IMMUNOLOGICAL TOLERANCE AND MODULATION PPT

1. IMMUNOLOGICAL
TOLERANCE
AND
MODULATION
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2. IMMUNOLOGICAL TOLERANCE
INTRODUCTION
Tolerance is a mechanism by which the humoral and cell
mediated immune response generated against the foreign
antigens do not react with the normal self-antigens.
Foreign antigen- The antigen produce outside the body
Self antigen- by convention antigens in the body of an
individual,
They are cellular proteins, peptides ,enzyme
complexs
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3. The tolerance is mediated by B- cell and T- cell.
T and B cells do not react with self antiogens is called self
tolerace.
SELF TOLERANCE---------------Autoimmune disease
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4. HISTORY
Ray D.Owen first observed immunologic tolerance in
Dizygotic bovine twin in 1945.
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5. Types of Tolerance
1)Central Tolerance
2) Peripheral Tolerance
Central Tolerance
 Central tolerance occurs in the primary lymphoid organ during
development .It operates in the thymus and bone marrow.
 It occurs during foetal life
 It is also know ass negative selection(because it eliminating
any developing T or B lymphocytes that are reactive to self
antigens )
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6. Mechanism of Central tolerance
B-Cell tolerance
 The B-cell attine maturity and tolerance in blood with presence of
IgM antibody
 The immature B-cell like pre-B-cells do not show tolerance, it
contain various surface markers and receptors
 The B-cell react own self antigen they called autoreactive B-cells
This autoreactive B-cells are removed or modified takes place in B
cell tolerance
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7. B-cell tolerance occures in 3 process
1.Receptor editing
2.Clonal deletion
3.Anergy
Receptor editing
 This process forms part of central tolerance to attempt to
change the specificity of antigen receptors(BCR) of self reactive
immature B-cells.
 The self reactive B-cell changes specificity by rearranging
genes and develops a new BCR that does not respond to self
antigen
 This process gives B-cell a chance for editing the BCR it us
signaled to apoptose or becomes anergic
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8. Clonal detection or Apoptosis
 During maturation of B-cells in the bone marrow, B-cells
are tested for interaction with self antigens is called
negative selection.
 If the maturing B-cells strongly interact with self antigens
they undergo death by apoptosis.
 Negative selection is important to avoid the production of
B-cells that could cause autoimmune disease
Anergy
 Unresponsive state of B-cell after bind Ag is called
anergy. In anergy state B-cell remain 2 to 3 in 2 lymphoid
organ they died .
 The bone marrow free from auto reactive B-cells
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9. B-cell tolerance K R MICRO NOTES 9

10. T-Cell Tolerance
• T-cell central tolerance occurs in thymus, T-cells undergo positive
and negative selection
• T-cell receptors must have the ability to recognize self MHC
molecules with bound non self peptide
• CD 4 and CD8 two T-cell receptors
• During this process T-cells with low affinity for MHC molecules are
selected and they alone survive is called Positive selection
• Unselected cells die by apoptosis
• In the next stage the cells lose either CD4 or CD8 these T-cells are
now exposed to self peptide [presented on the MHC molecules of
dendritic cells
• The CD receptor of T-cell adheres with the peptide MHC complex
of dendritic cells
• During this process T-cells with high affinity for peptide MHC
Complex undergo death by apotosis this process is called negative
selection
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11. T - Cell Tolerance K R MICRO NOTES 11

12. Peripheral Tolerance
 Peripheral tolerance is the second branch of immunological
tolerance ofter central tolerance.
 It takes places in the immune periphery, its main purpose is
to ensure that self reactive T and B cells which escape
central tolerance do not cause autoimmune disease
Peripheral tolerance can occur through one of three
mechanism
1)Clonal anergy
2)Apoptosis
3)Development of induced regulatory T cells(Tregs)
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13. Clonal anergy
•A state of inactivation in which the lymphocytes remain
alive but are unable to respond to antigen
(ex: If dendritic cells are not appropriately activated and
present self antigen to Tcells without signals 2 and
3(costimulastion and cytokine signals) they will produce T
cells that are tolerant or anergic to that self antigens)
Apoptosis
•Detection of autoreactive Tcells via apoptosis
Development of Tregs
•T cells exposed to the cytokine TGF beta can differentiate
into “induced” T regulatory cells in the peripheral tissues
•Induced Tregs cells have similar effector functions as natural
T regulatory cells but they are produced in the periphery rather
than in the thymus.
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14. K R MICRO NOTES 14

