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September 2014

Introduction
Body defense in Human

Introduction to Pharmacology
related to Inflammation &
Immune response

Defense against foreign agents (antigens)


2 divisions: Innate (inborn) & adaptive
(acquired / learned) immunity
Together to protect the body

System Pharmacology II
(HAS4916)
By Philip Mok

Ability to distinguish between self and non-self


(foreign agents; antigens)
Self tolerance
Immune response to non-self
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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.

Antigen presenting cells to activate T helper cells


Dendritic cells, monocytes-macrophages, B cells

Lymphocytes

Important cell types

T helper cells, T cytotoxic cells, B cells (Plasma cells)

Neutrophils, monocyte-macrophages, and NK cells

The defense is more effective when the adaptive


immunity is also involved
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Inflammation / Inflammatory
response

Antibodies (by plasma cells) for specific antigens


Cells & complement system
More effectively in the presence of antibodies
Neutrophils, monocytes-macrophages, eosinophils, basophils,
mast cells, NK cells, dendritic cells
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Inflammatory response
Acute inflammation

A response of living tissues to injury of any sort

Rapid onset with duration of days to weeks

Involvement of the body defense system


Innate & adaptive immune mechanisms
Cell-mediated and chemical-mediated
responses

Immediate reactions to tissue injury

Neutrophils as the predominant cell type


Prominent vascular response

Chronic inflammation

Purposes of the inflammatory response

Slow response that lasts for weeks, months, years

To contain (localize) and eliminate the cause of injury


To limit tissue damage, and
To prepared the damaged tissue for healing (ideally,
restoration of normal structure and function)

Persistent reactions to tissue injury

Macrophages and lymphocytes as the predominant


cell types
Less prominent vascular response
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System Pharmacology II - Introduction to


Pharmacology of Inflammation &
Immunotherapy/MOK

The response to specific to antigens


Slow onset for the initial exposure to a given
antigen, but a progressively more rapid onset
upon repeated exposure to the SAME antigen
Important cell types

September 2014

Classical signs & Underlying


processes of Acute inflammation

Cellular response in Acute


inflammation

At the site of injury


Redness (erythema)

Cell & tissue damage


Release of cell contents (due to cell lysis) and
exposure of extracellular matrix

Vasodilation (relaxation of vascular smooth muscle) & the


resultant increased blood flow to the site of injury

Heat (warmth)

Cellular response

Heat from the Increased blood flow

Synthesis & Release of inflammatory mediators


Chemotaxis & Migration of inflammatory cells to site
of injury
Phagocytosis

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)

Engulfment of debris or invading microorganisms (or both,


depending on the injury) by neutrophils and monocytesmacrophages

Loss of function
The result of cell / tissue damage
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Chemical responses of
Inflammation

Reaction

Several different inflammatory mediator systems


Interacting and together to produce inflammation
Many mediators with overlapping (redundant)
activities

PGs, NO, Histamine

Increased vascular
permeability

Vasoactive amines (histamine, serotonin)


C3a & C5a; Bradykinin; LTC4, LTD4, LTE4

Chemotaxis,
C5a; LTB4; PGs; Chemokines; IL-1, TNF
Leukocyte recruitment Bacterial products (e.g., LPS)
& activation

Vasodilation, Increased vascular permeability, Chemotaxis,


Opsonization, Activation of nociceptors, Activation of
platelets, etc.
No one chemical mediator is solely responsible for any one
feature of an inflammatory response

Fever

IL-1, TNF; PGs

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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Selected chemical mediators

PG: Prostaglandin; LT: Leukotriene; C: Complement factor; NO: Nitric oxide


IL: Interleukin; TNF: Tumor necrosis factor; LPS: Lipopolysaccharide

Selected chemical mediators


Kinin system

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

A group of small vasoactive peptides


Bradykinin (a 9-amino-acid peptide as the major
final product)
Multiples effects, such as production and release
of different mediators (such of nitric oxide,
prostaglandins, etc.) and subsequent effects such
as increased vascular permeability, vasodilation,
hypotension, pain, contraction of many types of
smooth muscle, etc.

