移植免疫.ppt

,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,1,第,18,章 移 植 免 疫,Transplant Immunology,2,Allografts:transplants from a genetically unrelated donor of the same species.,Allogeneic transplantation:the last resort for the treatment of chronic organ failure.,the major complication post-transplantation is rejection.,Rejection occurs in almost all transplant recipients,to varying degrees.,3,E.D.Thomas,J E.Murray,1954,年，,JE.Murray,首次,施行同卵双生姐妹之间的肾移植。,1956,年，,E.D.Thomas,首次,给一位白血病患者进行骨髓移植,.,Murray,和,Thomas,的工作标志器官移植成为临床疾病治疗的手段。,4,6,Peritransplant injury induces chemokines that increase inflammation and immunity,7,Content,Immunological mechanism in allogeneic graft rejection,Types of transplant rejection,Principles to prevent transplant rejection,Trends and advances in experimental transplant immunology,8,10,第,1,节 同种异体移植排斥的机制,11,Types of transplantation,Autologous,(,自体移植）,Syngeneic,（,同系移植,）,Allogeneic,（,同种移植,）,Most commonXenogeneic,（,异种移植,）,13,6 months,Transplant rejection is due to an antigen-specific immune response,with immunological memory.,Immunological basis of graft rejection,Primary rejection of,strain skin,e.g.10 days,Secondary rejection of,strain skin,e.g.3 days,Primary rejection of,strain skin,e.g.10 days,Nave mouse,Lyc,Transfer lymphocytes,from primed mouse,15,Histocompatibility and graft survival,16,一,.,引起同种移植排斥反应的抗原,人类主要组织相容性抗原（,HLA),HLA,型别的差异是发生移植排斥反应的主要原因,.,18,Simplified map of the HLA region,Maximum of 9 types of antigen presenting molecule allow interaction with a wide range of peptides.,Class III,MHC Class II,DP,LMP/TAP,DM,DQ,DR,1,B,C,A,MHC Class I,Polygeny,CLASS I:3 types HLA-A,HLA-B,HLA-C(sometimes called class Ia genes),CLASS II:3 types HLA-DP HLA-DQ HLA-DR.,4,5,3,3 extra DR,genes in some individuals can allow 3 extra HLA-DR molecules,19,IMGT/HLASequence Database Statistics,Allele Information,HLA Class I Alleles:1,156,HLA Class II Alleles:712,HLA Alleles:1,868,Other Alleles:67,（,Including 56 MICA alleles),20,Polymorphism in MHC Class I genes,Variation 1%at a single genetic locus in a population of individuals,In the human population,over 1300 MHC class I alleles have been identified-some are null alleles,synonyms or differ in regions outside the coding region,699,396,198,Data from September 2005,1318 alleles,(998 in October 2003),(657 in July 2000),8,2,15,Class I,A,B,C,No of,polymorphisms,E,F,G,21,Polymorphism in MHC Class II genes,Over 700 human MHC class II alleles have been identified-some are null alleles,synonyms or differ in regions outside the coding region,3,494,23,119,28,66,4,7,9,9,DR,DP,DQ,DM,DO,Class II,A,B1,A1,B1,A1,B1,No of,polymorphisms,A,B,A,B,22,次要组织相容性抗原（,m,inor Histocompatibility antigens,mH,抗原）,与性别相关的,mH,抗原,Y,染色体基因编码的,H-Y,抗原,.,非,Y,染色体连锁的,mH,抗原,(,HA-1HA-5,),mH,抗原,MHC,限制分子,群体表型频率,TCR,谱,H-Y,HLA-A1,A2,B7,B60,50%,可变,HA-2,HLA-A2,95%,HA-4,HLA-A2,16%,?,可变,24,KIAA0223,gene forms a diallelic system.,The two alleles differ in:,Two nucleotides,A single amino acid.,25,VL,H,DDLLEA