IMMUNOMODULATOR

Dr. Hj. Rika Yuliwulandari, PhD

Overview
I. Immune System Overview
II. History of Immunology
III. Current Treatment Techniques
Immunosuppressants
Immunostimulants
Immunization

Immune Response

Innate ImmunityAdaptive Immunity

Non-specific (Basically
just recognizes foreign
vs native)

First line of defense

Activation (endotoxin, MAF)
Phagocytosis (m,
neutrophils, All types of
White Blood Cells
(Leukocytes), Dendritic Cells

Lysis (NK)
Lysis (Complement
cascade)

Antigen specific
MHC restricted antigen
presentation
Humoral (antibody)
Cell-mediated (T cells)
DTH: Lymphokines
produced by Agstimulated T cells
recruit/activate m.
3

Characteristics
Characteristics of
of
Innate
Innate and
and Adaptive
Adaptive Immunity
Immunity

Innate Immunity

Adaptive Immunity

Antigen independent

Antigen dependent

No time lag

A lag period
Antigen specific

Not antigen specific

No
Immunologi
c
memory

Development
of memory
CMI and Humoral
(Ab) immunity)
4

Example of immunologic
cases
Transplantation Rejection
Allografts from different individuals
Xenograft from different species

Tissue rejection may occur by TH cells

recognizing different MHC II, aid TC to
destroy graft (recognize MHC I)
TH cells also release cytokines, cue
macrophages
Graft vs host disease (bone marrow
transplants)

Rheumatoid Arthritis
Disease that leads to
inflammation of the joints and
surrounding tissues
Can affect organs
The immune system confuses
healthy tissue with foreign and
begins to attack itself
Occurs at any age, usually
affects women more than men
Affects joints on both sides
equally
Wrists, fingers, knees, feet, ankles

http://www.scienceclarified.com/imag
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Systemic Lupus Erythematosus

Autoimmune disease
Symptoms:
Chest pain, fatigue, fever,
general discomfort, hair
loss, mouth sores,
sensitivity to sunlight, skin
rash, swollen lymph nodes,
arrhythmias, blood in urine,
abdominal pain, coughing
up blood, patchy skin colors

Other form: lupus

nephrititis
Can cause kidney failure
and lead to dialysis

http://www.taconichills.k12.ny.us/web
quests/noncomdisease/lupuspic.jpg

Other
Immunologic
al Diseases

Type I diabetes mellitus

Multiple sclerosis
Asthma
Allergies

Two categories

Drugs that suppress the immune system

Suppression overcomes rejection of
organ/tissue transplantation and reduces
effects of autoimmune diseases

Drugs that stimulate the immune

system
Stimulation enhances activity of immune
system against infectious agents and
neoplastic cells
9

Treatment
Strategies
Immunosuppression involves downregulating
immune system activity
Tolerance the idea that a body can be taught
not to reject something
Immunostimulation involves upregulating
immune system activity
Immunization active or passive

10

Immunosuppressive Agents
T-cell blockers/Calcineurin inh

Glucocorticoids

Cytotoxic drugs

CYCLOSPORINE
TACROLIMUS
SIROLIMUS
CORTICOSTEROIDS
CYCLOPHOSPHAMIDE
AZATHIOPRINE
MYCOPHENOLATE
MOFETIL
METHOTREXATE

Antibody reagents

ANTIBODIES
11

Main purposes
Three main purposes
- Suppress rejection of transplant organ
- To suppress graft-versus-host disease in bone
marrow transplantation
- To treat incompletely understood conditions: ITP,
haemolytic anaemia, Glomerulonephritis,
Myasthenia gravis, SLE, Psoriasis, Ulcerative
colitis

T-CELL BLOCKER

13

T-cell
T-cell blockers/Calcineurin
blockers/Calcineurin inh:
inh:
Cyclosporine,
Cyclosporine, Tacrolimus,
Tacrolimus, and
and Sirolimus
Sirolimus

Most
Most effective
effective // potent
potent
immunosuppressive
immunosuppressive drugs
drugs
Target
Target intracellular
intracellular signalling
signalling
pathways
pathways
Blocks
Blocks induction
induction of
of cytokine
cytokine
genes
genes
cyclosporine
cyclosporine and
and tacrolimus
tacrolimus act
act
on
on helper
helper T-cells:
T-cells:
Inhibit
Inhibit T-cell
T-cell proliferation
proliferation by
by
inhibiting
inhibiting IL-2
IL-2 release
release and
and
expression
expression of
of IL2
IL2 rec
rec
cyclosporine
cyclosporine may
may also
also inhibit
inhibit IgEIgEstimulated
stimulated mast
mast cell
cell degranulation
degranulation
and
and stimulate
stimulate TGF-
TGF- expression
expression

Cyclos
porin A

Tacrolimus:
Tacrolimus:

Very
Very similar
similar mechanism
mechanism to
to cyclosporin
cyclosporin
Much
more
potent
Much more potent

