、l-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 rele

20、ase 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 media

21、te 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 dependen

22、t cytotoxicity (CDC)IgG, IgMAb dependent cell mediated cytotoxicity (ADCC) IgG,T cell,Granule exocytosis: profin, granzymeApoptosis: Fas-FasL,,NK and Mφ,NK: same as CTL: Granule exocytosis, ApoptosisNK &

23、 Mφ: ADCCMφ: direct kill: release lysomal enzymes inhibit DNA, RNA, and Pro. synthesis,Cytokine,Lymphocytes differentiation and maturationEnhance molecules expression on lymphocytesDirect toxicityAnti-virus

24、es,Immunity to viruses病毒免疫,Viruses are obligate intracellular parasites病毒是專性胞內(nèi)寄生物Viruses have evolved strategies to avoid recognition by the host病毒通過進(jìn)化以逃避宿主識別Viruses may directly disrupt the function of the immune s

25、ystem病毒可以直接破壞免疫系統(tǒng)功能,Innate immune response to viruses天然免疫,Initial defence: Integrity of the body surface初始抵御：機(jī)體表面的完整性IFN stimulates inhibition of viral replicationIFN刺激抑制病毒復(fù)制NK cells are cytotoxic for virally infec

26、ted cellsNK細(xì)胞對被感染細(xì)胞的細(xì)胞毒作用Macrophages become active巨嗜細(xì)胞的活化,Adaptive immune response獲得性免疫應(yīng)答,Antibody and complement can limit viral spread or re-infectionAb和補(bǔ)體限制病毒播散或再感染Antibody can neutralize the infectivity of virus

27、es Ab中和病毒complements in involved in the neutralization of some free viruses補(bǔ)體中和一些游離病毒Abs mobilize complement &/ or effect cells to destroy virus-infected cellsAb動員補(bǔ)體和/或效應(yīng)性細(xì)胞殺傷病毒感染的細(xì)胞,Adaptive immune response獲得性

28、免疫應(yīng)答,T cell mediate viral immunity in several waysT細(xì)胞介導(dǎo)的抗病毒免疫M(jìn)ost of the Ab response is thymus dependent, requiring the presence of CD4+ T cells for class switching and affinity maturation.抗體應(yīng)答須要有CD4+ T 的輔助CD4+ T cel

29、ls also help in the induction of CD8+ CTL CD4+ T還可以輔助誘導(dǎo)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細(xì)胞CD8+ T cells are also effective in prevention

30、of re-infection.CD8+ T可有效地防止再感染,Tumor Immunology,Immune surveillance免疫監(jiān)視,Immune surveillance is a concept that envisages prevention of the development of most tumors through early destruction of abnormal cells by the h

31、ost’s immune sys機(jī)體免疫系統(tǒng)可以發(fā)揮免疫監(jiān)視作用，識別并消滅任何表達(dá)新抗原的“異己”成分或突變細(xì)胞，以保持機(jī)體內(nèi)環(huán)境的穩(wěn)定Surveillance is most effective against viruses not tumor cells,Immune surveillance免疫監(jiān)視的證據(jù),Postmortem data suggest that there may be more tumors than

32、 become clinically apparent尸檢資料顯示腫瘤實際發(fā)生率高于臨床發(fā)現(xiàn)Many tumors contain lymphoid infiltrates and in some tumors this may be favorable sign許多腫瘤有淋巴細(xì)胞浸潤，在某些腫瘤是預(yù)后好的征象Spontaneous regression of tumor occurred有腫瘤自行消退的現(xiàn)象Tumors o

33、ccurred more frequently in the neonatal period and in old age, when the immune sys functions less effectively免疫功能低下狀態(tài)腫瘤更易發(fā)生Tumors arise frequently in immunosuppressed individuals免疫抑制狀態(tài)腫瘤發(fā)生率高,Cause of common tu

34、mour viruses involvedimmunodeficiencytypesInherited lymphoma EBVimmunodeficiencylymphomaEBVcervical cancer papilloma virusesimmunosuppression skin cancer probablyfor organ transplants

35、papillomaor due to AIDS virusesliver cancerhepatitis B and CvirusesKaposi’s human herpessarcomavirus 8malariaBurkitt’sEBVlymphomaautoimmunitylymphomaEBV,T

36、umour viruses and immunodeficiency,,,,TumourOrganismAdult T-cell leukaemiaHuman T leukaemia virus I(HTLV I)Burkitt’s lymphoma and EBVLymphoma in immunosuppressionCervical cancerHuman papilloma viru

37、ses (HPV 16 and 18 and others)Liver cancerHepatitis B and CNasopharyngeal cancerEBVSkin cancerProbably human papillomavirusesStomach cancerHelicobacter pylori,Micro-organisms and human tumo

38、urs,,,,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 HL

39、A-restricted tumor AgsFusion proteins,Tumor antigens腫瘤抗原特性,Tumor Ags may be detected by immune cells or Abs腫瘤抗原可被T細(xì)胞或抗體所檢測Shared tumor Ags are viral origin腫瘤共有抗原通常為病毒原性Tumor specific transplantation Ags are due to

