IMMUNOMODULATOR

Immunosuppressants
Organ transplantation
Autoimmune diseases
Problem
Life long
use
Infection,
cancers
Nephrotoxicity

Klasifikasi Imunosupresan
Mekanisme Kerja

Imunosupresan

Inhibitors of Lymphocyte Gene

Expression

Glucocorticoids

Inhibitors of Lymphocyte Signaling

- Calcineurin inhibitor
- mTOR Inhibitor

Cyclosporine, Tacrolimus,
Sirolimus, Everolimus

Cytotoxic Agents
-Antimetabolites
-Alkylating agents
Cytokine Inhibitor
-TNF- inhibitor,
-IL-1 inhibitor,
-IL-2 inhibitor

Antibodies Againts Specific Immune

Cell Molecules
-Polyclonal Ab
-Monoclonal Ab

Azathioprine, Methotrexate,
Cyclophosphamide,
Leflunomide

Etanercept, Infliximab,
Adalimumab
Anakinra, Daclizumab,
Basiliximab

ATG (antithymocite Globuline)

Anti CD-52 Ab, Anti CD-3 Ab,

Glucocorticoids
Induce redistribution of lymphocytes
decrease in peripheral blood
lymphocyte counts
Intracellular receptors regulate
gene transcription
Down regulation of IL-1, IL-6
Inhibition of T cell proliferation and
function
Neutrophils, Monocytes display poor
chemotaxis
Broad anti-inflammatory effects on
multiple components of cellular

Glucocorticoids

USES - Glucocorticoids
Transplant rejection
GVH BM transplantation
Autoimmune diseases RA, SLE,
Hematological conditions
Psoriasis
Inflammatory Bowel Disease, Eye
conditions

Toxicity

Growth retardation
Avascular Necrosis of Bone
Risk of Infection
Poor wound healing
Cataract
Hyperglycemia

Hypertension

Calcineurin Inhibitor

Calcineurin Inhibitor

the absorption of is slow and

incomplete.
Peak concentrations in blood
or plasma
are reached in 1 to
Oral
administration
8 hours after dosing.
The bioavailability of
cyclosporin ranges from less
than 5% to 89% in transplant
patients;
poor absorption has
frequently been observed in
liver and kidney transplant
patients and in bone marrow
recipients.
Factors that affect the oral
absorption of cyclosporin
include the elapsed time after
surgery, the dose
administered, gastrointestinal
dysfunction, external bile
drainage, liver disease, and
food.

Cyclosporin

European journal of Clinical Pharmacology 1988

multicompartmental
behaviour.
The volume of distribution
intravenous
(whole blood; HPLC) ranges
administration
from 0.9 to 4.8 L/kg.
Cyclosporin is highly bound to
erythrocytes and plasma
proteins and has a blood to
plasma ratio of approximately
2.
In plasma, approximately 80%
of the drug is bound to
lipoproteins.
The distribution of cyclosporin
in blood can be affected by a
patient's haematocrit and
lipoprotein profile.
Cyclosporin is extensively
metabolised, primarily by
mono- and dihydroxylation as
well as N-demethylation, and
is considered a low-tointermediate clearance drug

Toxicity : Cyclosporine

Renal dysfunction
Tremor
Hirsuitism
Hypertension
Hyperlipidemia
Gum hyperplasia
Hyperuricemia worsens gout
Calcineurin inhibitors +
Glucocorticoids = Diabetogenic

Tacrolimus ( FK 506,
Prograf )

It binds to the immunophilin FKBP1A,

followed by the binding of the
complex to calcineurin and the
inhibition of its phosphatase activity.
In this way, it prevents the cell from
transitioning from the G0 into G1
phase of the cell cycle. Tacrolimus is
more potent than ciclosporin and has
less pronounced side-effects.

Use
-Prophylaxis of solid-organ allograft
rejection

Toxicity - Tacrolimus
Nephrotoxicity
Neurotoxicity-Tremor, headache,
motor disturbances, seizures
GI Complaints
Hypertension
Hyperglycemia
Risk of tumors, infections

Sirolimus (rapamycin, trade

name Rapamune)
Contrary to ciclosporin and
tacrolimus, drugs that affect the first
phase of T lymphocyte activation,
sirolimus affects the second
one( namely signal transduction and
lymphocyte clonal proliferation).
It binds to FKBP1A like tacrolimus,
however the complex does not inhibit
calcineurin but another protein,
mTOR (mammalian target of
rapamycin ).

 It indirectly inhibits several T

lymphocyte-specific kinases and
phosphatases, hence preventing
their transition from G1 to S phase of
the cell cycle.
Sirolimus prevents B cell
differentiation into plasma cells,
reducing production of IgM, IgG, and
IgA antibodies.