is encoded by an allele HA-1H.,VL,R,DDLLEA is encoded by an allele HA-1R.,26,HA-1(HA-1H)has a population frequency of 69%.,HA-1R represents the HA-1-negative allelic counterpart with a frequency of 31%in the population.,28,Peptides can be eluted from MHC molecules,Purify stable MHC-peptide complexes,Fractionate and microsequence,peptides,Acid elute peptides,29,The absence of the HA-1 R peptide in HLA-A*0201 suggests that this allele can be considered as a null allele with regard to HLA-A*0201-restricted T cell reactivity.,This further suggests that only BMT from an HA-1R/R donor to an HA-1H/H or HA-1H/R recipient and not the reverse would be significantly associated with GvHD.,31,其它参与排斥反应的抗原,人类,ABO,血型抗原,表达于红细胞,肝,肾组织细胞,血管内皮细胞的表面,.,不合导致超急性排斥反应,.,组织特异性抗原,表达于特定器官，组织或细胞表面,.,内皮细胞特异性（,VEC),抗原,.,SK,抗原：皮肤蛋白多肽抗原,.,32,Cytokines,TNF-a,IL-10,Mediator of immune response,SNP polymorphism,high or low producers,Cytokine receptors,Adhesion molecules,Co-stimulatory molecules,Genetic variability influencing allograft survival may reaches beyond that of the MHC molecules.,Other factors involved in the immune response to an allograft,33,二、,T,细胞识别同种抗原的机制,34,受者,T,细胞,供者,APC,供者,APC,受者,T,细胞,受者,TCR,供者,MHC,T,细胞,TCR,直接识别过路细胞表面完整的同种异型,MHC,分子,无需经过自身,APC,处理,无需自身,MHC,分子参与递呈,.,供者肽,移植排斥反应中的直接同种异型识别,（一）直接同种异型识别,35,Recognition of Alloantigens,Direct Presentation,Recognition of an intact MHC molecule displayed by donor APC in the graft,36,Activation of Alloreactive T cells and Rejection of Allografts,Donor APCs migrate to regional lymph nodes and are recognized by the recipients T cells.,Alloreactive T cells in the recipient are activated and they migrate into the graft and cause graft rejection.,37,38,HOST,CD8+T,细胞对异型,MHC,分子的直接识别,39,40,直接同种异型识别特点,过路细胞,(Passenger Cell),：,移植物残留的成熟树突状细胞,巨噬细胞。,表达,MHC-I,II,类分子和,B7,辅助刺激分子。,排斥反应,速度快,强度大,作用阶段,急性排斥反应,对免疫抑制药物敏感,41,间接识别,Indirect allo-recognition,受者,T,细胞识别经过受者,APC,加工处理的来源于移植物的,MHC,分子（肽段）或,mH,抗原,受者,T,细胞,TCR,供者抗原肽,受者,MHC,受者,APC,（二）,间接,同种异型识别,42,Indirect Presentation,Donor MHC is processed and presented by recipient APC,Basically,donor MHC molecule is handled like any other foreign antigen,43,HOST,44,Cellular Immune Response,(,Early Stage in acute rejection),1.Th1 Activation,2.Activation of CD8+CTL,3.Release of cytokines,chemokines,Humoral Immunity,(,In Super Acute Rejection),1.Opsonization,2 ADCC,3 CDC,Immunological Mechanisms,45,Renal Transplant Rejection,Hyperacute,Acute,Tubulointerstitial,Vascular,Chronic,第,2,节 移植排斥反应的类型,I.HVGR,（宿主抗移植物反应,),46,Hyperacute Rejection,Caused by preformed antibodies in the recipient,Occurs within minutes,Grossly kidney purple and swollen,Widespread acute arteritis and arteriolitis,Thrombosis of vessels,Ischemic necrosis,Results in loss of graft,47,Hyperacute rejection,Source of pre-existing antibody:,Repeated blood transfusions,Repeated pregnancies,Previous graft,Blood Ag:,ABO Ag,48,Hyperacute rejection:Thrombi in glomerulus and fibrin in artery.Anti-donor antibodies bind to donor