Tacrolimus
a.k.a. FK-506
14

CsA and FK506 mechanism

of action
Complex with binding
protein (CpN, FKBP)
inhibits calcineurin
(CaN)
CaN is required for dephosphorylation and
nuclear translocation
of NFAT (nuclear
factor of activated T
cells)
CaN inhibition, blocks
NFAT resulting in
inhibition of IL-2 gene
15

Absorption
Absorption and
and metabolism
metabolism of
of
cyclosporine,
cyclosporine, tacrolimus
tacrolimus

Can
Can be
be given
given oral
oral or
or iv
iv
Oral
Oral bioavailability
bioavailability low
low and
and variable
variable (20
(20 -50%
-50% cyclosporine;
cyclosporine; 6
6 -56%
56% tacrolimus)
tacrolimus)

new
new cyclosporine
cyclosporine microemulsion
microemulsion gives
gives more
more consistent
consistent absorption
absorption

Almost
Almost all
all excreted
excreted in
in bile
bile after
after liver
liver metabolism
metabolism by
by CYP3A
CYP3A
enzymes
enzymes

bioavailability
bioavailability subject
subject to
to drug
drug interactions
interactions that
that can
can increase
increase or
or
decrease
decrease blood
blood levels
levels
Pharmacokinetics
variable, incomplete oral absorption
extensive hepatic metabolism, excreted in bile
used alone or in combination with prednisone and
azathioprine (or other antineoplastic drugs)
Adverse Effects
nephrotoxicity, hepatotoxicity, hirsutism, neurotoxicity,
hypertension
16
Anorexia, lethargy, tremor, paraesthesia

Uses
Uses of
of calcineurin
calcineurin inhibitors
inhibitors
(T-cell
(T-cell blockers)
blockers)

Cyclosporine commonly used with prednisone

and other immunosuppressants to prevent
allograft rejections in renal, hepatic and cardiac
transplants, and in treatment of RA and psoriasis
Tacrolimus is approved for prevention of solidorgan allograft rejection, and eczema (topical)

17

Toxic
Toxic effects
effects of
of Cyclosporine
Cyclosporine and
and Tacrolimus
Tacrolimus

Nephrotoxicity (C>T)
Neurotoxicity (T>C)
GI problems (T)
Hypertension (C>>T)
Hyperkalemia (T)
Hyperglycemia and onset of diabetes
especially with glucocorticoids (T>C)
Increased incidence of infections and
secondary tumors
least of immunosuppressants
18

Sirolimus and Everolimus: new T-cell blockers with

different activity

Pre-drug sirolimus binds

FKBP, but the complex
inhibits mTOR kinase
mTOR activates p70S6K
mTOR inhibition prevents
activity of p34cdc2 which
complexes with cyclin E,
thus preventing
elimination of p27Kip
which is a negative
regulator of cdks and eIF4F
Results in inhibition of
cell cycle proogression at
G1 to S phase
19

Sirolimus and Everolimus:

new T-cell blockers
similar poor bioavailability as cyclosporine and
tacrolimus, much longer half-life; 62 h vs. 18 and
12 h
same metabolism (CYP3A) and potential drug
interactions
used for prophylaxis of organ transplant rejection
in combination with a calcineurin inhibitor and
glucocorticoids
toxicities include:
hyperlipidemia, lymphocoele, anemia,
leukopenia, thrombocytopenia, fever, GI effects,
hyper- or hypokalemia
20

GLUCOCORTICOID

25

Immunosuppression
Glucocorticoids

Dexamethasone

Prednisone

Cortisol

26

Glucocorticoid
Glucocorticoid uses
uses in
in Immunosuppression
Immunosuppression
Used with other immunosuppressants to
prevent transplant rejection and GVHD
(synergistic
synergistic effect/lower
effect/lower toxicity).
toxicity).
natural glucocorticoids not used due to
mineralocorticoid activity

prednisone and prednisolone are used orally

at high - moderate doses; Very high doses of
methylprednisolone used i.v. during acute
organ rejection
Used before and after antithymocyte Abs to
inhibit allergic reactions
27

Glucocorticoid-sensitive
Glucocorticoid-sensitive sites
sites of
of immune
immune
responding
responding

MHC Class I/peptides

APCs

GC

MHC Class II/peptides

APCs

X
IL-1

proliferation &
differentiation

CD8 T-cell

CD8 cytolytic T-cells

IL-2

GC

proliferation
CD4 immune cell
(delayed hypersensitivi

CD4 T-cell
(helper T-cells)

IL-1, -4,-5,-6

Protein antigen

B-cell

Plasma cell
proliferation &
differentiation

antibody
production
28

Glucocorticoid
Glucocorticoid effects
effects and
and toxicity
toxicity

Reduced immune cell

content in lymph nodes,
spleen and blood

lymphopenia,
lymphopenia, monocytopenia,
monocytopenia,
eosinopenia,
eosinopenia, but
but neutrophilia
neutrophilia

