1. Chapter16 Immunological Tolerance

2. Innate Immunity and adaptive immunity

3. Review . Classification of Immunity
Humoral immunity and Cell-mediated immunity

4. Immune response

6. Immune response

7. Effect of Humoral Immunity

8. Immune response

9. Effect of cell-mediated immunity
IL-12
CD4 Th1
IL-4
CD4+Th2
CTL

10. Antigen recognition and T activation
T cell expansion and differentiation
Differentiated effector T cells enter circulation
Effector T cells encounter antigen in peripheral tissues
Effector function of T cells

11. Immune response and Immunologic tolerance
Immunogenic antigens: antigens that induce immune response
Tolerogenic antigens: antigens that induce immunologic tolerance

12. Chapter16 Immunological Tolerance

13. Contents Introduction The discovery and type of Immunologic Tolerance
The conditions inducing Immunologic Tolerance
Mechanisms of Immunologic Tolerance
The significance and clinical application of Immunologic Tolerance

14. Introduction Immunologic tolerance:
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

15. General features of Immunologic tolerance
Specificity : specific unresponsiveness to an antigen, but response to other antigens
Memory : secondary unresponsiveness only to same antigen ,but not to other antigens
Induction : Its formation needs induction of antigen by the exposure of specific lymphocytes with a time lag

16. Difference among 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 factors ----non-specificity to Ag

17. Section I The discovery and type of Immunologic Tolerance

18. I. Discovery of immunologic tolerance
Owen first observed immunologic tolerance in Dizygotic bovine twin in
Medawar induced successfully immunologic tolerance in neonate period mice in 1955

19. Owen first observed phenomenon of immunologic tolerance in Dizygotic bovine twin in 1945
Graft of Skin
From A to B or
From B to A
No rejection
Self –tolerance
Suggested by Burnet
Need for tissue and organ graft drove the curiosity to understand the mechanisms of tolerance. The observations a zoologist, Owens, that Dizygotic bovine twins could accept grafts from each other but their siblings from other pregnancies could not tolerate such grafts led Medawar to perform a series of experiments to induce tolerance in mice.

20. Medawar induced successfully immunologic tolerance in neonate period mice in 1955
Induced tolerance

21. Immunologic features of tolerance
It is an antigen-induced, active process
it possesses specificity
It possesses immunologic memory
A kind of special immune response
Induction of tolerance is very similar to induction of an immune response.
Immunologic features of tolerance:
Tolerance is different from non-specific immunosuppression, and immunodeficiency. It is an active antigen dependent process in response to the antigen. Like immune response tolerance is specific and like immunological memory, it can exist in T-cell, B cells or both and like immunological memory, tolerance at the T cell level is longer lasting than tolerance at the B cell level.

22. for discovery of acquired immunological tolerance （1960）
Sir Frank Macfarlane Burnet ，Australia ，
Peter Brian Medawar，UK，

23. II. Types of Immunological tolerance
(I) Self –tolerance and induced tolerance
Self tolerance: to self antigen
Induced tolerance: to foreign antigen
(II) Central tolerance and Peripheral tolerance
Central tolerance :form in central immune organs
Peripheral tolerance : form peripheral immune organs

24. Self-tolerance Normal individuals are tolerant to their own antigens
(self antigen)
Tolerance to self antigens is a fundamental property of the normal immune system, the failure of self-tolerance leads to autoimmune disease.

25. Induced tolerance
Foreign antigens may be administered in ways that preferentially inhibit immune response by inducing tolerance in specific lymphocytes
Such as
Tumor cells can induce immunological tolerance during their proliferation .

