Chapter 16 Immunological Tolerance

Contents Part Ⅰ Introduction Part Ⅱ Mechanisms of Self Tolerance Part Ⅲ Factors affecting Induced Tolerance Part Ⅳ Clinical Significance of Immunological Tolerance Tolerance

Owen first observed immunological tolerance to allogenic antigen in fetal period in 1945 Part Ⅰ Introduction

A A B B Graft of Skin From A to B or From B to A ----No rejection cattle of dizygotic twin

Experiment of Medawar on immunological tolerance

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 Types: self-tolerance induced tolerance Immunological tolerance

General features of immunological 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  It can exist in B cells, T cells or both Tolerance in T cell is longer lasting than B cell.  It is an antigen-induced, active process  Like immunologic memory, it is antigen specific  It can exist in B cells, T cells or both Tolerance in T cell is longer lasting than B cell.

Tolerance in T and B cells

Difference of Immuologic tolerance & immunodeficiency, immunosuppression Immunodeficiency:Deficiency in the production of humoral and /or cell-mediated immunity--- non-specificity to Ag Immunosuppression: Suppression of immune responses to antigens. This can be achieved by various means, including physical, chemical---- non-specificity to Ag

Part II Mechanism of Self 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 T lymphocytes in the thymus or B lymphocytes in the bone marrow, 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

Clonal Selection of T cells in the Thymus

Negative selection of B cells in bone marrow

Clonal deletion of B cells in the bone marrow Stem cell (in red bone marrow) B cells BCRs Cell with autoantigens Apoptosis Blood vessel To spleen

2. Peripheral tolerance 1)Peripheral tolerance of T cells ① Clonal anergy functional inactivation without cell death: lack of co- stimulatory signal

② clonal ignorance: self-reactive lymphocytes remain viable and functional but do not react to the self antigens in any detectable way.

Clonal anergy Clonal ignorance

③ Regulatory T cells CD4+CD25+Foxp3+ Treg: TGF- , IL-10

④ AICD( activation-induced cell death) Repeated stimulation of lymphocytes by persistent antigens results in death of the activated cells by a process of apoptosis. --- FasL on activated T cell binds to Fas on activated T cell and then induces T cell apoptosis.

⑤ Immunologically privileged sites Anatomic Barrier Immunological Suppression: TGF- , IL-10

2) Peripheral tolerance of B cells 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

Part III Factors affecting tolerance induction 1.Role of antigen 2.Role of the host

1.Role of antigens (1)Types of antigen Large, aggregated, complex molecules, properly processed- immune response soluble, aggregate-free, simple small molecules, not processed- tolerance (2)Dosage of antigen Optical dosage-immune response Very high or very low-tolerance (3)Portal of entry Subcutaneous or intramuscular-immune response Oral or intravenous-tolerance Tolerance: Oral >Intravenous>Intraperitoneal>Intramuscular>subcutaneous (4) features of determinant

Low-zone tolerance high-zone tolerance Concentration of antibody Concentration of antigen T cells T 、 B cell TD-Ag TI-Ag Immune response

2.Role of the host (1)Ages Adult, immunologically mature---Immune response Embryo and newborn, immunologically immature--- immunological tolerance (2) Differentiation state of cells Fully differentiated; memory T & B cells — Immune response Relative undifferentiated B cell with only IgM, T cells in the thymic cortex---immunological tolerance (3) Species,Heredity, Gender, Health

Host age and antigen dose affect tolerance newborn adult

Part Ⅳ Clinical Significance of immunological tolerance

Prevent the rejection of organ allografts and xenografts Treat autoimmune diseases Treat allergic diseases 1. To induce immunological tolerance

2. To terminate immunological tolerance To treat tumor: enhance first signal or second signal To treat infection diseases

Summary Definition of immunological tolerance Features of immunological tolerance Induction of immunological tolerance Mechanism of immunological tolerance Clinical application of immunological tolerance