Transcript Part Ⅲ Mechanism of Immunologic Tolerance

Immunologic Tolerance
Contents
• Part Ⅰ Introduction
• Part Ⅱ Development of Immunologic Tolerance
• Part Ⅲ Mechanism of Immunologic Tolerance
• Part Ⅳ Immunologic Tolerance and Clinic Medicine
Part Ⅰ Introduction
• 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
General features of Immunologic 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
 Like immunologic memory, it can exist in B cells,
T cells or both
 Like immunologic memory, its easier to induce
and lasts longer in T cells than in B cell
Difference of Immuologic tolerance &
immunodeficiency, immunosuppression
Immunodeficiency: any condition in which there
is deficiency in the production of humoral and /or
cell-mediated immunity---non-specificity to Ag
Immunosuppression:
The suppression of
immune responses to antigens. This can be
achieved by various means, including physical,
chemical----non-specificity to Ag
Part Ⅱ Development of Immunologic
Tolerance
1. Induction of immunologic tolerance to
antigen in fetal period and neonate period
• Owen first observed
immunologic
tolerance to
allogenic antigen in
fetal period in 1945
cattle of dizygotic twin
Experiment of Medawar on immunologic tolerance
2. Induction of immunologic tolerance to
antigen in adult
Antigen and immunologic tolerance:
• Concentration of antigens
• Type of antigen: monomer, aggregates
• Pathway of antigen entering body
• Features of determinant: tolerogenic epitope
• Variation of antigen
High and low dose tolerance
Tolerance in T and B cells
Factors affecting tolerance
role 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
 Route of injection
 Subcutaneous or
intramuscular
 Oral or, sometimes,
intravenous
 Dose of antigen
 Optimal dose
 Very large or very small
dose
Individual and immunologic tolerance:
Heredity, Age, Gender, Health
Factors affecting tolerance
the role of host
Factors that
affect response
Favor immune
response
Favor tolerance
 Age of responding
animal
 Fully differentiated;
memory T & B cells
 Newborn (mice), immunologically immature
 Differentiation
state of cells
 Older, immunologically mature
 Relative undifferentiated B
cell with only IgM, T cells
in the thymic cortex
Host age and antigen dose affect
tolerance
newborn
adult
Part Ⅲ Mechanism of Immunologic
Tolerance
1. Central tolerance:
Central tolerance occurs in the central
lymphoid organs as a consequence of
immature self-reactive 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 lymphocytes in the
thymus for T cell or in the bone marrow for B
maturation, 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
Central Tolerance
Negative selection of B cells in
bone marrow
2. Peripheral tolerance
① clonal deletion and clonal ignorance:
large tissue specific antigen delete specific T cells.
self-reactive lymphocytes remain viable and
functional but do not react to the self antigens in
any detectable way.
② Clonal anergy and inactivation:
functional inactivation without cell death: lack costimulatory signal
Clonal anergy in T cells
Clonal anergy in B cells
③ Action of Suppressor lymphocyte (Ts)
④ Action of cytokines: TGF- , IL-10
⑤ Holdback in signal tranduction
⑥ Immunologically privileged sites
anatomic barrier: clonal ignorance
Pathways to Peripheral Tolerance
Proliferation & differentiation
Normal
Response
Activated
T cells
CD28 B7
Antigen Recognition
without co-stimulation
Anergy
CTL4-B7 interaction
Functionally
Unresponsive
CTLA4 B7
Activation Fas
induced
cell death
Fas-FasL interaction
Apoptosis
FasL
Cytokine-mediated suppression
Cytokine
regulation
cytokines
Inhibition of
proliferation &
effector action
The Two Signal Hypothesis for T-cell
Activation
Signal 1
MHC II
Mature
Dendritic
cell
APC
B7
TCR
Activated
TH
Tcell
H cell
CD28
Signal 2
Hypothetical mechanism of tolerance in
mature T cells
Signal 1
Resting
B-cell
APC
Tolerant
T
H0 cell
T cell
CD28
Tolerance (anergy or apoptosis)
from lack of signal 2
Summary: Lack of co-stimulation can
lead to tolerance (anergy)
Normal
Response
Proliferation &
differentiation
CD28
B7
Anergy
Antigen Recognition
without co-stimulation
Regulation by CTLA-4
CTLA4
CTLA4-B7 interaction
B7
Activated T cell
Functionally
Unresponsive (Anergic) T cell
Regulatory T cells
Production of IL-10 or TGF-
Regulatory
T cell
Functionally
Unresponsive T cell
Pathways to Peripheral
Tolerance
Inhibition by Antibody Feedback
• Passively administered antibody can prevent an
antibody response
• Antibody produced during an immune responses
leads to elimination of antigen (stimulus)
–Less antigen available to stimulate specific
cells
–Immune complexes can bind to inhibitory
receptors
Application: RhoGam for Erythroblastosis
Fetalis
Major Immune Inhibitory
Receptors
• B cells
– FcgRII
• T cells
– CTLA4
• NK cells
– KIR (killer cell Ig-like receptors),
Anti-Idiotypes and Immune
Regulation
• Definition
– anti-idiotype response-antibody produced
against immunoglobulin or TCR idiotypes
that serve to down-regulate immune
response
– The epitope for an responsive anti-idiotype
molecule (antibody, BCR, or TCR) is the
internal image formed by the CDR region
of the respective epitopes antigen receptor
Idiotype/Anti-idiotype network
Part Ⅳ Immunologic Tolerance and
Clinic Medicine
1. To induce immunologic tolerance
•
•
•
Prevent the rejection of organ allografts
and xenografts
Treat autoimmune diseases
Treat allergic diseases
2. To terminate immunologic
tolerance
• To treat tumor:
enhance first signal or second signal
• To treat infection diseases
And now for a clinical case….
Patient Presentation
• 6 year old male, ER with unexplained
bruising associated with minor trauma
• Patient has minimal clotting activity
• FVIII levels <1% of normal
• Patient given i.v. FVIII concentrate i.v.
and released but returns in two weeks
with same problem
• Repeated FVIII treatment
• However, FVIII is ineffective.
Issues
•
Coagulation factor inhibitors (anti-FVIII
activity)
• Basis?
• Lack of tolerance. Why?
• Prevalence/impact
• 20-30% FVIII, less FIX
• Treatment/problems
• FVIII concentrate or rFVIII
• Inhibitors develop that neutralize FVIII
• Therapy?
• Porcine FVIII with less cross-reactivity
• Tolerance (high dose)
• Gene therapy
What are Inhibitors?
• IgG; commonly subclass 4, mixed 1 & 4
• Occur in
• Congenital factor deficiency = alloimmune
• Previously unaffected = autoimmune
• Associated with pregnancy, autoimmunity,
malignancy, multi-transfusion, advanced age etc.
Summary
Definition of immunologic tolerance
Features of immunologic tolerance
Induction of immunologic tolerance
Mechanism of immunologic tolerance
Clinical application of immunologic tolerance