Immunomodulator Drugs

Herri S. Sastramihardja

Depart Of Pharmacology & Therapeutic

Medical School – Padjadjaran University
Introduction
• Immunopharmacology
The study of the use of pharmacological
agents as modulators of immune response

• The principal applications:

–Immunosuppressive agents
Compounds that suppress undesirable immune
responses
–Immunostimulating agents
Drugs/microorganism/biological products that
enhance/augment immune responses
Introduction (con’t…)
• 3 major indication for immunotherapy:
– Auto immune diseases
– Primary immunodefficiency
– Organ transplantation
Autoimmune Diseases
• Cells from the body’s immune system can on
occasion react against normal endogenous
proteins & thereby effect a reaction against
certain body tissues
abnormal immune responses
= autoimmunity

• Under circumstances, normal control is lost &

the aberrant immune reaction will result in
disease,
disease e.g myasthenia gravis, rheumatoid
arthritis
Autoimmune (con’t…)
• Immunosuppressive agents are offten
employed in debilitating cases of
autoimmune disease to cure the
production of autoantibodies.
Table some auto immune disorders treated
with immunosuppressive therapy
Autoimmune hemolytic anemia
Myasthenia gravis
Cranial arteritis
Idiopathic thrombocytopenic purpura
Membranous glomerulonephritis
Polymyalgia rheumatica
Polymyositis
Psoriatic arthropathies
Rheumatoid arthritis
Systemic lupus erythematosus
Ulcerative colitis
Uveitis
Wegener’s granulomatosis
Primary Immunodeficiency Diseases
(=PID)

• PID = Defects of the immune system that

are due to genetic abnormalities/some
failure in normal embryological
development

• Usually apparent at birth/develop shortly

there after
PID (con’t…)
• 70 PIDs have described, including:
including
– Specific for humoral immunity
• X-linked agammaglobulinemia
• Immune globulin A(=IgA) deficiency

– Cellular immunity
• Di George’s syndrome

– Both  severe combined immunodeficiency

syndrome
PID (con’t…)
• The treatment of a PID is based on the
aspect of the immune system is lacking
– Deficiencies in humoral immunity
• Antibody replacement (e.g immune globulin)
• Medical management of infections

– Deficiencies in cell-mediated immunity

• There is no effective pharmacological treatment
PID (con’t…)
• Clinical manifestations
– Vary with the aspect of the immune system affected

– Individuals with humoral immunity deficiecies

• Prone to infections from S.pneumoniae & H.influenzae
• Also prone to respiratory, GI & UTI

– Individuals with celullar-imediated immunity defects

• Prone to fungal,
fungal protozoal & virals infections
  Incidence of malignancy
Organ Transplantation
• Suppresion of the immune system is a
requirement during organ transplantation
because of the propensity of the recipient to
reject the foreign tissue by immunological
mechanism
• Since transplantation is usually performed in
patients with a poor prognosis for survival, the
use of immunosuppresive agents has potentially
great therapeutic benefit, because it provides
the only real hope of continued life for many
individuals
Organ (con’t…)
• Immunosuppression, however, is frequently an
adverse reaction when these drugs are used as
antineoplastic drugs