26. Central tolerance
induced in central immune organs as a consequence of immature self-reactive lymphocytes recognizing antigens

27. Peripheral tolerance
induced in peripheral immune organs as a result of mature self-reactive lymphocytes encountering self antigens under particular conditions

28. Section II The conditions of immunological tolerance formation
Antigen-associate factors
Host–associated factors

29. I. Antigen-associate factors
Types of antigen
does of antigens
Features of determinant
Pathway of antigen entering body

30. Factors which affect response
1. Types 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

31. 2. does of antigens High-zone tolerance T, B cell tolerance
Low-zone tolerance
T, B cell tolerance
T cell tolerance
Immune response

32. Comparison of T cell tolerance with B cell tolerance
________________________________________________
Contents T cell B cell __________________________________________________________
Tolerance formation easy difficult
Antigens TD -Ag TD- Ag and TI –Ag
Dose of antigens high or low high
Induced time shorter (1-2 days) longer (more than 10 days)
Maintaining time longer (a few months) shorter (a few weeks) ___________________________________________________

33. 3. Features of determinant
Determinants recognized by Ts or Treg induce tolerance
Determinants recognized by conventional T cells initiate immune response

34. 4.Pathway of antigen entering body
Oral
Intravenous
Intra-peritoneal
Intramuscular
subcutaneous
Immune response
tolerance

35. Factors affecting tolerance role 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
Tolerance to soluble antigens:
A state of tolerance to a variety of T-dependent and T-independent antigens has been achieved in various experimental models. Based on these observations it is clear that a number of factors determine whether an antigen will stimulate an immune response or tolerance (Table 1).

36. II. Host–associated factors
Species: easy in murine and rat
difficult in human
Status of host immune system:

37. Factors affecting tolerance the 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

38. Host age and antigen dose affect tolerance
newborn
adult

39. Section Ⅲ Mechanism of Immunologic Tolerance

40. .Central tolerance:
Central tolerance occurs in the central lymphoid organs as a consequence of immature self-reactive lymphocytes recognizing ubiquitous self-antigen.----negative selection
.Peripheral tolerance:
tolerance was induced in peripheral organs as a result of mature self-reactive lymphocytes encountering tissue-specific self antigens under particular conditions

42. I. Central tolerance T cell central tolerance : formation in thymus
clonal deletion in negative selection
B cell central tolerance: formation in bone marrow
clonal deletion
clonal anergy

43. Clonal deletion: negative selection of T cells in the thymus
Clonal deletion: Functionally immature cells of a clone encountering antigen undergo a programmed cell death. For example, auto-reactive T-cell are eliminated in the thymus following interaction with self antigen during their differentiation (negative selection). Clonal deletion has been shown to occur also in the periphery. B cells expressing only IgM (no IgD) on their surface when exposed to antigen are eliminated.

45. 1. T cell central tolerance
T cell Clonal deletion (apoptotic cell death)
During maturation of T lymphocytes in the thymus, immature T lymphocytes that recognize ubiquitous self-antigen with high affinity are deleted by mechanism of apoptosis

47. 2. B cell central tolerance
Clonal deletion
During maturation of B lymphocytes in bone marrow , immature lymphocytes that recognize membrane-bound self-antigen with high affinity are deleted by apoptosis
Clonal anergy
During maturation of B lymphocytes in bone marrow , immature lymphocytes that recognize soluble self-antigen are not deleted but are inactivated

48. Negative selection of B cells in bone marrow
Clonal deletion: Functionally immature cells of a clone encountering antigen undergo a programmed cell death. For example, auto-reactive T-cell are eliminated in the thymus following interaction with self antigen during their differentiation (negative selection). Clonal deletion has been shown to occur also in the periphery. B cells expressing only IgM (no IgD) on their surface when exposed to antigen are eliminated.

49. Clonal anergy in B cells
Also, B cells when exposed to large amounts of soluble antigen down regulate their surface IgM and become anergic and short lived. These cells also up regulate Fas molecules on their surface. An interaction of these B cells with Fas-ligand bearing cells result in their death via apoptosis.

