MucosalImmunization黏膜免疫.pptx
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1、Mucosal Immunization.Leslie Ann Mitchell,PhD.Gene Therapy Institute,Hadassah Ein KaremImmune Response.nInnate immunity:nmacrophages,NK cells,mucous,lysozyme,cytokines,etc.n Provides first line of defense to prevent colonization and infection.nDetermines which antigens will be recognized by B-and T-c
2、ells and the nature of the response.Immune Response.nAcquired immunity:B-and T-lymphocytes.nB-cells:produce antibodies that neutralize viruses and bacterial toxins,block attachment of microbes to host cells,or opsonize microbes for phagocytosisnT-cells:help(CD4+)or cytotoxic(CD8+)functions(eliminati
3、on of intracellular microbes and viruses)Local Immunity.nMost pathogens enter the body via mucosal surfaces.nLocal immunity(specific IgA,cellular immunity)is an important first line of defense vs.pathogens.nSystemic immunization is ineffective in inducing local immunity.Inherent Problems with Mucosa
4、l Immunization.nMost protein antigens are poorly immunogenic when delivered via the mucosal route.nImmunologic tolerance may be induced(especially via the oral route).nMucosal surfaces are easily tolerized:non-responsiveness has evolved to prevent unwanted inflammatory responses.Design of Mucosal Va
5、ccines:Important Factors.nAntigen must be protected from enzymatic digestion or acid hydrolysis.nAntigen uptake by mucosal M-cells and epithelial cells must be enhanced.nInnate immune system must be stimulated to ensure appropriate adaptive immune response.nImmunologic memory must be induced.Pathoge
6、n-associated molecular patterns(PAMPs).nConserved molecular structures found on bacterial and viral pathogens.nExamples:nGram+and bacteria:LPS,teichoic acid,peptidoglycans,CpG motifsnRNA virus:dsRNAnYeasts:mannansPathogen-associated molecular patterns(PAMPs).nNot present on mammalian cells but inter
7、act with non-clonal pattern recognition receptors(PPRs)on macrophages,dendritic cells,epithelial cells.nExamples:CD14,collectins,toll-like receptors(TLRs),mannose binding protein(MBP),serum amyloid P,C receptors,CD11b/CD18,DEC205PAMPs and PPRs:Mechanism of activation.Example:bacterial CpG binds to T
8、LR9nBinding of microbial molecules to TLRs transduces signals through a common adaptor(MYD88)and NFkB resulting in the generation of cytokines(IL-1,IL-12,TNF-a)and activation molecules(B7)on lymphocytes.nEnhances antigen presentation,T-cell activation,increases adaptive immune response.Mucosal Epith
9、elial Cells.nInterface between pathogen and immune system:nInnate(MHC Class I)and inducible(MHC Class II)antigen presentation functionnInduced by pathogens to synthesize and secrete:nAntimicrobial peptides and proteinsnImmunoregulatory cytokinesnColony-stimulating factorsnChemokines(recruitment of i
10、mmune cells)Helper T-Cell Subsets.nTH1:nIFN-g,TNF-bnCellular immunity vs.intracellular bacteria,small parasitesnInduction of neutralizing antibodies of the IgG2a subclass(in mice)nTH2:nIL-4,IL-5,IL-10,and IL-13nInduced by helminth parasites,allergens,immunization with soluble or alum-adsorbed antige
11、nsnImmunity to extracellular parasites,bacterianHelper function in production of IgA,IgE,and neutralizing IgG to bacterial toxinsRegulation of T-cell Response.nTH1 vs TH2:cross-regulation by TH cytokines or by cytokines from subsets of dendritic cells(DC1 and DC2).nIL-4 drives TH2 pathway.nMust be t
12、ightly regulated or immune-mediated hypersensitivity or autoimmune disease will result.Targeting T-cell Response in Vaccination Protocols.nCD4 T-cell response induced by:nAntigens targeted toward MHC Class II processing pathwaynLive or killed bacteria or virusesnPurified protein or peptide antigens
13、with adjuvants such as alum.nCD8 T-cell response induced by:nIntracellular viruses or bacterianDelivery systems targeting towards MHC Class I pathway:liposomes,ISCOMS,microparticles,naked DNARequirements for T-cell Activation.nAntigen recognition through TcR in the context of MHC Class I or II molec
14、ules.nCo-stimulatory molecular interactions between T-cell and APC:APC:T-cell:B7-1,B7-2CD28CD40CD40LICAM-3LFA-1LFA-3CD2Role of Dendritic Cells(DCs).nDCs of two lineages:lymphoid and myeloid differentially influence maturation of TH1 and TH2.nImmature DCs:phagocytic,express CCR5&CCR6,low levels of MH
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