Download Immunomodulators

Definition
 An immunomodulator is a substance(eg. a drug)
which has an effect on the immune system.
2 types
 Immunosuppressants
 Immunostimulants
The Immune Response - why and how ?
 Discriminate: Self / Non self
 Destroy:
 Infectious invaders
 Dysregulated self (cancers)
 Immunity:
 Innate, Natural
 Adaptive, Learned
Mechanisms of
immunomodulation
 Drugs may modulate immune mechanism by either
suppressing or by stimulating one or more of the following
steps:
 Antigen recognition and phagocytosis
 Lymphocyte proliferation/differentiation
 Synthesis of antibodies
 Ag –Ab interaction
 Release of mediators due to immune response
 Modification of target tissue response
 The importance of immune system in protecting the
body against harmful molecules is well recognized
 However, in some instances, this protection can result
in serious problems
 E.g, the introduction of allograft can elicit a damaging
immune
response
transplanted tissue
causing
rejection
of
the
IMMUNOSUPPRESSANTS
 The importance of the immune system
 In protecting the body against harmful foreign molecules is well
recognized.
 However, in some instances, this protection can result in
serious problems.
 For example, the introduction of an allograft (that is, the graft of
an organ or tissue from one individual to another who is not
genetically identical) can elicit a damaging immune response,
causing rejection of the transplanted tissue.
 Transplantation of organs and tissues (for example, kidney,
heart, or bone marrow)
 Has become routine due to improved surgical techniques and
better tissue typing.
 Also, drugs are now available that more selectively inhibit
rejection of transplanted tissues while preventing the patient
from becoming immunologically compromised.
 Earlier drugs were nonselective
 Patients frequently succumbed to infection due to
suppression of both the antibody-mediated (humoral) and
cell-mediated arms of the immune system.
 Today, the principal approach to immunosuppressive
therapy
 To alter lymphocyte function using drugs or antibodies
against immune proteins.
 Because of their severe toxicities when used as
monotherapy,
 A combination of immunosuppressive agents, usually at
lower doses, is generally employed.
 Immunosuppressive drug regimens
 Consist of anywhere from two to four agents
 With different mechanisms of action that disrupt various
levels of T-cell activation.
IMMUNE ACTIVATION CASCADE
 A three-signal model.
 Signal 1
 Constitutes T-cell triggering at the CD3 receptor complex by an
antigen on the surface of an antigen-presenting cell (APC).
 Signal 2, also referred to as costimulation,
 Occurs when CD80 and CD86 on the surface of apcs engage CD28
on T cells.
 Both Signals 1 and 2
 Activate several intracellular signal transduction pathways,
 one of which is the calcium calcineurin pathway

Which is targeted by cyclosporine and tacrolimus.
 These pathways trigger the production of cytokines such as
interleukin (IL)-2, IL-15, CD154, and CD25.
 IL-2 then binds to CD25 (also known as the IL-2 receptor) on the
surface of other T cells to activate mammalian target of rapamycin
(mTOR)
 Providing Signal 3, the stimulus for T-cell proliferation.
IMMUNOSUPPRESSANT DRUGS
 These categorized according to their MOA:
1.
2.
3.
Some agents interfere with cytokine production or action
(Calcineurin inhibitors/specific T-cell inhibitors)
Others disrupt cell metabolism, preventing lymphocyte
proliferation (cytotoxic drugs)
Mono, and polyclonal antibodies block T cell surface
molecules (antibodies)
IMMUNOSUPPRESSANT DRUGS CLASSIFICATION
1.
Calcineurin inhibitors (specific T –cell inhibitors):

Cyclosporine, Tacrolimus
2. M-TOR inhibitorsSirolimus, Everolimus
3. Antiproliferative drugs (cytotoxic drugs)

Azathioprine,
cyclophosphamide,
methotrexate,
chlorambucil, mycophenolate mofetil (MMF)
4. Glucocorticoids

