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Introduction
Body defense in Human
Introduction to Pharmacology
related to Inflammation &
Immune response
System Pharmacology II
(HAS4916)
By Philip Mok
Innate immunity
Adaptive immunity
Rapid onset
The response is not specific to any given antigen
and does not change over repeated exposure to
the same antigen
E.g., Release and activation of defense chemical
systems, phagocytosis, etc.
Lymphocytes
Inflammation / Inflammatory
response
Inflammatory response
Acute inflammation
Chronic inflammation
September 2014
Heat (warmth)
Cellular response
Swelling
Local edema due to Increased vascular permeability (endothelial
response) & Increased blood volume (hydrostatic pressure)
Pain
Activation of a nociceptor (a sensory neuron stimulated by injury,
usually resulting in the perception of pain)
Loss of function
The result of cell / tissue damage
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Chemical responses of
Inflammation
Reaction
Increased vascular
permeability
Chemotaxis,
C5a; LTB4; PGs; Chemokines; IL-1, TNF
Leukocyte recruitment Bacterial products (e.g., LPS)
& activation
Fever
Pain
PGs; Bradykinin
Tissue damage
Neutrophils, macrophages
Lysosomal enzymes; oxygen metabolites,
NO
Pharmacological interventions
Partial alleviation of some aspects of inflammation-related
medical conditions
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Complement system
A complex group of serum (from liver) and cell
membrane proteins under tight regulation with potent
destructive consequences upon activation
Activation without the presence of antibody
Antibody-mediated activation
Inflammatory mediators
Vasodilation
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September 2014
Chemical mediators of
Inflammation
Chemical mediators of
Inflammation
Histamine
A biogenic amine
A major mediator of inflammation,
anaphylaxis, and gastric acid secretion as
well a role in neurotransmission
Pharmacological intervention
Selective histamine receptor antagonists
H1 antagonists in management of allergies, nausea,
motion sickness
H2 antagonists in inhibition of gastric acid secretion
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Cytokines
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Acute-phase proteins
From liver
E.g., C-reactive protein
Binding of Cytokine
Cytokines
Cytokine receptor
Properties
Proteins and glycoproteins
Potent and short-lived
Nucleus
Gene expression
Protein synthesis
September 2014
Cell target
Biologic activity
IL-1
Monocytesmacrophages
B cells,
fibroblasts,
most epithelial
cells (including
endothelial
cells)
All cells
Migration of neutrophils
/ macrophages to the site
of injury
Shock, Fever
Acute-phase protein
production
Hematopoiesis
IL-2
TH1 cells
(Type 1 T
helper cells)
T cells, B cells
NK cells,
monocytesmacrophages
Immunoregulatory activities
E.g., IFN, IL-2
Pro-inflammatory activities
E.g., TNF, IL-1, IL-6, IFNs
Anti-inflammatory activities
E.g., TGF, IL-10, IL-11, IFN
CNS activities
As neurotransmitters and neuroregulators
E.g., IL-1 , TNF , and IFNs
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Cell target
Biologic activity
IL-6
TH2 cells,
Monocytesmacrophages
B cells,
Fibroblasts,
most epithelial
cells (including
endothelial
cells)
T cells, B cells,
Epithelial cells,
Hepatocytes,
Monocytemacrophages
Acute-phase protein
production
Growth & differentiation
of T cells and B cells
Growth & activation of
Osteoclasts
Myeloma cell growth
TNF
IL-12
Activated
macrophages,
Dendritic cells,
Neutrophils
B cells
T cells
NK cells
TNF
T cells,
B cells
Promotion of
inflammation,
Cell cytotoxicity
Lymph node & spleen
development
Cell target
Biologic activity
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All cells
Promotes antiviral activity
(Type I IFN Stimulates activity of T cell,
receptor)
macrophage, NK cell
Direct antitumor effects
Up-regulates MHC class I
antigen presentation
T cells
NK cells
All cells
Regulates activity of
(Type II IFN macrophage & NK cells
receptor)
Stimulates secretion of Ig by B
cells
Up-regulates MHC class II
antigen presentation
TH1 cell differentiation
(acidstable)
IFN-
(acid
labile)
Lymphocytes
Biologic activity
All cells
(including
virally
infected
cells)
Nave lymphocytes
Antigen-specific receptors on cell membrane for
detection of a specific antigen
IgM on B cells
T cell receptor (TCR) on T cells
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September 2014
Activation of Lymphocyte
Activation of Lymphocyte
APC
TCR
CD28
Co-stimulatory
signal
Memory
cells
Effector
cells
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Memory cells
Long-lived cells (years)
A more rapid immune response for future exposure to the SAME
antigen
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Immunoglobulin
L chain
H chain
Glycoproteins
Basic structure
4 peptide chains (2 identical light
chains & 2 identical heavy chains)
connected by disulfide bonds (-S-S-)
A Y shape with a flexible hinge
region
To accommodate 2 antigens
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Immunoglobulin
Enzymatic breakdown of an
immunoglobulin
Hypervariable regions
Antigenbinding site
of Light chains
Apoptosis
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Effector cells
Fc fragment
Nave lymphocytes
T helper cell
Activation of Lymphocyte
Fab fragment
A clone consisting of 2
groups of daughter cells
with the same antigenspecific receptors
Activated effector
cells for immediate
response
Memory cells for
future response
Ag
Hypervariable regions
of Heavy chains
Treated with papain
In vitro to break down
the Ig molecule into
2 fragments
Fragment crystallizable
The remaining H chain
5 isotypes with different biological effects
Fc receptors on different leukocytes
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September 2014
Immunoglobulin
Immunoglobulin
IgG
IgA
Secretory Ig
In body secretions, such as tears, saliva, nasal secretions, GI
fluid, and human milk
IgE
Presence of IgE Fc receptors on basophils & mast
cells
When antigen binds to IgE on basophils / mast cells,
inflammatory mediators will be released.
Type
Hypersensitivity reactions
Allergic responses
An inappropriate or exaggerated immune response to an antigen
(allergen) that can cause inflammation and organ dysfunction
Type I
Immediate,
anaphylactic
Mediated by IgE
Type 1 hypersensitivity
IgE-mediated, immediate-type response
Type II hypersensitivity
Cytotoxic hypersensitivity
IgG-mediated or IgM-mediated reactions
Type II
Cytotoxic
Mediated by IgM
or IgG
Type IV hypersensitivity
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Reaction
Allergen binds to IgE (bound to Mast cells
via Fc receptors)
Immediate phase (min.) : Degranulation
(e.g., histamine)
Late phase (~ 6 hr) : Other synthesized
mediators such as leukotrienes
Urticaria, rhinitis, edema,
bronchoconstriction, anaphylaxis
Antigens on cell surface combine with
antibody Complement activation
Cell lysis
Hemolytic anemia, ABO transfusion
reactions; or Rh hemolytic disease
Type
Reaction
Type III
Immune complex
Mediated by IgM
or IgG
Type IV
Delayed type
Cell-mediated
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Pharmacology of Immunotherapy
Drugs developed for autoimmune and inflammatory
diseases, allergy, cancers, infectious diseases, and
organ transplantation
Immunomodulating or immunosuppressive agents
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