Immunopharmacology

By: Debela Gemeda

Objectives:
 By the end of this session you will be able to;

• Define immunopharmacology
• Describe some of drugs used in
immunotherapy.
• Identify the therapeutic use, adverse
effect, and mechanism of action of some
Immunosuppressant and
Immunostimulants.
 Outline

• Introduction of Immunopharmacology

• Pharmacology of Immunosuppressants
• Classification
• Mechanism of action
• Clinical use and
• adverse effect of immunosuppressants

• Pharmacology of immunostimulants
Introduction

• Immunopharmacology concerns drugs that

suppress, modulate, or stimulate immune
functions

• Classified based on whether the drug

suppress undesirable immune responses or
enhance or augment immune function

• Immunosuppressive agents

• Immunostimulant
Classifications
Immunosuppressant
• Immunosuppressants are drugs which inhibit
cellular/humoral or both types of immune responses

• Have their major use in organ transplantation and

autoimmune diseases

• They suppress rejection and inhibit the autoimmune

process

• They also lead to the undesired consequences of

immunodeficiency, such as infection or malignancy,
and non-immune toxicity
• Clinically they are used to:
 Prevent the rejection of transplanted organs and
tissues (e.g. bone marrow, heart, kidney, liver)
 Treatment of autoimmune diseases or diseases
that are most likely of autoimmune origin (e.g.
Rheumatoid arthritis, myasthenia gravis,
systemic lupus erythematosus, Crohn's disease,
and ulcerative colitis)
 Treatment of some other non-autoimmune
inflammatory diseases (eg. long term Allergic
• Based on their mechanism of action they can be
classified as:
 Calcineurin inhibitors
• (Specific T-cell inhibitors): Cyclosporine (Ciclosporin),
Tacrolimus
 m-TOR inhibitors: Sirolimus, Everolimus
 Antiproliferative drugs (Cytotoxic drugs)
• Azathioprine, Methotrexate, Cyclophosphamide,
Chlorambucil, Mycophenolate mofetil (MMF)
 Glucocorticoids
Prednisolone and Methylprednisolone
 Biological agents
• TNFα inhibitors: Etanercept, Infliximab, Adalimumab
• IL-1 receptor antagonist: Anakinra
• IL-2 receptor antagonists: Daclizumab,
• anti CD-25 antibodies: Basiliximab
• Anti CD-3 antibody: Muromonab CD3
• Polyclonal antibodies: Antithymocyte antibody (ATG), Rho
Sites of action of immunosuppressants

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Calcineurin inhibitors
• Perhaps the most effective immunosuppressive drugs in
routine use are the calcineurin inhibitors
• Cyclosporine, Tacrolimus

• They target intracellular signaling pathways

induced as a consequence of T-cell-receptor
activation.

• Cyclosporine and Tacrolimus bind to an

immunophilin

• Cyclophilin ……….Cyclosporine

• FK 506- binding protein (FKBP-12) …… Tacrolimus

• Interaction with calcineurin block its
phosphatase activity

• Calcineurin-catalyzed dephosphorylation is
required for movement of a component of the
nuclear factor of activated T lymphocytes (NFAT)
into the nucleus.

• NFAT, in turn, is required to induce a number of

cytokine genes, including that for interleukin-2
(IL-2), a prototypic T-cell growth and
differentiation factor.
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Clinical Uses
• Cyclosporine has been approved for use in allogeneic
kidney, liver, and heart transplant patients and is
under study for use in pancreas, bone marrow, and
single lung, transplant procedures.