• In the past, immunosuppresion could be

achieved only through the use of non specific
cytotoxic drugs (e.g
cyclophosphamide/azathioprine)
 toxic to rapidly proliferating cells (bone
marrow, gonadal tissue, GI tract)  BM
depression, infections, sterility  limited their
usefullness
Organ (con’t…)
• Cyclosporin & tacrolimus
Relatively low toxicity
General Principles Of
Immunosuppresive Therapy
• Primary immune responses are more
readily inhibited than are secondary
responses
– The primary phase of the immune response
(processing, proliferation, differentiation)
more sensitive to drug action
– Unsensitized person show much less effect
General Principles (con’t…)
• Not all immune responses are equally
affected by immunosuppresive drugs
– Celullar & humoral immunity may be
affected differentially
– The different classes of immune globulin in a
humoral response may be variably affected
General Principles (con’t…)
• Beneficial effects other than
immunosuppression may result from
therapy with these drugs
– The antiinflammatory properties of certain
drug may be valuable because inflammation
often accompanies the immune response
 Individual drugs used
to suppress the imune system
Cyclosporine
• A potent inhibitor of antibody & cell-
mediated immune responses
Immunosuppressant of choice for the
prevention of transplant rejection; also
useful in the treatment of autoimmune
disease (RA, SLE, uveitis, IDD, psoriatik
arthropathies)
• Highly stable 11-amino acid cyclic
polypeptide and very lipophilic
Cyclosporine (con’t…)
• Mechanism of action
– Bind to cytosolic protein (cytophilin c) 
complex  inhibit calcineurin phosphatase
activity   synthesis & release of several
cytokines
– Impairs the proliferative response of T-Cells to
antigens
– High specific to T-Cells
Cyclosporine (con’t…)
• Pharmacokinetic:
– oral absorption slowly & incompletely
– Tmax = 3 – 4 hours; t½ = 10 – 27 hours
– Metabolized by liver & excreted via bile  feces
• Adverse effect:
– nephrotoxicity 75% (severe tubular necrosis 
chronic interstitial nephropathy)
– Hypertension 25%
– Hypertension, hyperlipidemia
– Transient liver dysfunction
– hirsutism
Corticosteroid
• Used alone or in combinatioin with other agents in the
treatment of autoimmune disorders and for the
prevention of allograft rejection
• Although posses immunosuppressive properties, their
real value is in controlling the inflammation that can
accompany transplantation and autoimmune disorders
• All phases of the inflammatory process are affected by
these drugs
• Corticosteroid therapy alone is successful in only limited
number of autoimmune diseases, such as idiopathic
thrombocytopenia, hemolytic anemia & polymyalgia
rheumatica
Tacrolimus
• A second generation immunosuppresive agent
that has been approved for use in liver
transplantation
• 10 – 100 times more potent than cyclosporine
• A macrolide antibiotic that selectively inhibits
transcription of a specific set of lymphokine
genes in T-lymphocytes (IL-2, IL-4, IF- & bind
to cytoplasmic proteins (=cytophilins) in
lymphocyte, which are important
– For intracellular folding of proteins
– In regulating gene expression
Tacrolimus (con’t…)
• Absorption from GI is variable, extensively
metabolized in liver & excreted in urine
• The principal side effect is nephrotoxicity
Sirolimus
• Structurally related to tacrolimus
• It is approved for use as an adjunctive agent in
combination with cyclosporine for prevention of
acute renal allograft rejection
• It blocks IL-2 dependent T-cell proliferation by
inhibiting a cytoplasma serine-threonine kinase
• MOA is different from tacrolimus & cyclosporine
 can  immunosuppresive effect of these
drugs
Azathioprine
• a derivate of 6-mercaptopurine
• very effective as an immunosuppresive
agent and replicating cell is a target for
this action
• Mechanism of action
– Inhibit DNA synthesis & therefore suppreses
lymphocyte proliferation

Inhibits both humoral & cell-

mediated immune reponses
Azathioprine (con’t…)
• Pharmacokinetic
– Well absorbed following oral administration
– Tmax = 1 – 2 hours; t½  5 hours
– Extensively metabolized to 6-MP and then
converted (liver, erythrocytes) to a variety of
metabolites including 6-thiouric acid
– Metabolites are excreted in the urine
Azathioprine (con’t…)
• Clinical uses :
– Related to direct immunosuppresive action &
antiinflammatory properties
– Combination with corticosteroid to inhibit
rejection of organ tranplants (kidney, liver)
– Reserved for patients who do not response to
cyclosporine + corticosteroids alone
– Autoimmune disorders mostly RA
– Wegener’s granulomatosis
Azathioprine (con’t…)
• Adverse effects
– BM suppression (leukopenia, thrombocytopenia,
both)
– GI toxicity, mild hepatotoxic
– Serious infections (due to immunosuppressive
action)
– Mutagenic & carcinogenic
Mycophenolate Mofetil
• By effectively inhibiting de novo purine
synthesis it can impair the proliferation of both
T & B-lymphocytes
• Combination with cyclosporine + corticosteroids
in the prevention of organ rejection in patient
renal & cardiac transplants
• Almost completely absorbed from GI,
metabolized (liver) to mycophenolic acid
(active), then to inactive glucuronide
• GI side effect are most common
Other cytotoxic drugs
• Cyclophosphamid (cycle specific agent)
• Methotrexate (phase specific agent)
• Chlorambucil (alkylating agent)
Antibodies
• Antiserum can used against lymphocytes
or thymocytes
• Can suppres cellular & often humoral
immunity against a variety of tissue graft
system
• Responses are variable
Antibodies (con’t…)
• Examples:
– Antithymocyte globulin
Has been used successfully alone/combination
with azathioprine + corticosteroids

– Muromonab (CD3)
For preventing rejection in kidney, liver, cardiac
and BM transplantation

– RHO(D) immunoglobulin
Human IgG that contains a high titer of antibodies
againts the Rh(D) red cell antigen
Individual drugs used to stimulasi
the immune system
Bacillus Calmette Guerin (=BCG)
• BCG is a viable attenuated strain of
M.bovis
• The smallest active compound is muramyl
dipeptide