Prednisolone and others
5. Biological agents TNFα inhibitors Etanercept, Infliximab, Adalimumab
 IL-1 receptor antagonist:
 Anakinra, Rilonacept
 IL-2 receptor antagonist:
 Daclizumab, Baciliximab
 Monoclonal antibodies Anti CD3 antibody:


Muromonab
Anti CD52 antibody:

Alemtuzumab
 Polyclonal Antibodies:

Antithymocyte Antibody (Atg), Rho (D) immuneglobulin.
///////////////////////
Philip F. Halloran:N Engl J Med 2004;351:2715-29
Immunosuppressants
 Organ transplantation
 Autoimmune diseases
Problem
 Life long use
 Infection, cancers
 Nephrotoxicity
 Diabetogenic
SELECTIVE INHIBITORS OF CYTOKINE PRODUCTION
AND FUNCTION
 Cytokines are soluble, antigen-nonspecific, signaling proteins
 That bind to cell surface receptors on a variety of cells.
 The term cytokine includes the molecules known as
 Interleukins (ILs), interferons (IFNs), tumor necrosis factors
(TNFs), transforming growth factors, and colony-stimulating
factors.
 IL-2, a growth factor
 That stimulates the proliferation of antigen-primed (helper) T
cells
 Which subsequently produce more IL-2, IFN-γ, and TNF-a.
 These cytokines collectively activate
 Natural killer cells, macrophages, and cytotoxic T lymphocytes.
 Drugs that interfere with the production or activity of IL-2,
 Such as cyclosporine, will significantly dampen the immune
response and, thereby, decrease graft rejection.
CYCLOSPORINE
 Cyclic peptide composed of 11 aa
 Extracted from a soil fungus
 Selectively inhibit
 T lymphocyte proliferation
 IL-2 & other cytokine production
 Response of inducer T cells to IL-1, without any effect
on suppressor T cells.
 Lymphocytes are arrested at G0 or G1 phase
MECHANISM OF ACTION
 Cyclosporine preferentially suppresses cell mediated
immune reactions
 humoral immunity is affected to a far lesser extent.
 After diffusing into the T cell,
 Cyclosporine binds to a cyclophilin (called an immunophilin)
 To form a complex that binds to calcineurin.
 The latter is responsible for dephosphorylating NFATc (cytosolic
Nuclear Factor of Activated T cells).
 Because the cyclosporine-calcineurin complex cannot
perform this reaction,
 NFATc cannot enter the nucleus
 To promote the reactions that are required for the synthesis of a
number of cytokines, including IL-2.
 The end result is a decrease in IL-2
 Which is the primary chemical stimulus for increasing the
number of T lymphocytes.
Activated T cells
produces IL2 via Dephosphorilation of NAFT
(nuclear factor activated T cell - a cytoplasmic transcription factor)
Calceneurin is needed for dephosphorilation
(Cytoplasmic Phosphatase)
Translocates to nucleus
Transcriptin of IL2 gene.
• Cyclosporine bind s to cyclophilin - binding protein.
• Tacrolimus binds to FKBP – FK binding protein.
(nuclear factor activated T cell)
TOXICITY : CYCLOSPORINE
 Renal dysfunction
 Tremor
 Hirsuitism (abnormal growth of hair on a woman's face





and body.)
Hypertension
Hyperlipidemia
Gum hyperplasia (Increase in the size of the gingiva
(gums).)
Hyperuricemia (abnormally high level of uric acid in the
blood)- worsens gout
Calcineurin inhibitors + Glucocorticoids = Diabetogenic
USES
 To prevent rejection of kidney, liver, cardiac, BM and
other allogeneic transplants.
 More
effective
admininistered.
when
glucocorticoids
are
also
 Useful in autoimmune disease as well.
 Alternative to methotrexate for the treatment of severe,
active RA.
 2nd line drug for uveitis, bronchial asthma, etc.
TACROLIMUS
 Structure-macrolide like
 Chemically different
immunosuppressant
from
cyclosporine,
newer
 Macrolide that is isolated from soil fungus
Mechanism
 Similar to cyclosporine except binds to different protein FK-
506 binding protein that inhibits calcineurin.
 Inhibits synthesis and release of IL-2
CLINICAL APPLICATION
 Approved for the prevention of rejection of liver and
kidney transplants
 Given with a corticosteroid and/or an antimetabolite.
 Favor over cyclosporine, Because of
 Its potency
 Decreased episodes of rejection
 Also lower doses of corticosteroids can be used

