Immunologic ToleranceImmunologic Tolerance

ContentsContents• Part Part Ⅰ IntroductionⅠ Introduction• Part Ⅱ Development of Immunologic Part Ⅱ Development of Immunologic

ToleranceTolerance• Part Part Ⅲ Mechanism of Ⅲ Mechanism of Immunologic Immunologic

ToleranceTolerance• Part Ⅳ Part Ⅳ Immunologic Tolerance and Clinic Immunologic Tolerance and Clinic

MedicineMedicine

• 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

Part Part Ⅰ IntroductionⅠ Introduction

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, immunosuppressionImmunodeficiency: 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 Part Ⅱ Development of Immunologic ToleranceImmunologic Tolerance

• Owen first observed immunologic tolerance to allogenic antigen in fetal period in 1945

1. Induction of immunologic tolerance to antigen in fetal period and neonate period

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 tolerancerole 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

Individual and immunologic tolerance: Heredity, Age, Gender, Health

Factors affecting tolerancethe 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

newborn adult

Part Part Ⅲ Mechanism of Ⅲ Mechanism of Immunologic ToleranceImmunologic 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 thym

us 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 inbone marrow

2. Peripheral tolerance

① clonal deletion and clonal ignorance: large tissue specific antigen delete specific T cells. self-reactive lymphocytes remain viable and functi

onal but do not react to the self antigens in any detectable way.

② Clonal anergy and inactivation: functional inactivation without cell death: lack co-sti

mulatory 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

Fas

FasL

cytokines

Apoptosis

Inhibition of proliferation &effector action

Activated T cells

NormalResponse

CD28 B7

Proliferation & differentiation

Antigen Recognitionwithout co-stimulation

Anergy

CTLA4 B7

FunctionallyUnresponsiveCTL4-B7 interaction

Fas-FasL interaction

Cytokine-mediated suppression

Activation induced

cell death

Cytokine regulation

Pathways to Peripheral Tolerance

The Two Signal Hypothesis for T-cell Activation

Mature Mature Dendritic Dendritic

cellcellAPCAPC

TTHH cellcell

CD28CD28B7 B7

MHC IIMHC II TCR TCR

Signal 2Signal 2

Signal 1Signal 1

Activated Activated TTHH cell cell

Hypothetical mechanism of tolerance in mature T cells

CD28CD28

RestingRestingB-cellB-cellAPCAPC

TTH0H0 cell cell

Tolerance (anergy or apoptosis) Tolerance (anergy or apoptosis) from lack of signal 2from lack of signal 2

Signal 1Signal 1

TolerantTolerant T cellT cell

NormalResponse

CD28 B7

Proliferation & differentiation

Summary: Lack of co-stimulation can lead to tolerance (anergy)

Antigen Recognitionwithout co-stimulation

Anergy

Regulation by CTLA-4

CTLA4

B7

FunctionallyUnresponsive (Anergic) T cell

CTLA4-B7 interaction

Activated T cell

Regulatory T cells

FunctionallyUnresponsive T cell

Production of IL-10 or TGF-

RegulatoryT 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 receptorsApplication: RhoGam for Erythroblastosis Fetalis

Major Immune Inhibitory Receptors

• B cells– FcRII

• 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 Part Ⅳ Immunologic Immunologic Tolerance and Clinic Tolerance and Clinic

MedicineMedicine

• Prevent the rejection of organ allografts and xenografts

• Treat autoimmune diseases• Treat allergic diseases

1. To induce immunologic tolerance

2. To terminate immunologic tolerance

• To treat tumor: enhance first signal or second signal• To treat infection diseases

And now for a clinical case….

• 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.

Patient Presentation

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.

SummarySummary Definition of immunologic tolerance Features of immunologic tolerance Induction of immunologic tolerance Mechanism of immunologic tolerance Clinical application of immunologic tolerance