Chapter16 Immunological Tolerance. Contents Part Ⅰ Introduction Part Ⅱ Mechanisms of Self...
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Transcript of Chapter16 Immunological Tolerance. Contents Part Ⅰ Introduction Part Ⅱ Mechanisms of Self...
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Chapter16 Chapter16 Immunological Immunological
ToleranceTolerance
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ContentsContentsPartPart IntroductionⅠ IntroductionⅠ
Part Mechanisms of Self Tolerance ⅡPart Mechanisms of Self Tolerance Ⅱ PartPart Factors affecting Ⅲ Factors affecting Ⅲ Induced ToleranceInduced Tolerance Part Clinical Significance of ⅣPart Clinical Significance of Ⅳ Immunological Immunological ToleranceTolerance
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• Owen first observed immunological tolerance to allogenic antigen in fetal period in 1945
Part IntroductionⅠPart IntroductionⅠ
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cattle of dizygotic twin
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Experiment of Medawar on immunological tolerance
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• Definition: A type of specific unresponsiveness to an antigen induced by the exposure of specific lymphocytes to that antigen, but response to other antigens.
• Tolerogens: antigens that induce tolerance
• Types: self-tolerance
induced tolerance
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General features of immunological tolerance
• Tolerance is antigenic specific and results from the recognition of antigens by specific lymphocytes.
• Normal individuals are tolerant of their own antigens(self antigen)----- Self-tolerance.
• Foreign antigens may be administered in ways that preferentially inhibit immune response by inducing tolerance in specific lymphocytes---antigen induction.
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Immunologic features of toleranceImmunologic features of tolerance
It is an antigen-induced, active process Like immunologic memory, it is antigen
specific Like immunologic memory, it can exist in
B cells, T cells or both Like immunologic memory, it's easier to
induce and last longer in T cells than in B cells
It is an antigen-induced, active process Like immunologic memory, it is antigen
specific Like immunologic memory, it can exist in
B cells, T cells or both Like immunologic memory, it's easier to
induce and last longer in T cells than in B cells
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Tolerance in T and B cellsTolerance in T and B cells
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Difference of Immuologic tolerance & immunodeficiency, immunosuppression
Immunodeficiency:Deficiency in the production of humoral and /or cell-mediated immunity---non-specificity to Ag
Immunosuppression: Suppression of immune responses to antigens. This can be achieved by various means, including physical, chemical----non-specificity to Ag
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Part Part II Mechanism of II Mechanism of Self ToleranceSelf Tolerance
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1. Central tolerance: Central tolerance occurs in the central lymphoid
organs as a consequence of immature self-reactive lymphocytes recognizing ubiquitous self-antigen.
2. Peripheral tolerance: tolerance was induced in peripheral organs as a
result of mature self-reactive lymphocytes encountering tissue-specific self antigens under particular conditions
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1. Central tolerance
Clonal deletion (apoptotic cell death)
During maturation of T lymphocytes in the thymus or B lymphocytes in the bone marrow, immature lymphocytes that recognize ubiquitous self-antigen with high affinity are deleted by negative selection
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Clonal deletion:negative selection of T cells in the thymus
Clonal deletion:negative selection of T cells in the thymus
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Negative selection of B cells inbone marrow
Negative selection of B cells inbone marrow
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2. Peripheral tolerance1.Peripheral tolerance of T
cells① Clonal anergy
functional inactivation without cell death: lack of co-stimulatory signal
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②clonal ignorance: self-reactive lymphocytes remain viable and
functional but do not react to the self antigens in any detectable way.
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③ Immunologically privileged sites
④ Regulatory T cells CD4+CD25+ Treg: TGF- , IL-10
⑤AICD( activation-induced cell death)
Repeated stimulation of lymphocytes by persistent antigens results in death of the activated cells by a process of apoptosis. FasL on activated T cell binds to Fas on activated T cell and then induces T cell apoptosis.
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2) Peripheral tolerance of B cells
• ①Clonal deletion• ②Lack of Th cells• ③Clonal anergy• ④Receptor editing
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Part III Factors affecting tolerance induction
1. Role of antigen
2. Role of the host
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1.role of antigens
(1)Types of antigen• Large, aggregated, complex molecules, properly processed-immune response• soluble, aggregate-free, simple small molecules, not processed-tolerance
(2)Dosage of antigen• Optical dosage-immune response• Very high or very low-tolerance
(3)Portal of entry• Subcutaneous or intramuscular-immune response• Oral or intravenous-tolerance
(4) features of determinant
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Low-zone tolerance high-zone
tolerance
抗体滴度
Concentration of antigen
T cells T 、 B cell
TD-Ag TD-Ag
TI-Ag
Immune response
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2.Role of the host(1)Ages• Adult, immunologically mature---Immune response• Embryo and newborn , immunologically immature---
immunological tolerance(2) Differentiation state of cells• Fully differentiated; memory T & B cells—Immune
response• Relative undifferentiated B cell with only IgM, T cells
in the thymic cortex---immunological tolerance(3) Species,Heredity, Gender, Health
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Host age and antigen dose affect tolerance
Host age and antigen dose affect tolerance
newborn adult
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Part Clinical Significance of ⅣPart Clinical Significance of Ⅳimmunological toleranceimmunological tolerance
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• Prevent the rejection of organ allografts and xenografts
• Treat autoimmune diseases
• Treat allergic diseases
1. To induce immunological tolerance
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2. To terminate immunological tolerance
• To treat tumor:
enhance first signal or second signal
• To treat infection diseases
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SummarySummary Definition of immunological tolerance
Features of immunological tolerance
Induction of immunological tolerance
Mechanism of immunological tolerance
Clinical application of immunological tolerance