Thus reducing the steroid-associated adverse effects.
ADVERSE EFFECTS
 Nephrotoxicity and neurotoxicity (tremor, seizures,
and hallucinations)
 Development of post transplant, insulin-dependent
diabetes mellitus.
 Other toxicities are the same as those for cyclosporine
 Except that tacrolimus does not cause hirsutism or gingival
hyperplasia.
 Have a lower incidence of cardiovascular toxicities
 Such as hypertension and hyperlipidemia
 Anaphylactoid reactions to the injection vehicle.
M-TOR INHIBITORS-SIROLIMUS
 Structure-macrolide like (Multi-membered lactone ring )
 Triene macrolide antibiotic
 From Streptomyces hygroscopicus
MECHANISM OF ACTION
 Sirolimus and tacrolimus bind to the same cytoplasmic FK



binding protein
But instead of forming a complex with calcineurin
Sirolimus binds to mTOR, interfering with Signal 3.
The latter is a serine-threonine kinase.
TOR proteins are essential for
 Many cellular functions, such as cell-cycle progression, DNA
repair, and as regulators involved in protein translation.
 Binding of sirolimus to mTOR
 Blocks the progression of activated T cells from the G1 to the S
phase of the cell cycle and, consequently, the proliferation of these
cells.
 Unlike cyclosporine and tacrolimus,
 Sirolimus does not owe its effect to lowering IL-2 production but,
rather, to inhibiting the cellular responses to IL-2.
ADVERSE EFFECTS
 A common adverse effect
 Hyperlipidemia (elevated cholesterol and triglycerides)
 The combination of cyclosporine and sirolimus
 More nephrotoxic
 Necessitating lower doses.
 Other untoward problems are
 Headache, nausea and diarrhea, leukopenia, and
thrombocytopenia.
 Impaired wound healing in obese patients and those with
diabetes.
CLINICAL APPLICATION
 Approved for use in renal transplantation
 To be used together with cyclosporine and corticosteroids.
 The combination of sirolimus and cyclosporine
 Synergistic
 Because sirolimus works later in the immune activation
cascade.
 The antiproliferative action of sirolimus has found
use in cardiology.
 Sirolimus-coated stents
vasculature
inserted
into
the
cardiac
 Inhibit restenosis
of the blood vessels by reducing
proliferation of the endothelial cells.
 In addition to its immunosuppressive effects
 Also inhibits proliferation of cells in the graft intimal areas
 Thus, is effective in halting graft vascular disease.
EVEROLIMUS
 Another mTOR inhibitor,
MECHANISM OF ACTION:
Same mechanism of action as sirolimus.
It inhibits activation of T cells by forming a complex with FKBP-12
and subsequently blocking mTOR.


CLINICAL APPLICATION:
 Approved for use in renal transplantation.
 in combination with basiliximab, cyclosporine, and corticosteroids
 It is also indicated for second-line treatment in patients with advanced
renal cell carcinoma.
ADVERSE EFFECTS:
 Adverse effects similar to sirolimus.
 An additional adverse effect


Angioedema
kidney arterial and venous thrombosis.
azathiopurine
 Antimetabolite
 DESCRIPTION
 Prodrug that releases 6-mercaptopurine
 Widespread use in organ transplantation
 MECHANISM
 Purine synthesis inhibitor
 Inhibiting the proliferation of cells, especially leukocyte.
 Converts 6-mercaptopurine to tissue inhibitor of
metalloproteinase, which is converted to thioguanine
nucleotides that interfere with DNA synthesis; thioguanine
derivatives may inhibit purine synthesis
 Prevents mitosis and proliferation of rapidly dividing cells,
such as activated B and T lymphocytes
•Azathioprine is metabolized to 6-mercaptopurine (6-MP), which is either inactivated by
two enzymes, thiopurine s-methyltransferase (TPMT) and xanthine oxidase (XO), or is
further metabolized to thioinosine monophosphate (TIMP).
azathiopurine
 Prescribed for
 FDA :