40、alterations in tumor genes or gene expression腫瘤特異性抗原通常是腫瘤基因改變后表達(dá)產(chǎn)物,Antigen name(s)Tumour typesNormal tissue distributionCancer/testis AgsMAGE 1Some melanomasTestisMAGE3and other tumourBAGEtype

41、sGAGEMelanocyte diff AgsMelanA/MART-1MelanomaNormalTyrosinasemelanocytesgp 100/Pmel 17gp 75/TRP-1Diff Ags of other PSA ProstateProstateCEAColon and otherColoncarcinomasMutated Ags

42、Mutated rasMany carcinomasNot presentHer-2/neuBreast and ovaryNot present,Human tumour-associated antigens recognized by T lymphocytes,,,,Name Source cDNA libraryCancer testis Ags HOM-Mel-40MelanomaN

43、Y-ESO-1MelanomaMAGE 1MelanomaDiff AgsTyrosinaseMelanomaGalectin-9Hodgkin’s diseaseCarbonic anhydraseRenal carcinomaHousekeeping genesPCNAMelanomaEndogenous retroviral genesMelanom

44、aHERV-K10Mutated Ags p53 (mutated)Colon carcinoma,Antigens identified by SEREX（Serological analysis of recombinant cDNA expression libraries）,,,,Serological analysis of recombinant cDNA expression libraries（SE

45、REX）,Active non-specificBCG, Corynebacterium parvum,levamisole, cytokinesspecificTherapeutic vaccines of tumour cells,cell extracts, purified or recombinantantigens, peptides, heat shock proteins

46、or DNA antigen-pulsed dendritic cellsPassivenon-specificLAK cellsspecificAntibodies alone or coupled to ddrugs, pro-drugs, toxins or radioiisotope,bi-specific antibodies T cellsCombinedLAK cells

47、 and bi-specific antibody,,Immunotherapy of tumours,Immunotherapy免疫治療策略,Immunization with tumor Ags腫瘤抗原免疫Immunization with dendritic cells樹突狀細(xì)胞免疫Non-specific stimulation of immune responses非特異性免疫Immunotherapy with

48、 cytokine can cause tumor regression細(xì)胞因子免疫治療Immunization with oncogenic viruses腫瘤性病毒,Passive Immunotherapy過繼性免疫治療,Therapy with LAK cellsImmunotherapy with T cellsTherapy with antibodies,DC免疫治療,TumourTarget antige

49、n 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

50、 Synthetic peptides in adjuvantLymphomaIg Recombinant proteinidiotype ldiotype single chain Fv-toxoid DNA construct DC pulsed with idiotypic proteinMelanomaVarious Allogeneic whole cells,cell

51、s trasduced with CK, Peptides, DC/ peptides or DC/ tumor lysateProstatePSA Liposome encapsulated PSA, DC / peptidesGlobo H Synthetic Ag-KLH conjugate with QS21 hexasaccharide adjuvant,Clini

52、cal trials of active immunization in man,,,,Type of BRM examplesmajor effectbacterial productsBCG, C. parvum,activate Mφ NKmuramyl dipeptidetrehalose dimycolateSynthetic pyran copolymer,induce IFN pro

53、d.molecules MVE, polyI:C,pyrimidinesCytokinesIFNαβγ， activate Mφ NKIL-2, TNF Hormones thymosin, thymulin, modulate thymopoietin T-cell functioin,Non-specfic active immunotherapy: biolo

54、gical response modifiers (BRMs),,,,Cytokinetumour typecytokine effects and possibleand resultsanti-tumour mechanismsIFNαprolonged remissionspossible cytostaticof hairy-cell leukaemiaeffect on tumour

55、weak effects on increased expression of some carcinomasMHC class I, cytostasisIFNΓineffective systemically, increased MHC class I and IIremissions of peritoneal macrophage activationcarcinoma o

56、f the ovary Tc activation, cytostasisIL-2 remissions in renalT-cell activationcancer and melanomaand proliferationNK-cell activationTNFαcan reduce?increased tumourmalignant ascitescell ad

57、hesion, macrophage and lymphocyte activation,Cytokine therapy for tmours,,,,腫瘤共刺激分子丟失,腫瘤細(xì)胞MHC分子表達(dá)缺失,腫瘤逃避免疫識別的機(jī)制,Obstacles to tumor immunitySelf-origin of tumor antigensMost proteins that are expressed b

58、y 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 autoi

59、mmunity, 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

60、. 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

61、of HLA class IResistance to CTLsT cells express cytolytic and apoptosis-inducing molecules such as FASL, TNF-α, perforin and granzyme. Tumous can down-regulate the receptors or the downstream signals that are activated

62、 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,Th

63、e 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-cel

64、l 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.

65、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 an

66、tigen 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 recipi

67、ent.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

68、 the tumor — a process that is controlled by the expression of tumor antigen receptors, homing receptors and chemokine receptors. Expression of these receptors is, again, dependent on the T-cell expansion conditions.,Cha