Post on 20-Jan-2016
Chapter16Chapter16
Immunological ToleranceImmunological Tolerance
Chapter16Chapter16
Immunological ToleranceImmunological Tolerance
Innate Immunity and adaptive immunity
Review . Classification of Immunity
Humoral immunity and Cell-mediated immunityHumoral immunity and Cell-mediated immunity
Immune response
Immune response
Effect of Humoral Immunity
Immune response
CD4 Th1
CD4+Th2
CTL
Effect of cell-mediated immunity Effect of cell-mediated immunity
IL-12IL-12
IL-4IL-4
Antigen recognition and T activation
T cell expansion and differentiation
Differentiated effector T cells enter circulation
Effector T cells encounter antigen in peripheral tissues
Effector function of T cells
Immunogenic antigens: antigens that induce immune response Tolerogenic antigens: antigens that induce immunologic tolerance
Immune response and Immunologic toleranceImmune response and Immunologic tolerance
Chapter16 Immunological
Tolerance
Contents• Introduction
• The discovery and type of Immunologic Tolerance
• The conditions inducing Immunologic Tolerance
• Mechanisms of Immunologic Tolerance
• The significance and clinical application of
Immunologic Tolerance
• Immunologic tolerance:
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
Introduction
• Specificity : specific unresponsiveness to an antigen, but
response to other antigens
• Memory : secondary unresponsiveness only to same antigen ,but not to other antigens
• Induction : Its formation needs induction of antigen by the exposure of specific lymphocytes with a time lag
General features of Immunologic tolerance General features of Immunologic tolerance
Difference among Immuologic tolerance , immunod
eficiency& immunosuppression
Immunodeficiency: any condition in which there is defici
ency in the production of humoral and /or cell-mediated
immunity---non-specificity to Ag
Immunosuppression: The suppression of immune respons
es to antigens. This can be achieved by various means, i
ncluding physical, chemical factors ----non-specificity t
o Ag
Section I
The discovery and type of Immunologic Tolerance
• Owen first observed immunologic tolerance in Dizygotic bovine twin in 1945---
• Medawar induced successfully immunologic tolerance in neonate period mice in 1955
I. Discovery of immunologic tolerance
AA BB• Graft of Skin
From A to B or From B to A No rejection
Self –toleranceSuggested by
Burnet
Owen first observed phenomenon of immunologic tolerance in Dizygotic bo
vine twin in 1945
Medawar induced successfully immunologic tolerance in neonate period mice in 1955
• Induced tolerance
Immunologic features of tolerance
Immunologic features of tolerance
It is an antigen-induced, active process
it possesses specificity
It possesses immunologic memory
A kind of special immune response
It is an antigen-induced, active process
it possesses specificity
It possesses immunologic memory
A kind of special immune response
Sir Frank Macfarlane Burnet ,Australia , 1899-1985
Sir Frank Macfarlane Burnet ,Australia , 1899-1985
Peter Brian Medawar , UK , 1915-1987
Peter Brian Medawar , UK , 1915-1987
for discovery of acquired immunological tolerance ( 1960 )for discovery of acquired immunological tolerance ( 1960 )
II. Types of Immunological tolerance(I) Self –tolerance and induced tolerance• Self tolerance: to self antigen• Induced tolerance: to foreign antigen
(II) Central tolerance and Peripheral tolerance
• Central tolerance :form in central immune organs
• Peripheral tolerance : form peripheral immune organs
• Normal individuals are tolerant to their own
antigens
(self antigen)
• Tolerance to self antigens is a fundamental property of the normal immune system, the failure of self-tolerance leads to autoimmune disease.
Self-toleranceSelf-tolerance
Induced tolerance
• Foreign antigens may be administered in ways that preferentially inhibit immune response by inducing tolerance in specific lymphocytes
• Such as
Tumor cells can induce immunological tolerance during their proliferation .