Renal transplantation
Rheumatoid Arthritis
 Non-FDA :
 Multiple Sclerosis (disease involving damage to the sheaths of
nerve cells in the brain and spinal cord),
 Crohn's disease (a chronic inflammatory disease of the intestines,
especially the colon and ileum)
 Myasthenia gravis, chronic ulcerative colitis, and autoimmune
hepatitis
 Side effect
 Leukopenia, bone marrow depression, liver
(uncommon); blood-count monitoring required
toxicity
CYCLOPHOSPHOMIDE
 More marked effect on B cells and humoral immunity.
 Used in BM transplantation in which short course with
high dose is given.
 In other organ transplantations it is employed only as a
reserve drug.
 In RA, it is rarely used.
 Low doses are occasionally employed for maintenance
therapy in SLE (autoimmune disease affect the skin,
joints, kidneys, brain, and other organs.) and
thrombocytopenic purpura.
METHOTREXATE
 Folate antagonist
 Markedly depresses
cytokine production and cellular
immunity and has anti-inflammatory property
 Used as 1st line drug in many autoimmune diseases like
rapidly progressing RA, severe psoriasis (a skin disease
marked by red, itchy, scaly patches), myasthenia gravis,
uveitis, chronic active hepatitis
 Low dose as maintenance therapy is relatively well
tolerated.
MYCOPHENOLATE MOFETIL
MECHANISM: As an ester, it is rapidly hydrolyzed in the GI tract to mycophenolic acid.
 Mycophenolic acid is quickly and almost completely absorbed after oral
administration.
 This is a potent, reversible, noncompetitive inhibitor of inosine
monophosphate dehydrogenase, which blocks the de novo formation of
guanosine phosphate.
 Thus,like 6-MP, it deprives the rapidly proliferating T and B cells of a
key
component of nucleic acids.
ADR:
 Most common adverse effects:

GI, including diarrhea, nausea, vomiting, and abdominal pain.
 High doses of mycophenolate mofetil

Associated with a higher risk of CMV infection.
CLINICAL APPLICATION: Replaced azathioprine because of its safety and effcacy in prolonging
graft survival.
 It has been successfully used in heart, kidney, and liver transplants.
GLUCOCORTICOIDS
 Potent immunosuppressant and antiinflammatory
MECHANISM:
 Inhibits several components of the immune response
 They particularly (-) MHC expression and proliferation of T
lymphocytes.
 Expression of several IL and other cytokine genes is
regulated by corticosteroids.
 The short lived rapid lymphopenic effect of steroids is due
to sequestration of lymphocytes in tissues.
Inhibition of gene expression
Glucocorticoids
Steroid hormones, have broad anti inflammatory activity.
Binds with glucocorticoid receptor.
glucocorticoid - glucocorticoid receptor complex translocate to nucleus.
Binds to GREs in specific genes
( glucocorticoid response elements)
Regulates the gene expression
down regulate the inflammatory mediators.
(IL1, IL4 TNFα etc.)
USES - GLUCOCORTICOIDS
 Transplant rejection
 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
IL-2 RECEPTOR ANTIBODIES
BASILIXIMAB
MECHANISM:-
_ Chimeric murine monoclonal antibody against human IL-2
receptor alpha subunit of activated T to block T cell
_ Blocks activation and inhibits clonal expansion of T cells
 Blockade of this receptor foils the ability of any antigenic
stimulus to activate the T-cell response system.
 GI toxicity as the main adverse effect.
USE:
_ Used to induce immunosuppression and to prolong organ
transplants in combination with immunosuppressants.
DACLIZUMAB
DESCRIPTION
 Humanized
monoclonal
antibody
(interleukin-2– receptor α chain)
against
CD25
MECHANISM
 Binds to and blocks the interleukin-2– receptor α chain
(CD25 antigen) binds with high-affinity to the Tac subunit of
the high-affinity IL-2 receptor complex and inhibits IL-2
binding
 on activated T cells, depleting them and inhibiting
interleukin-2–induced T-cell activation
DACLIZUMAB
PRESCRIBED FOR
• Renal, cardiac transplant
SIDE EFFECT
 Hypersensitivity reactions (uncommon)
 Gastrointestinal disorders
 Does not appear to increase the incidence of opportunistic
infections or malignancies
CYTOKINE INHIBITORS
 TNF inhibitors (disease modifiers to treat rheumatoid
arthritis)
 Etanercept