• Target cell:
– T-cell (principal target)
– Natural killer cell (NK-cell)
BCG (con’t…)
• BCG Immunotherapy, successful in the
treatment of bladder cancers
• Adverse effects
– Severe hypersensitivity & shock (most
dangerous)
– Chills, fever, malaise, immune complex &
renal disease
– ROA influences the nature of the side effect
Levamizole
• Originally, developed as an antihelminthic drug
• It potentiates the stimulatory effect of
antigens, mitogens, lymphokines & CTF on
lymphocytes, granulocytes & macrophage

• It has been shown to  T-cell mediated

immunity
• Clinical uses:
– Chronic infections (succesfull)
– Combination + FU, has been approved in the
treatment of colorectal cancer
Immune globulin
• Isolated from pooled human plasma
donors (general population/
hyperimmunized donors)
• Clinical uses:
– Primary humoral immunodeficiency
– Congenital agammaglobulinemia
– Common variable immunodeficiency
– Severe combined immunodeficiency
– Idiopathic thrombocytopenic purpura (=ITP)
– Autoimmune hemolytic anaemia
Immune globulin (con’t…)
• Principal side effects
– Anaphylactoid reactions
– Severe hypotension
Thymic factors (=TF)
• Substances that promote differentiation of T-
Lymphocytes & early stem cells into
prothymocytes
• Available preparation
– Thymic humoral factor
– Thymosin fraction s
– thymodulin

• By promoting the formation of T-lymphocytes,

TF are used to  T-lymphocytic functions
TF (con’t…)
• Clinical uses:
– Severe combined immunodeficiency
– Di George’s or Nezelof’s syndrome
– Viral disorders
– Thymodulin promising in treating symptoms in
asthmatics & allergic rhinitis

• The primary consideration in the use of TF for

immunodeficiency states is the presence of T-
lymphocyte precursors

• Side effect
Allergic disorder
Cytokines
• Interleukin-2 (IL-2/proleukin) &
recombinant IL-2 (rIL-2)
• Myeloid colony-stimulating factors
• Other cytokines
• Human recombinant interferon- (rIFN-
)
• rIL-1
• rIL-6
Interleukin-2
• IL-2 (proleukin) is a cytokine that promotes the
proliferation, differentiation & recruitment of:
- T & B lymphocyte
- Natural killer cell (NK-cells)

- Thymocytes
• Human recombinant IL-2 (rIL-2) binds to IL-2
receptors on responsive cell and induces:
- Proliferation & differentiation of T-helper
cells & T-cytotoxic cells
- B-lymphocyte proliferation, activate
macrophage activity &  cytotoxicity of NK-cells
IL-2 (con’t…)
• Clinical uses of rIL-2:
– Systematically as an immunostimulating agent in
AIDS patients &  specific antitumor immunity
– Effectively treated renal cell carcinoma or
melanoma (combined with adoptive transfer
immunotherapy

• Adverse effects of systemic rIL-2:

– Fever, nausea, vomiting, fatigue, malaise
– Flushing, diarrhea, chills, rash, edema, symptomatic
hypotension, renal disorders
– Occurs at increased dosage
Myeloid Colony Stimulating Factors
(myeloid CSF)
• Recombinant granulocyt macrophage CSF (GM-
CSF) & granulocyt CSF (G-CSF) are
cytokines/growth factors that support survival,
clonal expansion & differentiation of
hematopoietic cells
• Normally produced in the body by monocytes,
fibroblast & endothelial cells
• GM-CSF induces bone marrow progenitor cells
• G-CSF induces maturation of granulocyte
progenitor cells
M-CSF (con’t…)
• General indications:
Acceleration of the recovery of circulating
white blood cells in patients who have
depressed haematopoiesis
• Adverse effect (AE):
– Diarrhea, asthenia, rash, malaise, fever,
headache, bone pain, chills, myalgia
– Many AE can be ameliorated by analgesic-
antipyretics
Table.Clinical indications of M-CSF

M-CSF INDICATIONS
G-CSF, GM-CSF • Autologous allogenic BM tranplant
• HIV infections
• Primer for stem cell collection
• Acute myeloid leukemia
GM-CSF • Aplastic anemia
• Myelodysplasia
G-CSF Congenital neutropenia
Chemotherapy induced neutropenia
Cyclic neutropenia
Other cytokines
• Human recombinant interferon- (rIFN-
) & rIL-1 show promise as
immunostimulators, principally as
adjuvants in the treatment of viral &
malignant disorders
• rIFN- :
– Produced by leukocytes & inhibits viral DNA
& RNA replication
– At lower doses, stimulate macrophage, T-
lymphocyte & NK-cell activity
Other cytokines (con’t…)
• rIL-1
– Produced by macrophage in the host and is
necessary for activation & development of
immune cells
– IV  general augmentation of immune
responses
• rIL-6
Stimulates lymphocytes & megakaryocyte
proliferation
• rIL-6 & rIL-3 are ongoing trial