2. Definition
• An immunomodulator is a substance(eg. a drug)
which has an effect on the immune system.
2 types
• Immunosuppressants
• Immunostimulants
3. The Immune Response - why and how ?
• Discriminate: Self / Non self
• Destroy:
– Infectious invaders
– Dysregulated self (cancers)
• Immunity:
– Innate, Natural
– Adaptive, Learned
4.
5. 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
6. • 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 causing rejection of
the transplanted tissue
8. IMMUNOSUPPRESSANT DRUGS
• These categorized according to their MOA:
– 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)
12. CYCLOSPORINE
• Cyclic peptide composed of 11 aa
• Extracted from a soil fungus
• Selectively (-) 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
13. Mechanism of action
• It’s bind to the cytosolic protein cyclophilin
(immunophilin) of immunocompetent
lymphocytes, especially T-lymphocytes.
• This complex of cyclosporine and cyclophilin (-)
calcineurin, which, under normal circumstances, is
responsible for activating the transcription of IL 2.
• It also (-) lymphokine production and IL release, leads
to a reduced function of effector T-cells. It does not
affect cytostatic activity.
14.
15. CYCLOSPORINE
Cont…
• to prevent rejection of kidney, liver, cardiac, BM and
other allogeneic transplants
• Can be used alone
• More effective when glucocorticoids are also admini
• Most active when admini before antigen exposure
• Useful in autoimmune disease as well
• Alternative to methotrexate for the treatment of
severe, active RA
• 2nd line drug for uveitis, bronchial asthma, etc.
• Selectively suppresses CMI
16. CYCLOSPORINE
Cont…
• Prevents graft rejection and yet leaves the
recipient with enough immune activity
• Humoral immunity remains intact
• Free of toxic effects on BM and RE system
• For induction it is started orally 12 hrs before the
transplant and continued for as long as needed
• When graft rejection has started, it can be given
i.v
• Concentrated in RBCs and WBCs
• Metabolized in liver excreted in bile
• Biphasic t1/2: 4 -6hrs and 12 -18hrs
18. CYCLOSPORINE
Cont…
Drug interactions:
• All nephrotoxic drugs like
AGs, vancomycin, amphotericin B, and NSAIDs
↑ss its toxicity
• By depressing renal function can reduce
excretion of many drugs
• Enzyme inducers ↓ their levels –transplant
rejection
• Erythromycin, ketaconozole and related drugs
↑ their levels –toxicity
19. Tacrolimus (FK506)
• Chemically different from cyclosporine, newer
immunosuppressant
• Macrolide that is isolated from soil fungus
• Same MOA, 100 times more potent
• orally as well as i.v infusion
• Metabolized by CYP3A4 and excreted in bile
and plasma t1/2 is 12hrs
• Clinical efficacy as well as toxicity profile are
similar to cyclosporine
20. Antiproliferative drugs
Azathioprine:
• Purine antimetabolite, which has more
marked immunosuppressant than anti tumor
action
• The basis for this difference is not clear
• It selectively affects differentiation and
function of T –cells and (-) cytolytic
lymphocytes
21. Antiproliferative drugs: Azathioprine
• The most important application is prevention
of renal and other graft rejection
• But less effective than cyclosporine, generally
combined or used in pts developing
cyclosporine toxicity
• Used in progressive RA and some other auto
immune diseases
22. 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 pemphigus, SLE and
idiopathic thrombocytopenic purpura
23. 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, pemphigus, myasthenia gravis, uveitis,
chronic active hepatitis
• Low dose as maintenance therapy is relatively
well tolerated
24. Mycophenolate mofetil (MMF)
• Prodrug (mycophenelic acid)
• New immunosuppressant
• Selectively (-) inosine monophosphate dehydrogenase an
enzyme essential for denovo synthesis of guanosine
nucleotides in the T&B cells
• Lymphocyte proliferation, ab production and CMI are
inhibited
• Add on drug to Cyclo+gluco in renal transplantation
• It good or even superior to azathioprine, but should not be
combined with it
• Can help to reduce the dose of cyclosporine and thus its
toxicity
• Vomiting, diarrhoea, leucopenia and predisposition to CMV
infection, g.i. bleeds are the prominent A/E
25. Glucocorticoids
• Potent immunosuppressant and
antiinflammatory
• 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
26. Glucocorticoids
Cont…
• Widely employed as companion drug to
cyclosporine in various drug transplantations
• In case graft rejection sets in –large doses of
corticosteroids i.v. are employed for short
periods
29. Immunosuppressant antibodies
MUROMONAB CD3
• Muromonab CD3 ,used as induction therapy together
with cortico & azathioprine with delayed use of
cyclosporine in sequential regimen for organ
transplantation
• This serves to postpone potential nephro and
hepatotoxicity of cyclosporine
• Initial doses of muromonab CD3 are associated with flu
like symptoms: chills, rigor and wheezing
• Occasionally aseptic meningitis, intragraft thrombosis,
pulmonary edema, seizures and a shock like state are
produced
• High dose of corticosteroid pretreatment reduces the
reaction
31. Uses
• Treatment of acute organ transplant rejection
Toxicity
• “Cytokine release syndrome”
• High fever, Chills, Headache, Tremor, myalgia,
arthralgia, weakness
32. Antithymocyte globulin (ATG)
• Polyclonal Ab purified from horse or rabbit
immunized with human thymic lymphocytes
which binds to T lymphocytes and depletes
them
• Potent immunosuppressant and has been
used primarily to suppress acute allograft
rejection episodes especially in steroid
resistant cases or is combined with them
• It has the potential to produce serum sickness
or anaphylaxis but is less expensive than
muromonab CD3
33. 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, DU -ve women who delivered or
aborted an Rho-D +ve, DU +ve baby/ foetus
34. Anti –D immuneglobulin
Cont…
• 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 /DU +ve individuals
35. Sites of Action of Selected Immunosuppressive Agents on
T-Cell Activation
DRUG
•
•
•
•
•
•
•
•
Glucocorticoids
MuromonabCyclosporine
Tacrolimus
Azathioprine
Mycophenolate Mofetil
Daclizumab, Basiliximab
Sirolimus
SITE OF ACTION
•
•
•
•
•
•
•
•
Glucocorticoid response elements in
DNA (regulate gene transcription)
CD3T-cell receptor complex (blocks
antigen recognition)
Calcineurin (inhibits phosphatase
activity)
Calcineurin (inhibits phosphatase
activity)
Deoxyribonucleic acid (false nucleotide
incorporation)
Inosine monophosphate
dehydrogenase (inhibits activity)
IL-2 receptor (block IL-2-mediated T-cell
activation)
Protein kinase involved in cell-cycle
progression (mTOR) (inhibits activity)
37. Cytokines
•
•
•
•
INF
IL
TNF
Hemopoietic growth factors (G-CSF, M-CSF, GMCSF, etc)
• These are now available for use by rDNA
technology
• Applications in the treatment of viral infections,
autoimmune and neoplastic diseases
38. Levimazole
• An antihelminthic
• Appears to enhance the magnitude of T –cell
mediated immunity
• It has been tried in some immunodeficiency
diseases, RA and post surgery and colorectal
cancer
39. BCG and other adjuvants
• BCG and other microbial products (picibanil,
lentinan and pachymaran) are being tried as
adjuvants and probably act by activation of
macrophages
The transplant of an organ or tissue from one individual to another of the same species with a different genotype. For example, a transplant from one person to another, but not an identical twin, is an allograft. Allografts account for many human transplants, including those from cadaveric, living related, and living unrelated donors. Also known as an allogeneic graft or a homograft.