Central tolerance• induced in central immune organs as a conseq
uence of immature self-reactive lymphocytes recognizing antigens
Peripheral tolerance• induced in peripheral immune organs as a
result of mature self-reactive lymphocytes encountering self antigens under particular conditions
Section II The conditions of immunological tolerance formation
• Antigen-associate factors
• Host–associated factors
I. Antigen-associate factors
• Types of antigen
• does of antigens
• Features of determinant
• Pathway of antigen entering body
1. Types of antigen
Factors which affect response
Favor immune response Favor tolerance
Physical form of antigen
Large, aggregated, complex molecules, properly processed
soluble, aggregate-free, simple small molecules, not processed
2. does of antigens
High-zone tolerance
High-zone toleranceLow-zone
tolerance
Low-zone tolerance
T, B cell
tolerance T, B cell
tolerance T cell
tolerance T cell
tolerance Immune responseImmune response
Comparison of T cell tolerance with B cell tolerance________________________________________________ Contents T cell B cell
__________________________________________________________Tolerance formation easy difficult
Antigens TD -Ag TD- Ag and TI –Ag
Dose of antigens high or low high
Induced time shorter (1-2 days) longer (more than 10 days)
Maintaining time longer (a few months) shorter (a few weeks)
___________________________________________________
Comparison of T cell tolerance with B cell tolerance________________________________________________ Contents T cell B cell
__________________________________________________________Tolerance formation easy difficult
Antigens TD -Ag TD- Ag and TI –Ag
Dose of antigens high or low high
Induced time shorter (1-2 days) longer (more than 10 days)
Maintaining time longer (a few months) shorter (a few weeks)
___________________________________________________
3. Features of determinant
• Determinants recognized by Ts or Treg induce tolerance
• Determinants recognized by conventional T cells initiate immune response
4.Pathway of antigen entering body
• Oral
• Intravenous
• Intra-peritoneal
• Intramuscular
• subcutaneous Immune
response Immune
response tolerancetolerance
Factors affecting tolerance
role of antigen
Factors affecting tolerance
role of antigen
Factors which affect
response
Favor immune response
Favor tolerance
Physical form of antigen
Route of injection
Dose of antigen
Large, aggregated, complex molecules, properly processed
Subcutaneous or intramuscular
Optimal dose
soluble, aggregate-free, simple small molecules, not processed
Oral or, sometimes, intravenous
Very large or very small dose
II. Host–associated factors
Species: easy in murine and rat difficult in human
Status of host immune system:
Factors affecting tolerance
the role of host
Factors affecting tolerance
the role of host
Factors that affect
response
Favor immune response
Favor tolerance
Age of responding animal
Differentiation state of cells
Fully differentiated; memory T & B cells
Older, immuno-logically mature
Newborn (mice), immuno-logically immature
Relative undifferentiated B cell with only IgM, T cells in the thymic cortex
Host age and antigen dose affect tolerance
Host age and antigen dose affect tolerance
newborn adult
Section ⅢMechanism of Immunologic Tolerance
.Central tolerance: Central tolerance occurs in the central lymphoid organs
as a consequence of immature self-reactive lymphocytes recognizing ubiquitous self-antigen.----negative selection
.Peripheral tolerance: tolerance was induced in peripheral organs as a result of
mature self-reactive lymphocytes encountering tissue-specific self antigens under particular conditions
I. Central tolerance• T cell central tolerance : formation in thymus
clonal deletion in negative selection
• B cell central tolerance: formation in bone marrow clonal deletion
clonal anergy
Clonal deletion:negative selection of T cells in the thymus
Clonal deletion:negative selection of T cells in the thymus
1. T cell central tolerance
T cell Clonal deletion (apoptotic cell death)
During maturation of T lymphocytes in the thy
mus, immature T lymphocytes that recognize ubi
quitous self-antigen with high affinity are delete
d by mechanism of apoptosis
2. B cell central toleranceClonal deletion
During maturation of B lymphocytes in bone marrow , immature lymphocytes that recognize membrane-bound self-antigen with high affinity are deleted by apoptosis
Clonal anergy
During maturation of B lymphocytes in bone marrow , immature lymphocytes that recognize soluble self-antigen are not deleted but are inactivated
Negative selection of B cells in
bone marrow
Negative selection of B cells in
bone marrow
Clonal anergy in B cells
Clonal anergy in B cells
II. Peripheral tolerance• T cell Peripheral tolerance
Clonal anergy
Immunological ignorance
Regulatory T cells
Activation induced cell death, AICD
Immunity privilege
• B cell Peripheral tolerance
Clonal deletion
Clonal anergy
Receptor editing
I) T cell Peripheral tolerance
1. Clonal anergy:
• An experimentally induced state of antigen unresponsiveness
of a clone of T lymphocytes induced by recognition of antige
n in the absence of additional signals ( costimulatory signa
l)
• T cells survive but are rendered incapable of responding to
the antigen even if it is later presented by competent APCs
• viable and unfunctional
• Absence of costimulatory signal
If CD4+ T cells recognize peptide antigens
presented by APCs that are deficient in
costimulators , the T cells survive but are
rendered incapable of responding to the
antigen even if it is later presented by competent APCs
• Inhibition of costimulatory signal
Anergy may be induced if T cells use the
Inhibitory receptor for B7 molecules, CTLA4, to recognize costimulators
on APCs at the time that the cells are recognizing antigen
I) T cell Peripheral tolerance
2.Immunologic ignorance
A form of lymphocyte unresponsiveness in which
self antigens are ignored by the immune system even
though lymphocytes specific for those antigens
remain viable and functional.