Interference with antigen

presentation, T-cell and
macrophage functions

Major side effects are

common due to high
doses necessary for
suppression

Cushings syndrome
glucose intolerance
infections
bone dissolution
muscle wasting

29

Clinical Concerns with

Corticosteroids
Growth inhibition in pediatric transplants
Cataracts (10% incidence)
Bone disease (inhibition of osteoblastic activity,
decreased calcium absorption, increased urinary
calcium excretion)
Diabetes (insulin-resistance, gluconeogenesis)
Hyperlipidemia (40-60% posttransplant accelerated
atherogenesis, increased incidence if combined
with calcineurin inhibitors and sirolimus)
Hypertension (60-80% in transplant patients)
Increased cardiovascular risk factors
Predisposition to infection (decr. PMN, T cell
activity)
30

Immunosuppression
Glucocorticoids

Usually co-administered with other

suppressive agents to treat autoimmune disorders or treatment of
transplant rejection

Exact mechanism not elucidated

Very broad anti-inflammatory effects
Downregulate IL-1 and IL-6
Cause apoptosis in activated cells
31

CYTOTOXIC DRUGS

32

Mechanism of action of
mycophenolate mofetil

Because the salvage

pathway of purine synthesis
is less active than the de
novo pathway, lymphocytes
depend on PRPP conversion
to IMP and in turn GMP for
DNA synthesis

33

Uses of cytotoxic agents

Azathioprine; with cyclosporine and/or
prednisone for organ transplant
rejection and severe RA
Mycophenolate mofetil; with
cyclosporine and prednisone for renal
transplants

Cyclophosphamide; for BMT

Methotrexate; GVHD prophylaxis

34

ANTIBODY REAGENTS

35

Immunosuppression
Monoclonal Antibodies
Anti-CD3 Antibodies
Binds to chain of CD3, which is involved in T-cell
antigen recognition, signaling, and proliferation
Administration of mAb followed by depletion of T
cells from bloodstream and lymphoid organs
Lack of IL-2 production
Reduction of multiple cytokines
Not IL-4 and IL-10

Used to treat organ transplant rejection

Muromonab-CD3 (Orthoclone OKT3)
36

Immunosuppression
Monoclonal Antibodies
Anti-IL-2 Receptor [Anti-CD25]
Antibodies
Exact mechanism not understood
Binds to IL-2 receptor on surface of
activated T cells
No effect on resting T cells
Stops current response

Daclizumab and Basiliximab

37

Immunosuppression
Other Agents
Others include
Alemtuzumab (mAb) targets CD52,
causes lympholysis by inducing
apoptosis of targeted cells
IL-1 Inhibition
Alefacept protein, interferes with T-cell
activation

38

IMMUNOSTIMULANTS

39

Immunostimulants
Immunostimulants are applicable
during infections, immunodeficiency,
and cancer
Levamisole
Restores depressed immune function of
B and T Cells, monocytes, and
macrophages
Causes agranulocytosis
Removed from market
Levamisolein 2005
40

Immunostimulants
Thalidomide
Teratogenetic
BUT is useful to treat erythema
nodosum leprosum and multiple
myeloma

Thalidomide
41

Immunostimulants
Interferons
Bind to spefici cell-surface receptors that initiate
series of intracellular events
Induction of enzymes
Inhibition of cell proliferation
Enhancement of immune activity

Intron A - peptide used for tumor treatment and

infectious diseases;
Actimmune - peptide that activates phagocytes
and induces generation of oxygen metabolites
that are toxic to a number of microorganisms
42

Immunization
Active Stimulation with an Antigen
Passive Preformed antibody

43

Active immunization
Vaccines
Administration of antigen as a whole,
killed organism, or a specific protein
or peptide constituent of an organism
Booster doses
Anticancer vaccines immunizing
patients with APCs expressing tumor
antigen.
44

Immune Globulin
Indications
Individual is deficient in antibodies
immunodeficiency
Individual is exposed to an agent,
inadequate time for active
immunization
Rabies
Hepatitis B
45

 Nonspecific immunoglobulins
Antibody-deficiency disorders

Specific immune globulins

High titers of desired antibody
Hepatitis B, Rabies, Tetanus

46

Rho (D) Immune Globulin

Antibodies against Rh(D)
antigen on the surface of
RBC
Rh-negative women may be
sensitized to Foreign Rh
antigen on fetal RBC
Anti-RH Antibodies
produced in mother can
damage subsequent fetuses
by lysing RBCs
Hemolytic disease of
newborn
47

Immune tolerance
Induction and maintenance of
immunologic tolerance - active state
of antigenic specific
nonresponsiveness
Still experimental

48

Summary
Immunosuppresion
Calcineurin inhibitors
Glucocorticoids
Antimetabolites

Newer immunosuppresive agents

Effective control of rejection
Glucocorticoid withdrawal

49

Immunization
Active or passive
Active stimulation with antigen to develop
antigens for future prevention
Passive administration of antibodies to individual
already exposed or about to be exposed to antigens

Vaccines active; administration whole, killed

organism, live organism, or specific peptide
from organism
Immune Globulin used in passive
immunization; used in individuals deficient in
antibodies
50

Jacomini et al, 2011