immune tolerance

1. IMMUNE TOLERANCE CANCER AND
TRANSPLANTATION IMMUNOLOGY
Presenter – Dr. Vaishali T
Moderator – Dr. Vedavati B.I

2. IMMUNOLOGICAL TOLERANCE
• Immunological tolerance is defined as the unresponsiveness of the immune system
to an antigen.
• Normally immune system is self tolerant ( mature B and T cells).
• This process and mechanism that control it are collectively termed tolerance, or
self tolerance.
• An antigen can become an immunogen or tolerogen depending on
1. Dose , duration and route of antigen administration or exposure.
2. Maturation state of lymphocytes (B and T).
3. Forms and conditions of antigen.

3. It is mediated by two broad mechanism
1. Central tolerance – development of lymphocytes
2. Peripheral tolerance – regulation of lymphocytes in circulation

5. CENTRAL TOLERANCE
• This refers to the deletion of self-reactive T and B lymphocytes during there
maturation in Central lymphoid organs (i.e. in thymus for T cells and bone marrow
for B cells)
1. IN THYMUS- During the T cell development in thymus, if any self antigens
are encountered, they are processed and presented by thymic antigen presenting
cells(APCs).
i) Positive selection
ii) Negative selection

6. POSITIVE SELECTION
• Cells whose TCR fail to interact with MHC-self peptide molecules
undergo Death by neglect.
• Cells that bind too strongly to MHC self peptide complex also dies.
• Only cells that recognise the MHC molecule with Moderate/Low
affinity survive (POSITIVE SELECTION)

7. NEGATIVE SELECTION and CLONAL DELETION
• Cells that bind too strongly to MHC self peptide complex are induced
to undergo programmed cell death (APOPTOSIS).
• Affects class I and class II MHC restricted T cells – tolerance to CD4
and CD8 cells.
• This results in self tolerance

9. CENTRAL TOLERANCE
1. IN THYMUS
2. IN BONE MARROW- When developing immature B-cells in the
bone marrow encounter a self antigen during there development, the
tolerance is developed by
i ) Receptor editing
ii) Negative selection

10. i ) RECEPTOR EDITING- A process by which the Ig genes coding
light chains V(D)J are rearranged so that a different (edited) B cell
receptor is produced. Which no longer reacts to self antigen.
ii) NEGATIVE SELECTION- After receptor editing, if the B cells
again recognise a self antigen, then they are destroyed by subjecting
them to apoptosis.

11. ESCAPE FROM CENTRAL TOLERANCE
TWO FACTORS CONTRIBUTE TO THIS-
1. Not all self antigens are expressed in the central lymphoid organs
where negative selection occurs.
2. There is a threshold requirement for affinity to self antigens before
clonal deletion is triggered.

12. PERIPHERAL TOLERANCE
Mature self-reactive lymphocytes that recognise self antigens in
peripheral tissues are inactivated, killed or supressed. It is done by
various mechanisms.
1. Anergy
2. Suppression
3. Deletion

14. 1. ANERGY-
• It can be defined as unresponsiveness to antigenic stimulus.
• The self reactive T cells interact with APCs presenting the self antigen,
but the co-stimulatory signal (CD28 on T helper cell and CD80/86 on
APC) is blocked – no immune response.
 The B7 molecules on APC bind to CTLA-4 molecules on T cells
instead of CD28 molecules.

15. Mechanism of anergy

16. 2. Suppression of T reg cells:
• These are special subset of CD4 T h cells with high expression of IL-
2Rα( CD25).
• Express high CTLA4 – engages with CD80/86 on APC - ↑ IL6, TNF
α.
• APC – IDO (indolamine2,3 dioxygenase – kynurenine – inhibit
immune cells.
• T reg – IL10, TGFβ, IL 35.
• Supress bystander T cells – linked supression

18. DENDRITIC CELLS
• Dendritic cells uptake antigens in there immature state but cant present
to T cells
• Present antigen to T cells only when they are mature
• When certain immature DCs and tolerogenic DCs capture the self
antigen for processing, they act indirectly by induction of regulatory T
cells.

19. Deletion
• Extremely important for maintaining immune homeostasis in healthy
individuals.
• Activate Bim (pro apoptotic) – mitochondrial apoptotic pathway.
• Activation induced cell death (AICD)- Self reactive T cells are
activated after interacting with APCs presented with self antigen. But
the activation of T cells induces upregulation of Fas ligand which
subsequently interact with the death receptor Fas leading to Apoptosis.

21. SEQUESTRATION OF SELF ANTIGEN
• Self antigen may be sequestrated in some tissues and will never be
available to T cells
• Allows these antigens to avoid encounter with reactive lymphocytes
under normal circumstances
• 2 ways
1. Physical barrier- Location of antigen in privileged sites
2. Immunological barrier- Never processed by functional APCs

22. Privileged sites
• Cells ignore self antigens if they are expressed in immunologically
privileged sites.
1. The brain
2. The anterior chamber and lens of eye
3. Testes
• In these sites pro inflammatory lymphocytes are controlled by
1. Apoptosis
2. Cytokine secretion

23. IMPORTANCE OF INDUCED TOLERANCE
• To protect us from unpleasant, even dangerous, allergic reactions to
such things as food (e.g. peanuts), insect stings, grass pollen (hay
fever)
• To enable transplanted organs (e.g., kidney, heart, liver) to survive in
their new host (graft rejection)
• To reveal the mechanisms of autoimmunity for designing treatments
for systemic lupus erythematosus (SLE) and multiple sclerosis (MS)