• It is recommended that corticosteroids, such as

prednisone, be used concomitantly, although at half
or less of their usual dose
• Fewer side effects
• A decreased incidence of infectious complications
• A better history of patient survival
• Cyclosporine appears to have promise in the
treatment of autoimmune diseases
• Rheumatoid arthritis
• Uveitis
• Insulin dependent diabetes
• Systemic lupus erythematosus, and Psoriatic
• Arthropathies in some patients

• Toxicity is more of a problem in these

conditions than during use in transplantation
Adverse Effects
• Compared with previously available therapy, less
severe but still worthy of concern
• Nephrotoxicity, 75% of patients,
• This effect is generally reversible with dosage
reduction.
• Hypertension , 25%
• More frequently in patients with some degree
of renal dysfunction;
• The concomitant use of antihypertensive
drugs may prove useful.
• Hyperglycemia
• Hyperlipidemia
• Transient liver dysfunction, and
• Unwanted hair growth is also observed
Drug Interactions
• Substances that inhibit CYP3A can decrease
cyclosporine metabolism
• Ca2+ channel blockers (e.g., Verapamil, Nicardipine),
• Antifungal agents (e.g., Fluconazole, Ketoconazole),
• Antibiotics (e.g., erythromycin),
• glucocorticoids (e.g., methylprednisolone),
• HIV-protease inhibitors (e.g., indinavir), and
• Other drugs (e.g., allopurinol, metoclopramide).
• Grapefruit and grapefruit juice block CYP3A and the
multidrug efflux pump.
• Drugs that induce CYP3A activity can increase
cyclosporine metabolism, Such drugs include;-
• Antibiotics (e.g., Nafcillin, Rifampin),
• Anticonvulsants (e.g., Phenobarbital,
Phenytoin), and
• Other drugs (e.g., Octreotide, Ticlopidine).

• In general, close monitoring of cyclosporine

blood levels and the levels of other drugs is
required when such combinations are used.
Mammalian Target Of Rapamycin
(mTOR) inhibitors
• Rapamycin or Sirolimus inhibits a protein
kinase, designated mammalian target of
rapamycin (mTOR) which is involved in the
regulation of translation and by modulating
nuclear events

• Inhibition of mTOR blocks cell-cycle progression at

the G1 to S phase transition

• The drug has been shown to be efficacious in

prolongation of renal-allograft survival
• It blocks IL-2-dependent T-cell
proliferation by inhibiting a cytoplasmic
serine– threonine kinase.
• This mechanism of action is different
from those of tacrolimus and
cyclosporine.
• This allows sirolimus to augment the
immunosuppressive effects of these
drugs.
Sirolimus (rapamycin) works at a later stage in T-cell activation, downstream of the IL-2
receptor. Sirolimus also binds FKBP, but the FKBP- sirolimus complex binds to and inhibits
the mammalian target of rapamycin (mTOR), a kinase involved in cell-cycle progression
(proliferation). TCR, T-cell receptor.

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Antiproliferative drugs

Azathioprine

• is metabolized in the liver to inactive intermediate ( 6-

mercaptopurine), by the enzyme glutathione

• 6-mercaptopurine is further converted in to active

metabolites (6-thioguanine nucleotides) by enzymes

hypoxanthine guanine phosphoribosyl transferase

• These nucleotides act as metabolic analogs and are

thought to be responsible for both the

immunosuppressive activity and toxicity of

azathioprine
• Azathioprine is a phase-specific drug that kills
rapidly replicating cells.

• It inhibits proliferation of both T and B cells

as well as macrophages

• Used in combination with cyclosporine or

prednisone to prevent transplant rejection
and autoimmune disorders

• Toxicity- bone marrow depression and GIT

toxicity
 Mycophenolate mofetil (MMF)
• Releases active mycophenolic acid

• Antimetabolite that inhibit a key enzyme in the

de novo purine biosynthetic pathway (inosine

monophosphate dehydrogenase)

• The proliferation of T cells and B cells is inhibited

selectively compared with that of nonlymphoid

cells because the salvage pathway is

unavailable to lymphocytes
• Is used primarily as an adjunctive agent

in kidney transplantation

• Its use in combination with cyclosporine

or tacrolimus has led to a lower incidence

of acute allograft rejection, reducing the

need for high-dose corticosteroids

Glucocorticoids
• Prednisone, Methylprednisolone, and other used
alone or in combination with other
immunosuppressant for treatment of transplant
rejection and autoimmune disorders

• Although corticosteroids possess immunosuppressive

properties, their real value is in controlling the
inflammation that can accompany transplantation
and autoimmune disorders.

