Transcript 幻灯片 1 - Shandong University

Chapter 16
Immunological Tolerance
Contents
PartⅠ Introduction
PartⅡ Mechanisms of Self Tolerance
PartⅢ Factors affecting Induced Tolerance
PartⅣ Clinical Significance of Immunological
Tolerance
PartⅠ Introduction
• Owen first observed
immunological
tolerance to allogenic
antigen in fetal period
in 1945
cattle of dizygotic twin
• Graft of Skin
From A to B or
From B to A
----No rejection
A
B
Experiment of Medawar on immunological tolerance
Immunological tolerance
Definition: A type of specific unresponsiveness to an antigen
induced by the exposure of specific lymphocytes to that antigen,
but response to other antigens normally.
• Tolerogens: antigens that induce tolerance
• Types: self-tolerance
induced tolerance
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.
Immunologic features of tolerance
 It is an antigen-induced, active process
 Like immunologic memory, it is antigen
specific
 It can exist in B cells, T cells or both
• Tolerance in T cell is longer lasting than B
cell.
Tolerance in T and B cells
Difference of Immuologic tolerance &
immunodeficiency, immunosuppression
Immunodeficiency:Deficiency in the production
of humoral and /or cell-mediated immunity--non-specificity to Ag
Immunosuppression: S uppression of immune
responses to antigens. This can be achieved by
various means, including physical, chemical---non-specificity to Ag
Part II Mechanism of Self Tolerance
1. Central tolerance:
Central tolerance occurs in the central lymphoid
organs as a consequence of immature selfreactive 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
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
Clonal deletion:
negative selection of T cells in the thymus
Clonal Selection of T cells in the Thymus
Negative selection of B cells in
bone marrow
Clonal deletion of B cells in the bone marrow
Stem cell
(in red bone marrow)
B cells
BCRs
Cell with
autoantigens
Cell with
autoantigens
Apoptosis
Blood vessel
To spleen
2. Peripheral tolerance
1)Peripheral tolerance of T cells
① Clonal anergy
functional inactivation without cell death: lack of costimulatory signal
②clonal ignorance:
self-reactive lymphocytes remain viable and functional but do
not react to the self antigens in any detectable way.
Clonal anergy
Clonal ignorance
③ Regulatory T cells
CD4+CD25+Foxp3+ Treg: TGF- , IL-10
④ AICD( 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.
⑤ Immunologically privileged sites
Anatomic Barrier
Immunological Suppression: TGF- , IL-10
2) Peripheral tolerance of B cells
Clonal deletion :AICD
Lack of Th cell help : Th cell anergy
Clonal anergy : express insensitive mIg
lack costimulatory molecules
Receptor editing : from self-reactive B cell clone to foreign
antigen-reactive B cell lone
Part III Factors affecting
tolerance induction
1. Role of antigen
2. Role of the host
1.Role of antigens
(1)Types of antigen
•
Large, aggregated, complex molecules, properly processedimmune response
•
soluble, aggregate-free, simple small molecules, not processedtolerance
(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
Tolerance:Oral >Intravenous>Intraperitoneal>Intramuscular>subcutaneous
(4) features of determinant
Concentration of
antibody
Immune
response
Low-zone
tolerance
high-zone
tolerance
T cells
T、B cell
TD-Ag
TD-Ag
TI-Ag
Concentration of antigen
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
Host age and antigen dose affect
tolerance
newborn
adult
PartⅣ Clinical Significance of
immunological tolerance
1. To induce immunological tolerance
•
•
•
Prevent the rejection of organ allografts and
xenografts
Treat autoimmune diseases
Treat allergic diseases
2. To terminate immunological
tolerance
• To treat tumor:
enhance first signal or second signal
• To treat infection diseases
Summary
Definition of immunological tolerance
Features of immunological tolerance
Induction of immunological tolerance
Mechanism of immunological tolerance
Clinical application of immunological tolerance