A key role in body defense, but also a pathological


role in some autoimmune diseases
Elimination of invading microorganisms
Signs & symptoms of inflammation and tissue destruction

Presently no useful pharmacological


interventions available

Presently no useful pharmacological interventions


available
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System Pharmacology II - Introduction to


Pharmacology of Inflammation &
Immunotherapy/MOK

Inflammatory mediators

Vasodilation

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September 2014

Chemical mediators of
Inflammation

Chemical mediators of
Inflammation

Derivatives of arachidonic acid

Histamine

Prostanoids (Prostaglandins & Thromboxanes)


& Leukotrienes
Useful pharmacological interventions
Prostaglandins & analogs
Inhibition of prostaglandin synthesis: Nonsteroidal
antiinflammatory drugs (NSAIDs) for analgesic,
antipyretic, antiinflammatory, and antiplatelet
effects, etc.
Inhibition of leukotriene synthesis and leukotriene
receptor antagonists: For management of allergy
and asthma

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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Selected chemical mediators

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Selected chemical mediators

Platelet activation factor (PAF)

Cytokines

A phospholipid-derived mediator from mast cells & other


leukocytes after stimulation
Most of the cardinal features of inflammation

Small proteins as chemoattractants and activators for leukocytes


4 major classes: CXC chemokines, CC chemokines, C
chemokines, CX3C chemokines
2 receptor types: CXCR for CXC chemokines & CCR for CC
chemokines

A large heterogeneous group of soluble chemical


messengers (signaling molecules) released by
hematopoietic cells (such as activated T cells and
monocytes-macrophages) and many other nonhematopoietic cells
Local mediators that are important in regulation of
many physiological and immune responses as well as
the pathogenesis of many diseases
Naming: Cytokines are named based on presumed
targets (e.g., Interleukins (ILs) that targets leukocytes)
OR on presumed functions (e.g., G-SCF for
promotion & growth of granulocytes)

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Acute-phase proteins
From liver
E.g., C-reactive protein

Serotonin, nitric oxide, oxygen-derived free radicals,


substance P, etc.
Chemokines

Binding of Cytokine

Cytokines

Cytokine receptor

Properties
Proteins and glycoproteins
Potent and short-lived

Downstream signal transduction

Present in extremely low concentrations locally


Serum T1/2 in minutes
Act over short distances (Functions in an autocrine or a
paracrine manner, or both)

Nucleus
Gene expression

Diverse biological effects


By binding to their respective receptors on the cell
membranes of their target cells Intracellular signal
transduction to the nucleus Modification of Gene
expression (inhibition of some genes / expression of other
genes) & Transcription factors

System Pharmacology II - Introduction to


Pharmacology of Inflammation &
Immunotherapy/MOK

Protein synthesis

Cell activation, proliferation (growth), differentiation,


functional cell-surface molecule expression,
cellular effector functions
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September 2014

Physiological & Pathological


activities of Cytokines

Cytokine Cell source

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

T cell activation &


proliferation
B cell growth
NK cell activation &
proliferation
Activation & Cytolytic
activity of monocytemacrophages

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

Growth and differentiation of cells


E.g., Colony-stimulating factors (CSFs), stem cell
factors, growth factors (such as EGFs, VEGFs)

CNS activities
As neurotransmitters and neuroregulators
E.g., IL-1 , TNF , and IFNs
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Cytokine Cell source

Cell target

Biologic activity

Cytokine Cell source

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

MonocytesAll cells except


macrophages, erythrocytes
Mast cells,
Basophils,
Eosinophils,
NK cells,
B cells, T cells,
Fibroblasts,
Keratinocytes

Fever, anorexia, shock,


capillary leak syndrome
Enhanced cytotoxicty of
leukocytes
Enhanced NK cell
function
Acute protein synthesis
Induction of proinflammatory cytokines

IL-12

Activated
macrophages,
Dendritic cells,
Neutrophils
B cells

T cells
NK cells

Induction of TH1 cell


formation & lymphokineactivated killer cell
formation
Increase cytotoxic
activity of T cytotoxic
cells

TNF

T cells,
B cells

Promotion of
inflammation,
Cell cytotoxicity
Lymph node & spleen
development

Cell target

All cells except


erythrocytes

Biologic activity

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Cytokine Cell source Cell target


IFN-
IFN-

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)

Life cycle of Lymphocytes


Hematopoietic stem cells under influence of different
cytokines & local factors Mature nave lymphocytes in
circulation
Thymus: T cells
Bone marrow: B 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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System Pharmacology II - Introduction to