Sirolimus
Uses
Prophylaxis of organ transplant rejection
with other drugs
Toxicity
Increase in serum cholesterol,
Triglycerides
Anemia
Thrombocytopenia
Hypokalemia
Fever
GI effects
Risk of infection, tumors

Cytotoxic Agents: Antimetabolites

Azathioprin

Methotrexate

Azathioprine (Imuran )
the main immunosuppressive cytotoxic
substance. It is nonenzymatically
cleaved to mercaptopurine, that acts as
a purine analogue and an inhibitor of
DNA synthesis.
By preventing the clonal expansion of
lymphocytes in the induction phase of
the immune response, it affects both
the cell and the humoral immunity.

Uses
Prevention of organ transplant rejection
Rheumatoid arthritis

Toxicity - Azathioprine
Bone marrow suppressionleukopenia, thrombocytopenia,
anemia
Increased susceptibility to infection
Hepatotoxicity
Alopecia
GI toxicity
Drug interaction: Allopurinol

Cytotoxic Agents:Alkylating
Agents
Cyclophosphami
de

Mycophenolate Mofetil
Prodrug Mycophenolic acid
Inhibits IMPDH enzyme in guanine
synthesis (Inosine monophosphate
dehydrogenase (IMPDH) is a major target
for both antitumor and immunosuppresive
drug design.)
T, B cells are highly dependent on this
pathway for cell proliferation
Selectively inhibits lymphocyte
proliferation, function , Antibody
formation, cellular adhesion,
migration

Uses - Mycophenolate
Mofetil

Prophylaxis of transplant rejection

Combination: Glucocorticoids
Calcineurin Inhibitors
Toxicity
GI, Hematological
Diarrhea, Leucopenia
Risk of Infection

Drug Interaction
Decreased absorption when
co-administered with
antacids
Acyclovir, Gancyclovir
compete with mycophenolate
for tubular secretion

Antibodies
Against
lymphocyte cellsurface antigens
Polyclonal /
Monoclonal

Antibodies
Antithymocyte Globulin
Monoclonal antibodies

Anti-CD3 Monoclonal antibody

(Muromonab-CD3)
Anti-IL-2 Receptor antibody (Daclizumab,
Basiliximab)
Campath-1H (Alemtuzumab)

Anti-TNF Agents

Infliximab
Etanercept
Adalimumab

LFA-1 Inhibitor (lymphocyte function associated)

Efalizumab

Anti-thymocyte Globulin
Purified gamma globulin from
serum of rabbits immunized with
human thymocytes
Cytotoxic to lymphocytes & block
lymphocyte function
Uses
Induction of immunosuppression
transplantation
Treatment of acute transplant
rejection
Toxicity
Hypersensitivity

Monoclonal Antibodies

Anti-IL-2 Receptor
Antibodies
(Daclizumab and Basiliximab )
Bind to IL-2 receptor on surface of
activated T cells Block IL-2
mediated T-cell activation
Uses
Prophylaxis of Acute organ rejection
Toxicity
Anaphylaxis, Opportunistic Infections

Anti-CD3 Monoclonal Antibody

(Muromonab-CD3 )

Binds to CD3, a component of Tcell receptor complex involved

in
antigen recognition
cell signaling & proliferation

Uses
Treatment of acute organ
transplant rejection
Toxicity
Cytokine release syndrome
High fever, Chills, Headache,
Tremor, myalgia, arthralgia,
weakness
Prevention: Steroids

Cytokine release syndrome

is a common immediate complication
occurring with the use of anti-T cell antibody
infusions such as ATG, Muromonab_CD3(OKT3)
The pathogenesis is that the antibodies bind
to the T cell receptor, activating the T cells
before they are destroyed. The cytokines
released by the activated T cells produce a
type of systemic inflammatory response
similar to that found in severe infection
characterised by hypotension, pyrexia and
rigors.
the cytokine release syndrome is effectively a
type of non-infective fever.

Anti-TNF Agents
TNF Cytokine at site of
inflammation
Infliximab
Etanercept
Adalimumab

Infliximab
Uses
Rheumatoid arthritis
Chrons disease fistulae
Psoriasis
Psoriatic arthritis
Ankylosing spondylosis
Toxicity
Infusion reaction fever, urticaria,
hypotension, dyspnoea
Opportunistic infections TB, RTI, UTI

Etanercept
Fusion protein
produced through
expression of
recombinant DNA.
Ligand binding
portion of Human
TNF- receptor fused
to Fc portion of
human IgG1
Uses
Rheumatoid arthritis

