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IMMUNOMODULATORS
Definition
• An immunomodulator is a substance(eg. a drug)
which has an effect on the immune system.
2 types
• Immunosuppr...
The Immune Response - why and how ?
• Discriminate: Self / Non self
• Destroy:
– Infectious invaders
– Dysregulated self (...
Mechanisms of immunomodulation
• Drugs may modulate immune mechanism by either suppressing or

by stimulating one or more ...
• The importance of immune system in protecting
the body against harmful molecules is well
recognized
• However, in some i...
Immunosuppressants
IMMUNOSUPPRESSANT DRUGS
• These categorized according to their MOA:
– Some agents interfere with cytokine production or
ac...
IMMUNOSUPPRESSANT DRUGS Cont…
1. Calcineurin inhibitors (specific T –cell inhibitors):
–

Cyclosporine, Tacrolimus and Sir...
Immunosuppressants
• Organ transplantation
• Autoimmune diseases

Problem
•
•
•
•

Life long use
Infection, cancers
Nephro...
CYCLOSPORINE
• Cyclic peptide composed of 11 aa

• Extracted from a soil fungus
• Selectively (-) T lymphocyte proliferati...
Mechanism of action
• It’s bind to the cytosolic protein cyclophilin

(immunophilin) of immunocompetent
lymphocytes, espec...
CYCLOSPORINE

Cont…

• to prevent rejection of kidney, liver, cardiac, BM and
other allogeneic transplants
• Can be used a...
CYCLOSPORINE

Cont…

• Prevents graft rejection and yet leaves the
recipient with enough immune activity
• Humoral immunit...
Toxicity : Cyclosporine
•
•
•
•
•
•
•
•

Renal dysfunction
Tremor
Hirsuitism
Hypertension
Hyperlipidemia
Gum hyperplasia
H...
CYCLOSPORINE

Cont…

Drug interactions:
• All nephrotoxic drugs like
AGs, vancomycin, amphotericin B, and NSAIDs
↑ss its t...
Tacrolimus (FK506)
• Chemically different from cyclosporine, newer
immunosuppressant
• Macrolide that is isolated from soi...
Antiproliferative drugs
Azathioprine:
• Purine antimetabolite, which has more
marked immunosuppressant than anti tumor
act...
Antiproliferative drugs: Azathioprine
• The most important application is prevention
of renal and other graft rejection
• ...
Cyclophosphomide
• More marked effect on B cells and humoral
immunity
• used in BM transplantation in which short course
w...
Methotrexate
• Folate antagonist
• Markedly depresses cytokine production and
cellular immunity and has anti-inflammatory
...
Mycophenolate mofetil (MMF)
• Prodrug (mycophenelic acid)
• New immunosuppressant
• Selectively (-) inosine monophosphate ...
Glucocorticoids
• Potent immunosuppressant and
antiinflammatory
• Inhibits several components of the immune
response
• The...
Glucocorticoids

Cont…

• Widely employed as companion drug to
cyclosporine in various drug transplantations
• In case gra...
USES - Glucocorticoids
• Transplant rejection

• GVH – BM transplantation
• Autoimmune diseases – RA, SLE, Hematological c...
Toxicity
•
•
•
•
•
•
•

Growth retardation
Avascular Necrosis of Bone
Risk of Infection
Poor wound healing
Cataract
Hyperg...
Immunosuppressant antibodies
MUROMONAB CD3
• Muromonab CD3 ,used as induction therapy together
with cortico & azathioprine...
Muromonab-CD3
Antibody treatment
Rapid internalization of T-cell receptor
Prevents subsequent antigen recognition
Uses
• Treatment of acute organ transplant rejection
Toxicity
• “Cytokine release syndrome”
• High fever, Chills, Headache...
Antithymocyte globulin (ATG)
• Polyclonal Ab purified from horse or rabbit
immunized with human thymic lymphocytes
which b...
Anti –D immuneglobulin
• Human Ig G having high titre of antibodies
against Rh (D) antigen
• It binds the Rho Ag (-) antib...
Anti –D immuneglobulin