Pharmacology of Inflammation &
Immunotherapy/MOK

22

Short lifespan (days) unless being activated through


exposure to their specific antigens

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September 2014

Activation of Lymphocyte

Activation of Lymphocyte

Antigen binding to its specific receptors

Results of action: Cell


division & differentiation

IgM on B cells: Antigen (of diverse nature, such as proteins,


carbohydrates, etc.) binding directly to IgM
TCR on T cells: Peptide antigens presented by antigen
presenting cells (such as dendritic cells, monocytesmacrophages, B cells)

Co-stimulatory factors from neighboring cells


Cell-cell contacts
E.g., CD28 on Helper T cells & CD80 (= B7-1) or CD86 (= B7-2) on
antigen-presenting cells
Ag signal

Cytokines (e.g., IL-2)


Antigen-MHC
complex
B7

APC

TCR
CD28

Co-stimulatory
signal

Memory
cells

Effector
cells
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Ig from each clone of B cells


Reacting with One specific antigen
Monoclonal antibody (mAb)

The KEY regulator of immune response


To release many cytokines (e.g., IL-2, IL-4, IL-6, IFN etc.) for
activation of other cells (B cells, T cytotoxic cells, macrophages)

Activated T cytotoxic cells


To cause death (apoptosis) of infected cells (e.g., cells by virus) or
mutated cells

Plasma cells (from nave B cells)


To produce and release antibodies (immunoglobulins)

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

Fragment antigen binding


Specificity of the antibody
L chain + Part of H chain

Cell division &


Differentiation
(Clonal expansion)

Antibody / Immunoglobulin (Ig)

Short-lived cells (days)


Activated T helper cells

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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System Pharmacology II - Introduction to


Pharmacology of Inflammation &
Immunotherapy/MOK

5 isotypes: IgA, IgD, IgE, IgG, IgM


IgM
2 types
Bound IgM (along with IgD) on B cells as Antigen
receptors
Secreted IgM for elimination or inactivation of
antigens (such as through formation of a large
antigen-antibody complex, complement activation,
neutralization, etc.)
The predominant type in primary antibody response (first
response)
Present as pentamers in serum

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September 2014

Immunoglobulin

Immunoglobulin

IgG

IgA

Predominant type in secondary antibody response


(repeated response to the same antigen)
Longest serum T1/2 (~ 23 days)
Highest serum Ig levels in average adults (~ 75
85% of total serum Ig)
Placental transfer (protection to the fetus)
Presence of IgG Fc receptor on neutrophils,
monocytes-macrophages, dendritic cells, eosinophils,
NK cells
For elimination of antigen (through activities such as
complement activation, opsonization, neutralization,
etc.)
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Secretory Ig
In body secretions, such as tears, saliva, nasal secretions, GI
fluid, and human milk

Important in preventing viral infections in GIT and RT


Preventing viral binding to epithelial cells

IgE
Presence of IgE Fc receptors on basophils & mast
cells
When antigen binds to IgE on basophils / mast cells,
inflammatory mediators will be released.

Important in allergy, anti-parasitic responses

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 III hypersensitivity


Immune complex-mediated reactions
IgG- or IgM-mediated reactions

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

Cell-mediated or delayed-type reactions


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Type

Reaction

Type III
Immune complex
Mediated by IgM
or IgG

Antigen-antibody immune complexes


Deposition in tissues Complement
activation + Infiltration of neutrophils
Tissue damage
~ 8 hr
2 classical types -- Arthus reaction
(localized) & Serum sickness (generalized)
Sensitized TH cells encounter Antigen
Activation of other Lymphocytes &
Macrophages + Inflammation
Fibrin deposition Induration
~ 36 hr
Allergic contact dermatitis

Type IV
Delayed type
Cell-mediated

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System Pharmacology II - Introduction to


Pharmacology of Inflammation &
Immunotherapy/MOK

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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

Non-biological and biological agents


Corticosteroids, cytotoxic drugs, cyclosporine, etc.
Recombinant cytokines and cytokine inhibitors
Vaccines for active immunization
Polyclonal antibodies
Immunoglobulin preparations (including antisera) from donated
blood for passive immunization

Monoclonal antibodies (mAbs)


Recombinant products specific to a target molecule
A rapidly growing areas with many applications

Agents for blocking T cell activation


Tolerance induction

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