Chapter 13 Immunological Chapter 13 Immunological Tolerance (3) Tolerance (3)

I. Introduction

Concept

Natural tolerance

Acquired tolerance

II. Factors Affecting Tolerogenicing of

Antigen

III. Mechanisms of Tolerance Induction

IV. Clinical significance of immunologic tolerance

Concept

Immunological tolerance is a state of unresponsiveness that is specific for a particular antigen; it is induced by prior exposure to that antigen.

II. Factors Affecting Tolerogenicing of Ag

1. The structure of antigen

2. The antigen dosage

3. The route of administration

Low –zone tolerance High –zone tolerance

Tolerance cells T cells T and B cells

Speeds 24 hours slow ( 1-2 weeks)Time long (months) short (weeks)Antigens TD-Ag (low-dose) all Ag (high-dose)

Experimental induction of tolerance at low and high doses of antigen

Experimental induction of tolerance at low and high doses of antigen

Serum anti-BAS Response to secondary immunogenic dose of BSA% of control

Priming dose of BSA,g

100%

10-12 10-9 10-6 10-3 1.0

Low-zonetolerance

High-zonetolerance

Immunity

Control: signalImmunogenic Dose of BSA

III. Mechanisms of Tolerance InductionIII. Mechanisms of Tolerance Induction

1. Clonal deletion therapy

Central thymic tolerance to self Ags-positive and negative selection.

2. Clonal anergy

a.  Lack of signal of activation can cause unresponsiveness

b. The blocking of immunocompetent cells

c. Lack of helper cells

3. The Suppressant effect of various cells

Mechanisms of Tolerance InductionMechanisms of Tolerance Induction

• Clonal deletion: physically deleting cells from the repertoire at come stage during their lifespan.

• Clonal anergy: downregulating the intrinsic mechaism of the immune response.

• Suppression: inhibiting cellular activity through interaction with other cells, such as those producing inhibitory cytokines or idiotype-specific lymphocytes which recognize the antigen receptor itself.

B(A)

(C)

(B)

B

B B

B

B

Blocking of BCRBlocking of BCR

IV. Clinical significance of immunologic tolerance

1. The induction and maintenance of immunologic tolerance

2. The elimination of immunologic tolerance

Chapter14 Regulation of the Immune Response (4)

• Regulation by antigen

• Regulation by antibody

• Regulation by lymphocytes

• Idiotypic modulation of responses

• Neuroendocrine modulation of

immune responses

Regulation by antigen

A decline in Ag levels ultimately results in diminished clonal proliferation and a decline in further homuoral or cell-mediated responses.

APCB B

Immune complexes

FcRBCR

suppress enhance

Immune regulation by immune complexes

TH1

IFN-IFN-R

M

TH2

IL-10

IL-10R

TNF-IL-2 IFN-

IL-4IL-5IL-6

IL-10IL-13

Immune regulation by TH

B7 IL-12

Idiotypic modulation of responses

According to the network theory, a series (or network) of anti-idiotype antibodies are induced during an immune response; these anti--idiotype antibodies act to upregulate the immune response in some cases and to downregulate it in other cases.

Idiotypic modulation of responses

Anti-idiotype

2

4

3

1

Internal image group

Nonspecific parallel group

idiotype

Ag

1： ARC（ antigen reaction cell）2： ARC stimulate cells

3： ARC suppress cells

4： idiotype and ARC same cells

It has long been known that stressful conditions may lead to a suppression of immune functions, for example, reducing the ability to recover from infection. There is considerable evidence demonstrating that the nervous, endocrine and immune systems are interconnected. Broadly, there are two main routes.

a.  Most lymphoid tissues receive direct sympathetic innervation, both to the blood vessels passing through the tissues, and directly to the lymphocytes themselves.

b. The nervous system directly or indirectly controls the output of various hormones, in particular, corticosteroids, growth hormone, thyroxine and adrenaline.

Neuroendocrine modulation of immune responses

hypothalamus

anteriorpituitary

thyroid

thymus

gonads

islets

Lymphoidtissue

adrenal

interleukin-1

T cellsthymic

hormones

insulin

Sex hormones

corti

coste

roids

catecholamines

Groeth horm

one

Neuroendocrine modulation of immune responses