why need immunomodulators

Now, become
 very popular & center of medicine

 people realize the important of immune

system as a health center

 environmental  rich in infectors/pathogens

 difficult to avoid from the infector

 immunomodulators
 Daily activity
 stress
 immune system disturbance
 Herbal industry
 develop plant as immunomodulator
  Deficiency immune system
 HIV, bird flu, swain flu
  Autoimmune disease:
 SLE
 Multiple sclerosis
 Myasthenia gravis  need
immunomodulator
Immunomodulator is a substance that have
activity to regulate immune system

Regulate
 normalize or optimize immune response
 IMMUNOMODULATOR

(IDEAL) If administered to patient

 immune system deficiency

 can enhance immunity

 Overactive immune system

 can normalized

  not booster
but normalize immune system
 Immun-
suppressive
Immuno-
stimulation
 Organ
Transplanted
IMMUNO-
Immune def
 Autoimmune MODULATOR
diseases:
diseases: HIV-AIDs,
SLE, RA, bird flu,
MS, MG Tolerogen Tumor,
Chronic,
Infectious diseases

Block co-stimulation
 Immunomodulator

 is substance or biological product used in

immunotherapy to
stimulate,
potentiate, or Immune response
suppress

 Inhibit or enhance certain subclass

of immunocyte
 IMMUNOMODULATORS
• Immunostimulant
 Substances that stimulate immunity
» Antisera
– antibodies
– anti cobra venom
– transient but instant protection
» Vaccines
– whole or part of infectious bacteria/virus
– develop our own immunity
» Cytokines
– interferon, etc maria immaculata iwo, sf itb
 Immunostimulant

 is a substance that could stimulate or enhance

immune system function

∆ Vaccination/immunization ?
H. Wagner: paramunity
 UNSPECIFICALLY
Complement ACTING OF B Lymphocytes
IMMUNOMODULATORS

Granulocyte Macrophages T lymphocytes

Microphagocytosis Macrophagocytosis T-helper cells

T-suppressor cells
Cytotoxic, NK cells

Liberation of mediators Liberation of lymphokines

(i.e. interferon α, interleukin, (i.e, IL-2 or γ interferon)
tumor necrosis factor,
protaglandins, O2‾ ,
lyzosomal enzymes, etc)

Fig. Paramunity effect (Wagner)

 Source of immunomodulators

 Plant, animal, microbial (probiotics) or

as synthetic products

 Low MW: alkaloid, steroid/terpenoid, flavonoid,

quinine, dll

High MW: - Many polysaccharides

- Proteins
- Glycoprotein/lectins
- Nucleotide
 Source of immunomodulator

 So far,
no structure-activity relationships have been found
amongst low & high molecular weight compounds.

 The same substance can act as an immunostimulant

or as immunosuppressive agent,
 depending on the dose.
 Compound having immunomodulatory effect
Compound/ Source Immunomodulatory
class activity
Con A Plant lectin Activates T lymphocytes and
Phytohemagglutinin cause them to secret
various lymphokines
(PHA)
Lipopolysaccharide Microbial product Activates B lymphocyte
(LPS) directly
Polysaccharide Higher plants, fungi, Activates macrophages, NK
(Zymosan, lentinan, mushrooms, cells, and cytotoxic T
seaweeds, algae, lymphocytes and having anti
pachymaran) tumor activity
lichens, vegetables
Gallic acid and Higher plant Higher plant stimulation
protochatechuic acids stimulation of of phagocytosis
(Catechols) phagocytosis
BCG Microbial product activates macrophages
Thymosin animal lnduce the maturation of
(protein hormon) pre-T cells
 • Levamisol,
• Isoprinosin,
• Pentoxifilin, Synthetic
• simetidin, immunomodulators
• thiabendazol,
• DEC,
• Thalidomid

