Immune Tolerance

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Immune Tolerance
Dr. Prakash Nagarkatti Associate Dean for Basic
Science 733-3180 pnagark_at_gw.med.sc.edu
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Self-nonself discrimination
Non-self or foreign
Self
No response
Strong response
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Tolerance

• Tolerance---gtspecific unresponsiveness triggered
  by previous exposure to Ag.
• Natural Tolerance (self tolerance)
  Unresponsiveness to self Ags.
• Acquired tolerance
• Unresponsiveness to foreign Ags.

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Tolerance
Tolerance in non-identical cattle twins
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Tolerance
Burnets Hypothesis(1949)

• During neonatal stage of life, or when immune
  system is developing, all Ags present are
  recognized as self.
• Immune system becomes tolerant to these Ags.
• How is tolerance accomplished?
• By clonal deletion--cells which come across
  self-Ag undergo apoptosis.

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Tolerance
Medawar proves Burnets Hypothesis
The above result was specific.

• Burnett Medawar won Nobel Prize in 1960.

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Mouse Chimera
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Radiation Bone-marrow Chimeras
A
1000R
B
Lymphoid cells--gt strain A
B
Non lymphoid---gt strain B
This procedure is used in cancer patients.
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Tolerance

• Why is it imp. to study tolerance?
• Autoimmunity
• Cancer
• Transplantation
• Infections
• Vaccines

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Factors affecting tolerancerole of antigen
Physical form of antigen
Large, aggregated, complex molecules
soluble, aggregate-free, simple small molecules
Antigen processing
properly processed
improperly processed
Subcutaneous or intra-muscular
Oral or, sometimes, intravenous
Route of injection
Very large or very small dose
Optimal dose
Dose of antigen
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Factors affecting tolerancerole of antigen
Age of responding animal
Adult, immunologically mature
Newborn (mice) Immunologically immature
Fully differentiated, Memory
Differentiation state of cells
Undifferentiated B cell with only IgM, T cells in
the thymic cortex
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Mechanisms of tolerance

• There are multiple mechanisms of tolerance.
• Clonal deletion.
• Regulatory T cells (formerly called suppressor T
  cells).
• Anti Idiotypic Abs.

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T cell Development in the thymus
Dendritic cells
Cortical epithelium
MHC Class I and II
High TCR
V
Low TCR
V
CD4
CD4
CD4-CD8-TCR-
CD8
V
TCR
BM Stem cell
Thymocyte
CD8
Mature T cell
Negative selection
Positive selection
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Regulatory T cells

• Several different regulatory T-cell subsets have
  been described.
• The CD4 regulatory T cells have been categorized
  into two major subgroups
• Forkhead box P3 (Foxp3)CD4CD25 regulatory T
  cells which develop in the thymus and are present
  in normal mice and healthy individuals from birth
  
• Inducible regulatory T cells, which are generated
  in the periphery under various tolerogenic
  conditions.

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Foxp3

• Foxp3, an X chromosomeencoded forkhead
  transcription factor family member, is
  indispensable for the differentiation of
  regulatory T cells.
• Genetic mutations in Foxp3 in humans leads to
  development of a severe and rapidly fatal
  autoimmune disorder known as Immune
  dysregulation, Polyendocrinopathy, Enteropathy,
  X-linked (IPEX)syndrome.
• Foxp3 mutations lead to massive
  lymphoproliferation, diabetes, exfoliative
  dermatitis, thyroiditis and enteropathy.

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Regulatory T cells

• Defective regulatory T cells in genetic diseases
  
• Patients with WiskottAldrich syndrome,
  autoimmune polyglandular syndrome type 2 and
  autoimmune lymphoproliferative syndrome are the
  few autoimmune diseases caused by known genetic
  defects. These patients have also defects in
  regulatory T cells.
• Regulatory T cells can be used in the treatment
  of autoimmune diseases in future.

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Regulatory cells

• The precise mode of action of regulatory T cells
  is not clear.
• Cell-cell contact and soluble factors such as
  IL-10 or TGF-ß play a role.
• Regulatory T cells play a crucial role in oral
  tolerance. Ex Colitis can be prevented by
  transfer of regulatory T cells.

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Role of anti-idiotypic Ab in tolerance.
Anti-idiotype
Ag
epitope
Idiotype
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Activation-induced Cell Death(AICD)
Plays a key role in peripheral T cell
tolerance. Defiency of Fas or FasL triggers
Lympho- Proliferative Disease.
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Defect in Fas or FasL triggers Autoimmunity
Fas
Fas
Fas-
Normal
Fas L
Fas
Autoimmunity and lymphoproliferative disease
Fas L
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Summary

• Immune system recognizes both self and non-self.
  
• Immune tolerance is a specific mechanism through
  which the host tries to evade responding to
  self-Ags.
• Clonal deletion and Regulatory T cells are the
  primary mechanisms.
• Breakdown of tolerance leads to autoimmune
  disorders.

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Thank you