Recombinant version of TNF receptor
 Infliximab
Chimeric human/murine anti-TNF monoclonal
antibody
 Anakinra

 Human IL-1 receptor antagonist
 Disease modifier agent for Rheumatoid arthritis
MUROMONAB-CD3
 Description
 Murine monoclonal antibody against CD3 component of Tcell–receptor signal-transduction complex
 Mechanism
 Monoclonal IgG2a antibody
 Binds to the T cell receptor-CD3-complex on the surface of
circulating T cells, interfering with the receptor-antigeninteraction
 Resulting in a transient activation of T cells, release of
cytokines, and blocking of T-cell proliferation and
differentiation
 T-cell function usually returns to normal within
approximately 48 hours of discontinuation of therapy.
MUROMONAB-CD3
 PRESCRIBED FOR
 Renal, heart and liver transplant
 SIDE EFFECT
 Severe cytokine-release syndrome, pulmonary edema,
acute renal failure, gastrointestinal disturbances, changes
in central nervous system
 Pyrexia(fever),myalgia, nausea and diarrhoea
ALEMTUZUMAB
 DESCRIPTION
 Humanized monoclonal antibody against
CD52, a 25-to-29-kD membrane protein
 MECHANISM
 Binds to CD52 on all B and T cells, most
monocytes, macrophages, and natural killer
cells, causing cell lysis and prolonged
depletion
ALEMTUZUMAB
 PRESCRIBED FOR
 CLL and T cell lymphoma
 SIDE EFFECT
 Hypotension, fever, shortness of breath, bronchospasm,
chills, and/or rash
POLYCLONAL ANTIBODY
 Antithymocyte
Antithymocyte
Thymoglobulin®)
 Description
globulin-equine
globulin-rabbit
(Atgam®),
(RATG,
 Polyclonal antibodies are directed against lymphocyte
antigens, directed against multiple epitopes
POLYCLONAL ANTIBODY
 MECHANISM
 Agents contain antibodies specific for many common T cell
antigens including CD2, CD3, CD4, CD8, CD11a, CD18
 Effectively depletes T-cell concentration in the body
through complement-dependent cytolysis and cell
mediated opsonization
 Following with T cell clearance from the circulation by the
reticuloendothelial system
POLYCLONAL ANTIBODY
 SIDE EFFECT
 Leukopenia
 serum sickness (cross-reactivity with other tissue antigens)
 adversely affects the ability of the patient to make
antibodies against foreign protein
 thrombocytopenia
 pruritis
 fever
 arthralgias
 opportunistic infections
 malignancies
ANTI –D IMMUNEGLOBULIN
 Human Ig G having high titre of antibodies against Rh
(D) antigen
 It binds the Rho Ag (-) antibody formation in Rh -ve
individuals
 It is used for prevention of postpartum /post –abortion
formation of antibodies in Rho-D negative.
 Administered within 72 hrs of delivery /abortion, such
treatment prevents Rh hemolytic disease in future
offspring.
 It has also been given at 28th week of pregnancy
 Never be given to Rh +ve individuals
THANK YOU
-PHARMA WORLD