• Biological Product:
 Sitokin: interleukin, interferon, etc
 Molecules that influence cellular metabolism,
i.e. PG Inhibitor,
enzyme inhibitor : bestatin, amastatin
 Tolerogen
Immune cells still active
but no responsiveness to
an antigen
 Immunosuppressants
 use to treat autoimmune
diseases
» Prevent rejection of transplants
» Treat autoimmune disease
» CORTICOSTEROIDS
– depress T-cells, antibody production &
macrophage responsiveness
» CYCLOSPORIN
– blocks T-cell proliferation
» AZATHIOPRINE
– suppress all immune cell proliferation
maria immaculata iwo, sf itb
 immunosuppressive

 Suppress immune system function:

 inhibit DNA synthesis

 Activated T suppressor cell
 inhibit Th cell activity

 inhibit humoral and cellular responses

 immunosuppressant
• Inhibitor T cell specific :
Inhibit Th cell activation and proliferation
Siklosporin, Takrolimus

• Cytotoxic drugs
Block proliferation and differentiation of B and T
cells (Azathioprin, Siklofosfamid, Methotreksat,
Mikofenolat mofetil, klorambusil)

• Glucocorticoid
Inhibit MHC expression and cytokines production (IL-1,
IL-2, IL-6,  T cells were not activated)
prednisolon

• Monoclonal Antibodi
Muromonab CD3, Antithymosit globulin (ATG), Rho (D) imunoglobulin
 CD
Glu.

Ab
Siklo.,
Takrol.

CD
 TOLEROGENS

 Tolerogens are agents used to induce and

maintenance the immune tolerance, the active
state of antigen-specific non-responsiveness.

 The induction of immunological tolerance is

necessary to avoid self-reactivity and useful
for organ transplantation process.
 TOLERANCE

• Tolerance refers to the specific immunological non-

reactivity to an antigen resulting from a previous
exposure to the same antigen.
• the most important form of tolerance is non-
reactivity to self antigens,
• it is possible to induce tolerance to non-self antigens.

 When an antigen induces tolerance, it is

termed tolerogen.
 Immunoprophylaxis

1. The way of acquired specific immunization

2. The classification and characteristics of

Artificial immunization

3. Biological product and their application

1. The way of acquired specific
immunization

 Natural  Active
immunization: immunization:
- heredity, - natural,
- non-specific - artificial

 Acquired  Passive
immunization: immunization:
- acquired, - natural,
- specific - artificial
 DIFFERENT MODES OF ACQUIRING IMMUNITY

Immunity
Adoptive
transfer of
immune cells
Natural resistance Acquired

Passive Active

Artificial Natural Artificial Natural

Ab or Ig, Placental transfer of IgG,

Immune cells Colostral transfer of IgA
 ACQUIRED IMMUNITY NATURAL ACQUIRED
Produced by prior exposure to Of PASSIVE IMMUNITY
or via antibody production Conferred by transfer
of maternal antibodies
across placenta or
in breast milk

ACTIVE IMMUNITY
Produced by antibodies that PASSIVE IMMUNITY
develop in response to antigen Produced by transfer of
(immune response) antibodies from another person

INDUCED ACTIVE NATURALLY

ACQUIRED INDUCED PASSIVE
IMMUNITY IMMUNITY
ACTIVE IMMUNITY
Develops after Conferred by administration
Develops after
Administration of of antibodies to
exposure to antigen
antigen combat infection
in environment
to prevent disease
 Immunity can be acquired through
active and passive immunization

Type acquired through

Active :  Natural infection or unapparent

immunization infection
 Artificial infection:
vaccine, toxoid, attenuated organisms
inactivated organisms purified microbial
macromolecules

Passive  Natural maternal antibody

Immunization  Artificial immune serum
2. The classification characteristics of
Artificial immunization

Artificial active immunization:

Artificial passive immunization:
Comparison:
Artificial active immunization

Features:
1. The production of the effect: slow
(induction phase: 1-4weeks)
2. The persistent time of immunity: long
(months-years)
3. The application: specific prophylaxis
4. The agents: Ag (immunogen): vaccine, toxoids
Artificial passive immunization