• Corticosteroid therapy alone is successful in only a

limited number of autoimmune diseases
Mechanism of Action

• The specific mechanism(s) of their

immunosuppressive action remains somewhat
elusive.
• Glucocorticoids lyse and induce the redistribution
of lymphocytes, causing a rapid, transient
decrease in peripheral blood lymphocyte counts.
• To affect longer-term responses, steroids bind to
receptors inside cells;
• Glucocorticoid-receptor complexes, curtailing
activation of NF-B, which increases apoptosis
of activated cells.
• Additionally, of central importance, key
proinflammatory cytokines such as;-
• IL-1 and IL-6 are down regulated.

• T cells are inhibited from making IL-2 and

proliferating.
• The activation of cytotoxic T lymphocytes is
inhibited.

• Neutrophils and monocytes display poor

chemotaxis and decreased lysosomal enzyme
release.
Therapeutic Uses

• They commonly are combined with other

immunosuppressive agents to prevent and
treat transplant rejection.

• High dose pulses of IV methylprednisolone

sodium succinate are used to reverse acute
transplant rejection and acute exacerbations
of selected autoimmune disorders.
• They are used routinely to treat autoimmune disorders
such as;-
• Rheumatoid and other arthritides,

• Systemic lupus erythematosus,

• Systemic dermatomyositis,

• Psoriasis and other skin conditions,

• Asthma and other allergic disorders,

• Inflammatory bowel disease,

• Inflammatory ophthalmic diseases,

• Autoimmune hematologic disorders, and

• Acute exacerbations of multiple sclerosis

• In addition, glucocorticoids limit allergic reactions that

Toxicity
• Unfortunately, the extensive use of steroids often results in

disabling and life-threatening adverse effects include;-

• Growth retardation in children, Avascular necrosis of

bone, Osteopenia,

• Increased risk of infection, Poor wound healing, Cataracts,

• Hyperglycemia, and Hypertension.

• The advent of combined glucocorticoid / cyclosporine

regimens has allowed reduced doses of steroids, but steroid-

induced morbidity remains a major problem in many

transplant patients
Antibodies
• Antiserum can be raised against lymphocytes or
thymocytes by the repeated injection of human
cells into an appropriate recipient, usually a horse.

• The use of such antiserum or the immune globulin

fraction derived from it has been used to produce
immunosuppression.
• Antithymocyte globulin (ATG)
• Muromonab-(CD3)
• Rho(D) Immune Globulin
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• Rho(D) immune globulin

• A solution of human IgG globulin containing

antibodies against Rh(D) antigen on RBC
and derived from pooled human blood

• Used for Rh- negative mothers to prevent

sensitization to Rh (D) antigen (blocks
primary antibody response to foreign
antigen)
Monoclonal antibodies
• Are immunoglobulins that are produced exogenously from
a single parent cell
• Are produced by isolating beta cells from immunized
animals and fusing these beta cells with myeloma cells
• During nomenclature the suffix denotes of the degree of
human versus nonhuman components

.
Muromonab-CD3
• A murine monoclonal antibody, is directed
against human CD3 (the T cell receptor)

• Indicated for acute graft rejection refractory to

corticosteroids

• This murine antibody was therapeutically

unsuccessful because after the first few
treatments, patients began developing
antibodies to the murine portions 40

• chimeric and humanized monoclonal antibodies were

developed
Humanized monoclonal antibody

• The human IgG framework (constant regions) have

been substituted for the mouse framework, retaining

the mouse antigen-binding regions and creating a

"chimeric" monoclonal antibody

• Alternatively, the mouse complementarity-determining

regions can be left intact to create a "humanized"

monoclonal antibody

• Humanized or chimeric monoclonal antibodies do not

stimulate the production of neutralizing antibodies and

therefore are not limited by host antibody response

Antithymocyte Globulin
• ATG is purified immune globulin obtained from
hyperimmune serum of horses immunized with
human thymus lymphocytes.

• It has been used successfully alone and in

combination with azathioprine and corticosteroids
to prevent renal allograft rejection.