Cont…

• Administered within 72 hrs of delivery
/abortion, such treatment prevents Rh
hemolytic di...
Sites of Action of Selected Immunosuppressive Agents on
T-Cell Activation
DRUG
•
•
•
•
•
•
•
•

Glucocorticoids
MuromonabC...
Immunostimulants
Cytokines
•
•
•
•

INF
IL
TNF
Hemopoietic growth factors (G-CSF, M-CSF, GMCSF, etc)
• These are now available for use by r...
Levimazole
• An antihelminthic
• Appears to enhance the magnitude of T –cell
mediated immunity
• It has been tried in some...
BCG and other adjuvants
• BCG and other microbial products (picibanil,
lentinan and pachymaran) are being tried as
adjuvan...
Thank you
Immunomodulators(VK)
Immunomodulators(VK)
Immunomodulators(VK)
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Immunomodulators(VK)

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Immunomodulators(VK)

  1. 1. IMMUNOMODULATORS
  2. 2. Definition • An immunomodulator is a substance(eg. a drug) which has an effect on the immune system. 2 types • Immunosuppressants • Immunostimulants
  3. 3. The Immune Response - why and how ? • Discriminate: Self / Non self • Destroy: – Infectious invaders – Dysregulated self (cancers) • Immunity: – Innate, Natural – Adaptive, Learned
  4. 4. 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
  5. 5. • 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
  6. 6. Immunosuppressants
  7. 7. 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)
  8. 8. IMMUNOSUPPRESSANT DRUGS Cont… 1. Calcineurin inhibitors (specific T –cell inhibitors): – Cyclosporine, Tacrolimus and Sirolimus 2. Antiproliferative drugs (cytotoxic drugs) – Azathioprine, cyclophosphamide, methotrexate, chlorambucil, mycophenolate mofetil (MMF) 3. Glucocorticoids – Prednisolone and others 4. Antibodies – Muromonab CD3,antithymocyte globulin (ATG), Rho (D) immunoglobulin
  9. 9. Immunosuppressants • Organ transplantation • Autoimmune diseases Problem • • • • Life long use Infection, cancers Nephrotoxicity Diabetogenic
  10. 10. 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
  11. 11. 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.
  12. 12. 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
  13. 13. 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
  14. 14. Toxicity : Cyclosporine • • • • • • • • Renal dysfunction Tremor Hirsuitism Hypertension Hyperlipidemia Gum hyperplasia Hyperuricemia – worsens gout Calcineurin inhibitors + Glucocorticoids = Diabetogenic
  15. 15. 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
  16. 16. 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
  17. 17. 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
  18. 18. 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
  19. 19. 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
  20. 20. 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
  21. 21. 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
  22. 22. 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
  23. 23. 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
  24. 24. USES - Glucocorticoids • Transplant rejection • GVH – BM transplantation • Autoimmune diseases – RA, SLE, Hematological conditions • Psoriasis • Inflammatory Bowel Disease, Eye conditions
  25. 25. Toxicity • • • • • • • Growth retardation Avascular Necrosis of Bone Risk of Infection Poor wound healing Cataract Hyperglycemia Hypertension
  26. 26. 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
  27. 27. Muromonab-CD3 Antibody treatment Rapid internalization of T-cell receptor Prevents subsequent antigen recognition
  28. 28. Uses • Treatment of acute organ transplant rejection Toxicity • “Cytokine release syndrome” • High fever, Chills, Headache, Tremor, myalgia, arthralgia, weakness
  29. 29. 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
  30. 30. 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
  31. 31. 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
  32. 32. 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)
  33. 33. Immunostimulants
  34. 34. 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
  35. 35. 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
  36. 36. 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
  37. 37. Thank you

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