15. Immunomodulation
Immunomodulation is modulation(regulatory adjustment) of
the immune system. It has natural and human induced forms.
Immunomodulator- is a substance(ex:drugs) which has an
effect on the immune system
All drugs which modify immune response generally
categorised as immunomodulators these can either function :
1) Immunosuppressants
2) Immunostimulants
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16. Mechanisms of immunomodulation
Drugs may modulate immune mechanism by either
supressing or stimulating one or more of the following steps
•Antigen recognition and phagocytosis
•Lymphocyte proliferation
•Synthesis of antibodies
•Ag-Ab interaction
•Relese of mediators due to immune response
•Modification of target tissue response
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17. Immunosupressants
Immunosupressants are the drugs which inhibit cellular/humoral or
both types of immune response and have their use in organ
transplantation and autoimmune disease.
Problems
Life long use
Infection,Cancers
Nephrotoxicity
Diabetogenic
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18. Glucocorticoids
INTRODUCTION USES TOXICITY
Inhibits several
components of
immune response
They particularly
MHC expression
and prolioferation of
T lymphocytes
Potent
immunosuppresant
s and anti
inflammatory
 Transplant rejection
GVH-BM transplantation
Autoimmune diseases-
RA(Rheumatoid arthritis),
SLE(Systemic Lupus
Erythematosus)
Hematological conditions
Inflammatory Bowel
disease, Eye conditions
Psoriasis(Skin disease)
Growth retardiation
Avascuklar Necrosis of
Bone
Poor wound healing
Hyperglycemia(high blood
sugar)
Hypertension(high blood
pressure)
Cataract(clear lens of the
eye)
Poor wound healin Hypertension Cataract
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19. Cyclosporine
INTRODUCTION MECHANISM OF ACTION
Extracted from a soil fungi
Selectively inhibits T lymphocyte
proliferation, IL-2 and other
cytokine production and response
of induce T cell to IL-1,without any
effect on suppressor T cells
Lymphocytes are arrested at G0
or G1 phase
Binds to cytosolic protin
cyclophilin(immunophilin)of
immunocompetent lymphocytes,
especially T- lymphocytes
This complex of cyclosporine and
cyclophilin calcineurin, which under
normal circumstanes,is responsible for
activating the transcription of IL2
It also lymphokine production and IL
relese,leads to a reduce function of
effector T cells. It does not affect
cytostatic activity
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20. USES TOXICITY
To prevent rejection of
kidney, liver cardiac, and
other allogenic transplants
Useful in autoimmune
disease
Most active when admini
before antigen exposure
Concentrated in RBC and
WBC
Hypertension
Hyperlipidemia(blood as
too many Lipids or fat)
Tremor(muscle rigidity)
Hyperuricemia(excess of
uric acid in the blood)
 Gum hyperplasia
(Overgrowth of gum tissue
around the teeth)
CYCLOSPORINE
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21. 3. Antiproliferative drugs
DRUGS USES
Azathioprine Prevention of renal and graft rejection
Used in progressive RA
Cylophosphomide Used in bone marrow transplantation
Mycophenolate mofetil Reduce the dose of cyclosporine
Methotrexate Used as 1st line drug in many
autoimmuno disease
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22. Antibodies
Antithymocyte
Globulin(ATG)
Antibody D(Rh ) Muromonab-CD3
Polyclonal Ab purified
from horse or rabbit
immunized with human
thymic lymphocytes
which binds to T
lymphocytes
It has potential to
produce serum
sickness or anaphylaxis
but is less expensive
Rho (D) is a
concentrated solution of
human Ig G containg
higher titer of antibodies
against Rh(D)antigen of
red blood cells
Administrated within
72 hrs of delivery such
treatment prevents Rh
hemolytic disease in
future offspring
Never be give Rh +
individuals
It is a murine
monoclonal antibody
Prepared by
hybridoma technology
Directed against
glycoprotein CD3
antigen of human T
cells
The drug binds to CD3
protein on T lym leading
to disruption of T lym
function their depletion
and decreased immune
responce
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23. IMMUNOSTIMULANTS
Immunostimulants are substances that stimulate the immune
system by induced activation or incresing activity of any of its
compounds
EX: BCG, Cytokines,Levimazole
BCG and other microbial products are being tried as
adjuvants and probably act by activation of macrophage
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24. Cytokines
 cytokines is now available for use by rDNA technology
 Application in the treatment if viral infections, autoimmune
and neoplastic disease
Levimazole
 It has been tried in some immunodeficiency disease, RA
and post surgery
 Appears to enhance the magnitude of T cell mediated
immunity
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25. REFERANCES
 Immunology sixth edition
--Roitt, Brostoff ,Male
 SraraS Microbiology
-- N.Arumugam, A.Mani, A.M.Selvaraj,
L.M.Narayanan
 Immunology(second edition)
- S.S.Lal
S.Kumar
 Immunology (seventh edition)
--Richard coico, Geoffrey Sunshine
 Immune tolerance- Wikipedia
 Immunomodulators-www.google.com
 www.immunopaedia.org.za
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