• Although it has benefits when administered

prophylactically

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• Antithymocyte globulin binds to circulating T
lymphocytes in the blood, which are subsequently
removed from the circulation by the
reticuloendothelial system.

• This globulin also reduces the number of T

lymphocytes in the thymus-dependent areas of the
spleen and lymph nodes.

• Since the preparations are raised in heterologous

species, reactions against the foreign proteins may
lead to serum sickness and nephritis.

• The concomitant use of corticosteroids may alleviate

this response 43
Immunostimulants
Introduction

• Immunostimulants (also known as biological

response modifiers) these drugs enhance the body’s
immune response

• A few immunostimulatory drugs have been

developed with applicability to infection,
immunodeficiency, and cancer.

• The drugs may work on cellular or humoral immune

systems or both
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• They can be extracts and derived from
bacteria, yeast, and fungi.

• They also include a variety of peptides,

cytokines, and synthetic compounds.

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Levamisole
• Levamisole was synthesized originally as an
anthelmintic but appears to "restore" depressed
immune function of B lymphocytes, T lymphocytes,
monocytes, and macrophages.

• Levamisole has been used successfully in treating

chronic infections.

• It also has been approved for use in combination with

fluorouracil in the treatment of colorectal cancer.

• Where it occasionally has been associated with fatal

agranulocytosis.
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Bacillus Calmette-Guérin (BCG)

• Bacillus Calmette-Guérin (BCG) is a viable

attenuated strain of Mycobacterium bovis

• Nonviable strains of the bacterium also have

been shown to augment the immune
response.

• The smallest active compound derived from

BCG thus far has been identified as muramyl
dipeptide.
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• The T cell is a principal target for BCG.

• It also appears to stimulate natural killer cells,

which in turn can kill malignant cells.

• It has been suggested that BCG cross-reacts

immunologically with tumor cell antigens.
• BCG immunotherapy has been most
successful in the treatment of bladder cancers.
• It is instilled directly into the bladder, where
it is held for 2 hours before urination.

• The most dangerous complications of BCG

therapy are;-
• Severe hypersensitivity and shock
• Chills, fever, malaise, and
• Renal disease.

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Cytokines
• An exciting application of immunomodulating
therapy is in the use of cytokines (lymphokines,
monokines).

• Immune cell function is regulated by cytokines

produced by leukocytes or other supporting cells.

• With the advent of genetic engineering,

cytokines can be produced in pure form and in
large quantities

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Interleukin-2
• IL-2 (Proleukin) is a cytokine that promotes the
proliferation, differentiation, and recruitment of T and
B lymphocytes, natural killer cells, and thymocytes.

• Human recombinant IL-2 is designated as rIL-2.

• rIL-2 binds to IL-2 receptors on responsive cells and

• Induces proliferation and differentiation of T

helper cells and T cytotoxic cells.
• It also can induce B-lymphocyte proliferation,
activate macrophage activity, and augment the
cytotoxicity of natural killer cells.
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• rIL-2 is administered systemically as an
immunostimulating agent in patients with AIDS and to
augment specific antitumor immunity

• Patients with renal cell carcinoma or melanoma have

been effectively treated with rIL-2

• Systemic administration of rIL-2 causes;-

• Fever, nausea, vomiting, fatigue, malaise. flushing,

diarrhea, chills, rash, edema, symptomatic
hypotension, and certain renal abnormalities.
• These tend to occur at increased dosage levels
and are attenuated by reducing the dosage.
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• Antibiotics
• Some antibiotics has been shown to enhance
and or restore several immune functions in
vitro and ex vivo and to be effective in various
experimental models of infections
• Cephalosporins (cefodizime, cefpimizole,
cefpimizole)
• Quinolones (ciprofloxacin)

• Macrolides (clarithromycin)
• Major toxicities associated with
immunostimulants
• Acute phase response

• Cell and tissue injury

• Cytokine release/cytokine storm

• Tumor lysis syndrome

• Vascular leak

• Autoimmunity
Thank you