Clonal anergy Clonal anergy Clonal ignorance Clonal ignorance
I) T cell Peripheral tolerance
3.Regulatory T cells
A population of T cells that inhibit the
activation proliferation of other T cells and
may be necessary to the maintaining of
peripheral tolerance to self antigens
Regulatory T cells
• Regulatory CD4+T cells: CD4+CD25+ T cells
• Regulatory CD8+ T cells: CD8+CD28-T cells
Qa-1- restricted CD8+
• NK T cells
• Double negative regulatory T cell:
CD3+CD4-CD8-
Induced Treg Induced Treg
CD4CD4++CD25CD25++TregsTregs
In vivoIn vivo• MaintainMaintain immune toleranceimmune tolerance• Inhibit autoimmunityInhibit autoimmunity• prevent transplant rejectionprevent transplant rejection• Interfere with anti-cancer Interfere with anti-cancer
immunityimmunity• Potential in immune deficiencyPotential in immune deficiency
40
30
20
10
0
3H
up
take
(x1
0-3)
CD25– CD25+ CD25–
+CD25+
•In vitro• 5-10% of CD4+ T cells•Anergic to TCR stimulation•Suppress T cell proliferation
100 101 102 103 104
FL1-Spl/PBS/CD4
L090905.005
R2
100 101 102 103 104
FL4-Spl/PBSCD25
L090905.005
CD4
CD
25
Fo
xp3
FACS
CD25
CD25 Foxp3
Microscopy Co-culture
10% >90%
I) T cell Peripheral tolerance
4. Activation-induced cell death (AICD)
Repeated stimulation of T lymphocytes by persistent antigens results in death of the activated cells by a process of apoptosis
I) T cell Peripheral tolerance
5. Immunologically privileged sites anatomic barrier
Action of Suppressor lymphocyte (Ts)
Action of cytokines: TGF- , IL-10
II) B cell Peripheral tolerance 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
Clonal anergy Clonal anergy
Section I VSignificance and clinical application
of immunologic Tolerance
I. The significance of theoretical research
II. The significance and application on clinical therapy
• Immunologic tolerance is very important for maintaining homeostasis
Homeostasis: The maintaining of constant number of cells called homeostasis
Immune response to foreign antigens are eliminated, returning the immune system t
o its basal resting state. Deletion ( AICD),
• Immunologic tolerance is an very important mechanism of immunoregulation
I. The significance of theoretical research
II. The significance and application on clinical therapy
(I) Induce immunologic tolerance to treat autoimmune diseases
• Block costimulaotry signal CD28/B7 CD40/CD40L CD137/CD137L• enhance inhibition of regulatory T cell CD4+CD25+ Treg
• Oral tolerance : the oral administration of a protein antigen often leads to a marked suppression of systemic humoral and cell-mediated immune response to immunization with the same antigen
(II) Induce immunologic tolerance to prevent or treat hypersensitivity
(III) Induce immunologic tolerance to prevent or treat graft rejection
• Block costimulaotry signal CD28/B7 CD40/CD40L CD137/CD137L• enhance inhibition of regulatory T cell CD4+CD25+ Treg
• Oral tolerance : the oral administration of a protein antigen often leads to a marked suppression of systemic humoral and cell-mediated immune response to immunization with the same antigen
• Enhance costimulaotry signal
CD28/B7
CD40/CD40L
CD137/CD137L
• Deletion of regulatory T cell
CD4+CD25+ Treg
(IV) Break up tumor immune tolerance
to treat tumor