endothelial cells and activate the complement cascade and clotting cascade.,Fibrin in artery,Thrombus in Glomerulus,49,Acute Rejection,Occurs as early as 10-14 days.May occur months to years later.,CD4 T mediated DTH,Effector cells:CD4 T,CD8 T,NK cell,Decreased renal function.May have fever and tenderness of the graft.,Tubulointerstitial or vascular,50,Acute tubulointerstitial rejection:Mononuclear interstitial infiltrate.,51,Chronic Rejection,After fourth month,Vascular changes,Intimal fibrosis,Progressive luminal narrowing,Interstitial fibrosis and tubular atrophy,Ischemic glomerulosclerosis,No effective therapy,52,Chronic Transplant Vasculopathy Concentric Fibrous Intimal Thickening,53,II.GVHR,（移植物抗宿主反应）,移植受者免疫功能极度低下时，由移植物中的抗原特异性淋巴细胞识别宿主组织抗原所发生的一种严重的排斥反应。,第,2,节 移植排斥反应的类型,54,宿主免疫功能低下；,移植物含足够免疫活性细胞；,识别受者,MHC,抗原、,mH,抗原；,产生针对宿主组织器官损伤；,主要见于异基因骨髓移植。,55,Complications of Allogeneic BM Transplants,Graft versus host disease,Immunologically competent cells from donor,Affects liver,skin,gut(jaundice,rash,diarrhea),Acute or chronic,Graft versus leukemia effect may be beneficial,Rejection of allogeneic marrow cells.,56,Acute GVH,R,57,移植物抗白血病效应,Graft versus leukemia effect,BMT(,同卵双生，自体移植）,:,无,GVHD,，高复发率。,Allo-BMT:,复发率明显减少。,58,NK cells express inhibitory receptors that are specific for MHC class I alleles.,In humans these molecules are known as Killer Immunoglobulin-like Receptors(KIRs).,59,移植物,NK,细胞杀伤受者残留肿瘤细胞,KIR,基因具有高度的群体遗传多样性，主要表达于,NK,细胞,T,细胞亚群的细胞膜表面,.,KIR,：,HLA-I,分子形成受体：配体关系,.,主要产生抑制信号，调节,NK,细胞的活化,60,HLA genes are located on chromosomeat loci,KIR genes are located at,6p21.3,19q13.4,61,供受体可能出现,HLA,相同，而,KIR,不合的情况,.,相应,KIR,受体分子或,HLA-I,配体分子的缺如，将改变,NK,活化阈值,.,62,Lysis,Lysis,leukemia,DC,NK,DC,DC,NK,NK,Donor alloreactive,NK cells,Lysis,T,T,T,Kill recipient APCs=,protection from GvHD,Kill recipient T cells=,improved engraftment,Kill leukemia=,GvL effect,NK Cells for Stem Cell Transplantation,63,Alloreactive NK cells could be deliberately infused to prevent leukemic relapses.,Alloreactive NK cells kill the host dendritic cells(DCs).,Removal of DCs prevents the presentation of host antigens to graft T cells which is the crucial step in initiating GvH reactions.,64,Immune privilege in the cornea,Keratoplasty is the oldest and one of the most successful forms of solid tissue transplantation.,Does not require the aid of tissue typing or systemic immunosuppressive drugs.,65,Contributing factors,Expression of MHC class I molecules is markedly reduced.,There is no constitutive expression of MHC class II molecules.,Lacks both blood and lymph vessels.,Lacks bone marrow-derived antigen-presenting cells(APC).,66,第,3,节 移植排斥反应的防治原则,67,Methods of Increasing Graft Survival,Screening of preformed allo-antiboby.,ABO blood groups,Panel reactive antibody,HLA matching.,Crucial for Allo-BMT,SNPs typing,Oligonuleotide Microarrays,mH antigen,Immunosuppression of the recipient.,68,HLA matching and graft survival,69,Tissue typing:the MLR scheme,MLR:Mixed Lymphocyte Reaction,70,71,PRA(panel reactive antibody),来源：输血、妊娠、移植、透析治疗、疾病（,SLE,）。