ExpectedandObservedTBCasesUnitedStates,1980-199350Observedrate40Expectedrate302063,000ExcessCases108081828384858687888990919293#Year85299-1
Expected and Observed TB Cases United States, 1980 -1993 Year C a s e s x 1,0 0 0 ( L o g S c ale ) C a s e s x 1,0 0 0 ( L o g S c ale ) 85299-1 50 80 93 63,000 Excess 63,000 Excess Cases Observed rate Observed rate Expected rate Expected rate 40 30 20 10 81 82 83 84 85 86 87 88 89 90 91 92
IMMUNOLOGICALQUESTIONSWhatare the necessary and sufficient immunologicalmechanismsforprotection?What are the roles of acquired and innate Immunity?Thcells,CTL,Tregs,antibodies?What is required foractivating macrophages tokillintracellular TB? Extracellular TB?WhatisthemechanismofTissueDamage?What are immunological correlates/surrogates forprotection?
IMMUNOLOGICAL QUESTIONS • What are the necessary and sufficient immunological mechanisms for protection? • What are the roles of acquired and innate Immunity? • Th cells, CTL, Tregs, antibodies? • What is required for activating macrophages to kill intracellular TB? Extracellular TB? • What is the mechanism of Tissue Damage? • What are immunological correlates/surrogates for protection?
AnimalModelsMiceImmuneresponseswell characterizedRelativelyResistantPathologynot likehumansGuinea PigsVerysensitiveBetterpathologyRabbitsVery limited immunologyModeratelysensitivePathology similartohumansNon-humanPrimatesTwo genera, different degrees of resistanceHumansThe real thing文
Animal Models • Mice • Immune responses well characterized • Relatively Resistant • Pathology not like humans • Guinea Pigs • Very sensitive • Better pathology • Rabbits • Very limited immunology • Moderately sensitive • Pathology similar to humans • Non-human Primates • Two genera, different degrees of resistance • Humans • The real thing
ROLEOFADAPTIVEIMMUNITYAntigen-specificreceptors,diverse,preexistantBcells-IgReceptorTcells-TcellReceptorClonalExpansionDelayedbutamplifiableresponse1?
ROLE OF ADAPTIVE IMMUNITY • Antigen-specific receptors, diverse, preexistant • B cells – Ig Receptor • T cells – T cell Receptor • Clonal Expansion • Delayed but amplifiable response
TYPESOFIMMUNERESPONSESAntibodyResponseMadebyBcellsandPlasmaCellsIgG,IgA,T-helper CellDependentCell-MediatedResponse·TCells-ProduceCytokines。T1-produceIFNy-ActivatemacrophagesT2-produceIL-4,IL-10-help'B-cellsCytotoxic T cells- (CTL)-Kill target cells
TYPES OF IMMUNE RESPONSES • Antibody Response • Made by B cells and Plasma Cells • IgG, IgA, T-helper Cell Dependent • Cell-Mediated Response • TH Cells – Produce Cytokines • TH1 – produce IFNγ – Activate macrophages • TH2 - produce IL-4, IL-10 – ‘help’ B-cells • Cytotoxic T cells – (CTL) – Kill target cells