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