Features:

1. The production of the effect: fast

2. The persistent time of immunity: short (2-3 weeks)
3. The application: treatment and urgent prophylaxis
4. The agents:
Ab: antitoxin, antiserum, human gammaglobulin,
synthetic peptides
 Artificial active Artificial passive
` immunization immunization

Injecting
agents: Ag (vaccines, toxids) Ab (antitoxin,
antiserum)
Producting
time: slow at once
(induction phase:1-4W)
Persistenting
time: long (months or years) slow (2weeks or
months)
The main
application: specific prophylaxis urgent prophylaxis
(infectious diseases) or treatment
3. Biological product and their application

Biological product

a. Vaccine: Live vaccine (attenuated vaccine)

Killed vaccine
Live vaccine
Chemical vaccine or subunit vaccine
Compound vaccine
Genetic engineering vaccine
Anti-idiotype vaccine

b. Toxoid
 Immunotherapy
Conception
1. Immunopotentiator
2. Immunosuppressant

(Immunomodulator)
 1. Immunopotentiator and indication

a. Immunopotentiator:
- Chemical agents:
levomisole, cimetidine, isoprinosine (ISO)
- Microbiological agents: BCG,
- Proteins of immune system: Ig,

b. Indication:
e.g. Tumor, Immunodeficiency, Infectious
diseases
 2. Immunosuppressant and indication

a. Immunosuppressant:
- Chemical agents: Cyclophosphamide, Azathioprine
- Hormone: steroids
- Microbiological agents: CyclosporineA (CsA),
Tacrolimus, FK-506

b. Indication:
- Organ transplantation
- Hypersensitivity diseases
- Autoimmune diseases
 Immunosuppression with Drugs

Cyclosporin Azathioprine

IL-2 Tc
IFN
IL-2R
Steroids Th
proliferation
CD4 CD8 Tc
TCR-CD3
TCR-CD3
MHC-II MHC-I

APC
Tc

M

Graft cells
Hypersensitivity Disease, Autoimmunity Disease
Graft rejection responses

Ag

APC MHC TH
TCR

inactivation
B7

CD28

Anti-B7Ab
CTLA4 Ig
Anti-CD28

co-stimulatory signals
3. Immunomodulator and the use of them

a. Biological response modifier, BRM

b. Classification and function of BRM
Classification and function of BRM
1. Immunoreconstitution:
haemopoietic stem cell and thymus

2. Monoclonal antibodies (McAb) and targeted drug

McAb: Anti-CD3, Anti-CD4, Anti-CD8
Targeted drug: Immunotoxin, IT
Immunoconjugate,
Radioimmunoconjugate

3. Cytokines and activated immune cells

Cytokines : ILs, IFN, TNF, CSF, TGF and Small
molecular polypeptides.
immune cells: LAK, T cell

4. Tumor vaccine
5. Gene therapy
 McAb-toxin
McAb-medicine

Tumor

McAb-isotope
McAb-enzyme
 Cytokine therapy for tumors
Cytokine tumor type and results Cytokine effects and possible
anti-tumor mechanisms
Prolonged remissions of possible cytostatic
hairy-cell leukemia effect on tumor
IFN weak effects on some increased expression of
carcinoma MHC class I, cytostasis

remission of peritoneal increased MHC class I and II

IFN carcinoma of the ovary macrophage activation
Tc activation, cytostasis
Remission in renal cancer T-cell activation and
IL-2 and melanoma proliferation
NK-cell activation
? Increased tumor cell adhesion
TNF can reduce macrophage and lymphocyte
malignant ascites activation
Enhancing immune response: Tumor immunity treatment

Ag
MHC TCR
Tumor cell CTL
Signal 1 CTLactivated
Killer tumor cell
signal2
CD28

Ag
MHC TCR
Tumor cell CTL
Signal 1
CTLactivated
signal2 Killer tumor cell
B7
CD28

TransfectionB7gene