Immunology 2008 Lecture 21 Immunological Tolerance 4 November

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  • 1. Complement Ag/Ab complexes ANTIGEN Killing of bacteria Inflammation Immunology 2008 APC TOLERANCE Inactivation of viruses Allergy TODAY Proliferation Lecture 21 Antigen processing (MΦ et al.) Antigen- specific B Differentiation AFC ANTIBODY AUTOIMMUNITY triggering TH2 T-cell Immunological Immunological Tolerance, Chapter 19 Antigen "presentation" T "help" T-CELL FUNCTIONS TC T-cell killing: transplants, Autoimmunity, Chapter 20 tumor cells Tolerance TH1 Mixed Lymphocyte Reaction (MLR) Delayed type hypersensitivity, (DTH); e.g. tuberculin reaction T Suppression/Regulation (Tolerance) 4 November S/R AFFERENT CENTRAL EFFERENT Note: “Peripheral” vs. “Central” Tolerance, anatomical distinction… THREE "LIMBS" OF THE IMMUNE RESPONSE Central Problem of Tolerance: Tolerance in dizygotic cattle twins Owen, 1942 Human dizygotic twins, unlike cattle, do not normally share a common placenta. However… Random generation of diversity Shared placenta, exchange of hemopoietic stem Souter et al. (2003) A Report of Dizygous (G.O.D.) is dangerous. cells Monochorionic Twins. N. Eng. J. Med. 349:154 Stable chimeras • Sex-discordant twins How to deal with self-reactive • Monochorionic, shared fetal circulation No formation of isoantibodies receptors?? • Blood chimerism (many allelic DNA markers) No rejection of tissue grafts. • Product of in vitro fertilization (relevant?) These siblings should display the same mutual tolerance shown by Owen’s cattle twin chimeras – but not yet examined. 1
  • 2. Hypothesis: Tolerance develops to Three mechanisms for Clonal Deletion of Self-Reactive AFCPs antigens present during development of immune system maintenance of tolerance Self- reactive Dies Burnet, “Clonal Selection” hypothesis – Clonal deletion of self- B reactive cells occurs during the development of * Clonal deletion B immunocompetent cells. Suppression pre-B-cell no membrane Ig Immature Not Survives B Medawar experiments - Induction of tolerance to skin grafts B-cell self- can be induced by inoculation of F1 spleen cells into parental Receptor blockade membrane Ig random receptor reactive Mature B-cell inbred newborn mice. Burnet & Medawar shared the Nobel Prize in 1960 Intrathymic T-cell maturation: Two ways to die T-Cell diversity poses a special Strength of interaction Result = clonal deletion negative Experimental Model of Clonal Deletion: Strong Death problem selection positive Cytoxan-Induced Tolerance Epithelial I TC Intermediate Emigration ~3-5% cell - + selection CD4 8 CD8 T-Cells require the ability to recognize Weak/none Death no positive selection • Antigen followed by cytoxan “death by self-MHC – how to prevent this from neglect” • Proliferating cells are selectively killed (Class II-based becoming autoreactive?? ++ CD4 8 CD4+8- TH selection for TcRs occurs in the same • Short-term tolerance way as illustrated Immature T-cell above for Class I...) Thymus (compare with Mishell/Dutton 3HTdR experiments) Positive & Negative Selection Blood during intrathymic development -- CD4 8 Pre-T …in Humans? Not yet. Thymic T-Cell Education: Positive & Negative Selection 2
  • 3. Clonal deletion cannot account for Three mechanisms for all models of tolerance maintenance of tolerance Prediction: If tolerance is maintained by clonal deletion, Spleen cells from tolerant donor then the tolerant state should not Clonal deletion be transferable. NO REJECTION; TOLERANT! * Suppression Newborn Test adult with skin graft Receptor blockade Transfer of tolerance to H-Y antigen Must hypothesize active “suppression”, TReg cells Three mechanisms for Graca et al. (2002) Identification of Regulatory T DaVeroelen, Brand and Claas (2004) Pretransplant Cells in Tolerated Allografts. J. Exp. Med. 195:1641 Blood Transfusions Revisited: A Role for CD4+ maintenance of tolerance Regulatory? Transplantation 77, S26–S28 • Mouse skin graft model • Induce tolerance to allogeneic grafts It has long been observed that multiple blood Clonal deletion • Transfer tolerance with tolerated skin grafts transfusions prior to grafting increase the survival of Suppression • Grafts are colonized by CD4+ regulatory T-cells human kidney transplants. Recent findings reviewed in which can emigrate in a new recipient and this publication suggest that this effect may be due to * Receptor blockade establish a permanent state of tolerance the presence of CD4+ suppressor cells in the transfusions. 3
  • 4. Antigen phagocytosed by macrophage T/B Cooperation in C H H C H C C H H H H C C H Primary Response H H C H H H Excess of soluble antigen, H Antigen C H receptor occupancy without "processing" Ag-presentation: H (Ag/ClassII + C H H cross-linking. C H costimulation) H H No Signal 1 C poor APC C 7 28 H antigen processing Tolerance II H II CD C H 4 C H B -CELL Little Class II H TH(V)-CELL C H H H Ag-presentation H C H H C Antigen 1 bound by Ig B (V) -CELL T-cell help: receptors IL-4 B-CELL TOLERANCE BY RECEPTOR BLOCKADE 2 ("C"=carrier determinant, "H"=hapten determinant) Differentiation to AFC ANTIGEN PRESENTATION BY MACROPHAGE TO T H(V)-CELL Ag excess – no cross-linking C H C H H C H C Three mechanisms for Immune Reactions: H H H Excess of soluble antigen, H H receptor occupancy without Balance between Immunity and Tolerance maintenance of tolerance C C H H cross-linking. H H No Signal 1 C poor H antigen processing II Tolerance H H B -CELL “CENTRAL” C Little Class II H C H Ag-presentation No Signal 2 (…for BM) Clonal deletion TOLERANCE Tolerance TS/R Antigenic TH Immunity Challenge Suppression B-CELL TOLERANCE BY RECEPTOR BLOCKADE Receptor blockade “PERIPHERAL” TOLERANCE Significant mechanism for maintaining tolerance to serum proteins (soluble and abundant) 4
  • 5. Immunity vs. Tolerance Influencing To Induce To Induce Fin Factor Immunity: Tolerance: • Nature of Aggregated, Monomeric, antigen insoluble soluble • Dose of Moderate Very high or antigen dose low doses • Route of Subcutaneous, Intravenous immunization intramuscular • Adjuvant Use of adjuvant No adjuvant 5