50. II. Peripheral tolerance
T cell Peripheral tolerance
Clonal anergy
Immunological ignorance
Regulatory T cells
Activation induced cell death, AICD
Immunity privilege
B cell Peripheral tolerance
Clonal deletion
Receptor editing

51. I) T cell Peripheral tolerance
Clonal anergy:
An experimentally induced state of antigen unresponsiveness of a clone of T lymphocytes induced by recognition of antigen in the absence of additional signals ( costimulatory signal)
T cells survive but are rendered incapable of responding to the antigen even if it is later presented by competent APCs
viable and unfunctional

52. Absence of costimulatory signal
If CD4+ T cells recognize peptide antigens
presented by APCs that are deficient in costimulators , the T cells survive but are rendered incapable of responding to the
antigen even if it is later presented by competent APCs
Inhibition of costimulatory signal Anergy may be induced if T cells use the
Inhibitory receptor for B7 molecules, CTLA4, to recognize costimulators on APCs at the time that the cells are recognizing antigen

54. I) T cell Peripheral tolerance
2.Immunologic ignorance
A form of lymphocyte unresponsiveness in which
self antigens are ignored by the immune system even though lymphocytes specific for those antigens remain viable and functional.

56. Clonal ignorance
Clonal anergy

57. I) T cell Peripheral tolerance
3.Regulatory T cells
A population of T cells that inhibit the activation proliferation of other T cells and may be necessary to the maintaining of peripheral tolerance to self antigens

58. Regulatory T cells
Regulatory CD4+T cells: CD4+CD25+ T cells
Regulatory CD8+ T cells: CD8+CD28-T cells
Qa-1- restricted CD8+
NK T cells
Double negative regulatory T cell:
CD3+CD4-CD8-

59. Induced Treg

60. CD4+CD25+Tregs In vitro 5-10% of CD4+ T cells
FACS
Microscopy
Co-culture 40 30 20 10
3H uptake (x10-3)
CD25–
CD25+ +
10%
>90%
Foxp3
CD25
CD25
Foxp3
CD4
CD25
In vivo
Maintain immune tolerance
Inhibit autoimmunity
prevent transplant rejection
Interfere with anti-cancer immunity
Potential in immune deficiency
In vitro
5-10% of CD4+ T cells
Anergic to TCR stimulation
Suppress T cell proliferation

62. I) T cell Peripheral tolerance
4. Activation-induced cell death (AICD)
Repeated stimulation of T lymphocytes by persistent antigens results in death of the activated cells by a process of apoptosis

64. I) T cell Peripheral tolerance
5. Immunologically privileged sites
anatomic barrier
Action of Suppressor lymphocyte (Ts)
Action of cytokines: TGF- , IL-10

65. II) B cell Peripheral tolerance
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

66. Clonal anergy

69. I. The significance of theoretical research
Section I V Significance and clinical application of immunologic Tolerance
I. The significance of theoretical research
II. The significance and application on clinical therapy

70. I. The significance of theoretical research
Immunologic tolerance is very important for maintaining homeostasis
Homeostasis: The maintaining of constant number of cells called homeostasis
Immune response to foreign antigens are eliminated, returning the immune system to its basal resting state. Deletion ( AICD),
Immunologic tolerance is an very important mechanism of immunoregulation

71. II. The significance and application on clinical therapy

72. (I) Induce immunologic tolerance to treat autoimmune diseases
Block costimulaotry signal
CD28/B7
CD40/CD40L
CD137/CD137L
enhance inhibition of regulatory T cell
CD4+CD25+ Treg
Oral tolerance ：the oral administration of a protein antigen often leads to a marked suppression of systemic humoral and cell-mediated immune response to immunization with the same antigen

73. (II) Induce immunologic tolerance to prevent or treat hypersensitivity

74. (III) Induce immunologic tolerance to prevent or treat graft rejection
Block costimulaotry signal
CD28/B7
CD40/CD40L
CD137/CD137L
enhance inhibition of regulatory T cell
CD4+CD25+ Treg
Oral tolerance ：the oral administration of a protein antigen often leads to a marked suppression of systemic humoral and cell-mediated immune response to immunization with the same antigen

75. (IV) Break up tumor immune tolerance to treat tumor
Enhance costimulaotry signal
CD28/B7
CD40/CD40L
CD137/CD137L
Deletion of regulatory T cell
CD4+CD25+ Treg