Immunomodulator Drugs

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
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
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 -prevention of
transplant rejection
useful in the treatment of autoimmune
disease -RA, SLE, uveitis, IDD, psoriatik
arthropathies
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