,种类：,IgG,、,IgM,、,IgA,、,自身抗体。,参与超急性排斥反应。,72,免疫抑制疗法,免疫抑制药：环孢素,A,、,FK506,、雷帕霉素,.,生物制剂：,针对免疫细胞膜抗原的各种抗体,.,抗淋巴细胞球蛋白（,ALG,）,抗胸腺细胞球蛋白（,ATG,）,Anti-CD3,，,Anti-CD4,，,Anti-CD8 mAb.,通过,CDC,机制清除体内的,T,细胞或胸腺细胞,.,73,74,75,第,4,节 移植相关的免疫学问题,诱导同种移植耐受的主要策略,76,长期存活移植受者体内含有供者来源白细胞。,受者淋巴细胞与相应供者淋巴细胞,MLC,阴性。,微嵌合,（,Microchimerism),现象,77,双向排斥模式,（,Two-way paradigm,）,与微嵌合,移植物中过路细胞刺激受者免疫细胞，产生,HVGR,。,受者白细胞进入移植物，刺激供者免疫细胞,产生,GVHR,。,药物（免疫抑制剂）的持续干预，同时抑制,HVGR,和,GVHR,。,HVGR,和,GVHR,最终达到一种无反应性的平衡状态，即供、,受者白细胞共存的微嵌合体状态。,长期微嵌合状态,可能,形成对移植器官的耐受。,78,Transplant Tolerance Induction,Blockade of TCR recognition of allo-types,For example,synthesized supermotif binds to allo-reactive TCR.,TCR specific mAb,Anti-TCR idiotype Ab,79,TCR,MHC,供者肽,T,细胞,T,细胞,APC,APC,人工合成的多肽,Synthesized supermotif blocks the TCR recognition,of allo-MHC molecule.,80,Blockade of costimulatory Signals,B7-CD28/CTLA-4;CD40-CD40L,Gene expression interference,Antibody,Soluble ligand,Transplant Tolerance Induction,81,CTLA4-Ig and anti-CD40 ligand can both prevent and reverse acute allograft rejection,significantly prolonging the survival of major histocompatibility complex-mismatched renal allografts in primates without the need for chronic immunosuppression.,82,Nave,Alloreactive,T cell pool,Transplantation,MHC antigens,With Co-stimulation,Few apoptotic cells,Acute rejection,Memory T cell,Chronic Rejection,(Time),83,Nave,Alloreactive,T cell pool,Transplantation,MHC antigens,Without Co-stimulation,Many apoptotic cells,No rejection,Anergic and,suppressor,T cell,Tolerance,(Time),+CTLA4 Ig,+anti-CD40L,Few effector T cell,84,85,86,不成熟,DC,细胞与微嵌合及移植耐受,不成熟,DC,细胞,:,低表达,MHC,分子；缺乏,B7,协同刺激分子,.,不能激活,T,细胞，诱导,HVGR,和,GVHR,的能力弱,.,主要分布于非淋巴组织（肝、肾、心）,.,87,肝移植后发生的排斥反应通常最弱。,DC,细胞以不成熟,DC,和,DC,祖细胞为主,器官移植（肾、心）后输入供者骨髓促进移植物存活。,肝肾联合移植可减轻肾移植排斥的发生率。,不成熟,DC,促进移植物存活,88,CD4+CD25+regulatory T cell,The majority of regulatory T cells(T regs),identified to date lie within the CD4+population.,Transplant Tolerance Induction,89,Cytotoxic T lymphocyte-associated antigen 4(CTLA-4)is specifically implicated in the mechanism of action of CD4+CD25+regulatory cells.,Unlike other resting T cell populations,CD4+CD25+cells have been shown to express CTLA-4 constitutively in both mice and humans.,90,T,reg,CD4,CD25,CTLA-4,T,reg,cell phenotype,CD25:,-IL-2Ra,-Key T,R,growth factor,CTLA-4,-Binds to B7 on APC,-acts as co-stimulatory,molecule for T,R.,(blocking CTLA-4 inhibits T,R,),FoxP3,-critical for T,R,activity and development,Foxp3,91,Tolerance induction:Treg,secretes IL-10 and TGF-,.,92,Summary,Both cellular and humoral immune response are involved in transplant rejection.,Allorecognition can be classified as the“direct”or“indirect”pathway.,Donor-versus-recipient natural killer cell alloreactivity could eliminate leukemia relapse and graft rejection and protect patients against GVHD.,Induction of allograft tolerance,is the ultimate goal in organ transplantation.,