Adalimumab
Uses :
moderate to severely active crohns disease

Recombinan
t human
anti-TNF
mAb

TNF Blockers

rmation on the FDA approved uses of three selected TNF alpha blockers. (May 2

Rheumatoid
Arthritis (RA)
Polyarticular
Juvenile
Idiopathic
Arthritis (JIA)
Psoriatic Arthritis
Ankylosing
Spondylitis (AS)
Plaque Psoriasis
Crohns disease
Ulcerative colitis

Etanercept
(Enbrel)
Yes

Infliximab
(Remicade)
Yes

Adalimumab
(Humira)
Yes

Yes

No

Yes

Yes
Yes

Yes
Yes

Yes
Yes

Yes
No
No

Yes
Yes
Yes

Yes
Yes
No

LFA-1 Inhibitor Efalizumab

Specifically designed to bind to the CD11a
chain of leukocyte function antigen-1 (LFA-1),
which is an integrin expressed on all
leukocytes
Blocks interaction between LFA-1 on T-cell and
intracellular adhesion molecule (ICAM) on APC,
endothelium and keratinocytes
Uses
Organ transplantation
Psoriasis

Efalizumab Blocks Activation

of T-cells in Dermis and Epidermis
Activated APC

T-cell

Immunologic
Synapse

ICAM

CD11a

LFA-1

Antigen-Peptide
MHC

CD3

T-cell
Activation
Signals

TCR
CD4/CD8

LFA-3
CD40
B7

CD2
CD40L
CD28

Costimulatory
Signals

Costimulator
y Molecules
ICAM

LFA-1

Cytokine
production
Keratinocyte
hyperproliferation
Inflammatory
response

T-cell Activation,
Proliferation, and Cytokine
Production

Concept based on : Krueger JG. J Am Acad Dermatol. 2002;46:1-23.

Immunostimul
ants

Immunostimulants

USES:

immunodeficiency
disorders
Chronic infections
cancer

specific Immunostimulants

Levamisole
Thalidomide
BCG
Recombinant Cytokines
Interferons
Interleukin-2

Other drugs
inosiplex, azimexon, imexon, thymosin,
methylinosine monophosphate
Immunization
Vaccines , Immune Globulin , Rho (D) Immune
Globulin

Levamisole
Antihelminthic
Restores depressed immune function
of B, T cells, Monocytes, Macrophages
USES:
Adjuvant therapy with 5FU in colon
cancer
Used to treat immunodeficiency
associated with Hodgkins disease.
Toxicity
Agranulocytosis

Thalidomide
Birth defect
Contraindicated in women with
childbearing potential
Enhanced T-cell production of
cytokines IL-2, IFN-
NK cell-mediated cytotoxicity
against tumor cells
USE:
Multiple myeloma

Bacillus Calmette-Guerin
Live, attenuated culture of BCG strain
of Mycobacterium Bovis
It causes activation of macrophages to
make them more effective killer cells.
used as intravesical therapy for
superficial bladder cancer.
Adverse Effects
Hypersensitivity
Shock
Chills

Interferons
Antiviral
Immunomodulatory activity
Bind to cell surface receptors
initiate intracellular events
Enzyme induction
Inhibition of cell proliferation
Enhancement of immune activities
Increased Phagocytosis

Interferon alfa-2b

Hairy cell leukemia

Malignant melanoma
Kaposi sarcoma
Hepatitis B

Adverse reactions
Flu-like symptoms fever, chills,
headache
CVS- hypotension, Arrhythmia
CNS- depression, confusion

Interleukin-2
(aldesleukin)
Proliferation of cellular immunity
Lymphocytosis, eosinophilia, release
of multiple cytokines TNF, IL-1, IFN
Uses
Metastatic renal cell carcinoma
Melanoma
Toxicity
Cardiovascular: capillary leak
syndrome, Hypotension

Capillary leak syndrome

(systemic capillary leak syndrome or
Clarkson syndrome)
A rare medical condition where the
number and size of the pores in the
capillaries are increased which leads
to a leakage of fluid from the blood to
the interstitial fluid, resulting in
dangerously low blood pressure (
hypotension), edema and multiple
organ failure due to limited perfusion.

Immunization
Active Stimulation with
an Antigen
Passive Preformed
antibody

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:
Vaccinating patients with autologous
antigen presenting cells (APC) expressing
tumor-associated antigens (TAA)

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

 Nonspecific
immunoglobulins
Antibody-deficiency
disorders
Specific immune globulins
High titers of desired
antibody
Hepatitis B, Rabies,
Tetanus

Rho (D) Immune

Globulin
Antibodies against
Rh(D) antigen on the
surface of RBC
prevent the
immunological
condition known as
Rhesus disease (or
hemolytic disease of n
ewborn
).
treating chronic
idiopathic thrombocyto
penic purpura