Download 09Immunological Tolerance

Chapter 13 Immunological
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
Speeds
Time
Antigens
T cells
24 hours
long (months)
TD-Ag (low-dose)
T and B cells
slow ( 1-2 weeks)
short (weeks)
all Ag (high-dose)
Serum anti-BAS
Response to secondary
immunogenic dose of
BSA% of control
Immunity
Control: signal
Immunogenic
Dose of BSA
100%
Low-zone
tolerance
10-12
10-9
High-zone
tolerance
10-6
Priming dose of BSA,g
Experimental induction of tolerance
at low and high doses of antigen
10-3
1.0
III. 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 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.
(A)
(B)
(C)
B
B
B
Blocking of BCR
B
B
B
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 cellmediated responses.
Immune complexes
BCR
FcR
B
B
suppress
enhance
Immune regulation by immune complexes
M
TNF-
IL-2
IFN-
IL-10R
B7
IL-12
IL-10
IL-4
IL-5
IL-6
IL-10
IL-13
TH1
TH2
IFN-R
IFN-
Immune regulation by TH
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
2
Internal image group
idiotype
1
Ag
Anti-idiotype
3
1：ARC（antigen reaction cell）
2：ARC stimulate cells
3：ARC suppress cells
4
Nonspecific parallel group
4：idiotype and ARC same cells
Neuroendocrine modulation of
immune responses
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.
hypothalamus
Neuroendocrine
modulation of
immune responses
anterior
pituitary
thyroid
thymus
T cells
thymic
hormones
Lymphoid
tissue
islets
gonads
adrenal
catecholamines