1. IMMUNOMODULATORS
Dr. Manjunath

2. The Immune Response - why and how ?
Discriminate: Self / Non self
Destroy:
Infectious invaders
Dysregulated self (cancers)
Immunity:
Innate, Natural
Adaptive, Learned

3. Who are involved ? Innate Adaptive: Complement Granulocytes
Monocytes/macrophages
NK cells
Mast cells
Basophils
Adaptive:
B and T lymphocytes
B: antibodies
T : helper, cytolytic, suppressor.

5. Immunosuppressants Immunostimulants IMMUNE MODIFIERS
? Immune tolerance

6. Immunosuppressants Glucocorticoids Calcineurin inhibitors
Cyclosporine
Tacrolimus
Antiproliferative / antimetabolic agents
Sirolimus
Everolimus
Azathioprine
Mycophenolate Mofetil
Others – methotrexate, cyclophosphamide, thalidomide and chlorambucil

7. Antibodies Antithymocyte globulin Anti CD3 monoclonal antibody
Muromonab
Anti IL-2 receptor antibody –
Daclizumab, basiliximab
Anti TNF alpha – infliximab, etanercept

8. Immunostimulants Levamisole Thalidomide BCG Recombinant Cytokines
Interferons
Interleukin-2

9. Immunosuppressants Problem Organ transplantation Autoimmune diseases
Life long use
Infection, cancers
Nephrotoxicity
Diabetogenic

10. Glucocorticoids
Induce redistribution of lymphocytes – decrease in peripheral blood lymphocyte counts
Intracellular receptors – regulate gene transcription
Down regulation of IL-1, IL-6
Inhibition of T cell proliferation
Neutrophils, Monocytes display poor chemotaxis
Broad anti-inflammatory effects on multiple components of cellular immunity

11. USES - Glucocorticoids
Transplant rejection
GVH – BM transplantation
Autoimmune diseases – RA, SLE, Hematological conditions
Psoriasis
Inflammatory Bowel Disease, Eye conditions

12. Toxicity Growth retardation Avascular Necrosis of Bone
Risk of Infection
Poor wound healing
Cataract
Hyperglycemia
Hypertension

13. Calcineurin inhibitors
Cyclosporine
Tacrolimus
Most effective immunosuppressive drugs
Target intracellular signaling pathways
Blocks Induction of cytokine genes

15. Cyclosporine
More effective against T-cell dependent immune mechanisms – transplant rejection, autoimmunity
IV, Oral
Uses
Organ transplantation: Kidney, Liver, Heart
Rheumatoid arthritis, IBD, uveitis
Psoriasis
Aplastic anemia
Skin Conditions- Atopic dermatitis, Alopecia Areata, Pemphigus vulgaris, Lichen planus, Pyoderma gangrenosum

16. Toxicity : Cyclosporine
Renal dysfunction
Tremor
Hirsuitism
Hypertension
Hyperlipidemia
Gum hyperplasia
Hyperuricemia – worsens gout
Calcineurin inhibitors + Glucocorticoids = Diabetogenic

17. Drug Interaction : Cyclosporine
CYP 3A4
Inhibitors: CCB, Antifungals, Antibiotics, HIV PI, Grape juice
Inducers: Rifampicin, Phenytoin
Additive nephrotoxicity: NSAIDs

18. Tacrolimus Inhibits T-cell activation by inhibiting calcineurin Use
Prophylaxis of solid-organ allograft rejection

19. Toxicity - Tacrolimus Nephrotoxicity
Neurotoxicity-Tremor, headache, motor disturbances, seizures
GI Complaints
Hypertension
Hyperglycemia
Risk of tumors, infections
Drug interaction
Synergistic nephrotoxicity with cyclosporine
CYP3A4

20. Antiproliferative and Antimetabolic drugs
Sirolimus
Everolimus
Azathioprine
Mycophenolate Mofetil
Others:
Methotrexate
Cyclophosphamide
Thalidomide
Chlorambucil

21. Sirolimus Inhibits T-cell activation and Proliferation
Complexes with an immunophilin, Inhibits a key enzyme in cell cycle progression – mammalian target of rapamycin (mTOR)

23. Sirolimus
Uses
Prophylaxis of organ transplant rejection along with other drugs
Toxicity
Increase in serum cholesterol, Triglycerides
Anemia
Thrombocytopenia
Hypokalemia
Fever
GI effects
Risk of infection, tumors
Drug Interactions: CYP 3A4

24. Everolimus Shorter half life compared to sirolimus
Shorter time taken to reach steady state
Similar toxicity, drug interactions

25. Azathioprine Purine antimetabolite Incorporation of false nucleotide
6 Thio-IMP Thio-GMP Thio-GTP
Inhibition of cell proliferation
Impairment of lymphocyte function
Uses
Prevention of organ transplant rejection
Rheumatoid arthritis

26. Toxicity - Azathioprine
Bone marrow suppression- leukopenia, thrombocytopenia, anemia
Increased susceptibility to infection
Hepatotoxicity
Alopecia
GI toxicity
Drug interaction: Allopurinol

27. Mycophenolate Mofetil
Prodrug  Mycophenolic acid
Inhibits IMPDH – enzyme in guanine synthesis
T, B cells are highly dependent on this pathway for cell proliferation
Selectively inhibits lymphocyte proliferation, function – Antibody formation, cellular adhesion, migration

28. Uses - Mycophenolate Mofetil
Prophylaxis of transplant rejection
Combination: Glucocorticoids
Calcineurin Inhibitors
Toxicity
GI, Hematological
Diarrhea, Leucopenia
Risk of Infection

29. Drug Interaction
Decreased absorption when co-administered with antacids
Acyclovir, Gancyclovir compete with mycophenolate for tubular secretion

30. FTY720 S1P-R agonist – sphingosine 1 receptor
Reduce recirculation of lymphocytes from lymphatic system to blood and peripheral tissues
“Lymphocyte homing” – periphery into lymph node
Protects graft from T-cell-mediated attack
Uses
Combination immunosuppression therapy in prevention of acute graft rejection

31. Toxicity Lymphopenia Negative chronotropic effect
S1P-receptor on human atrial myocytes

32. Antibodies Against lymphocyte cell-surface antigens
Polyclonal / Monoclonal

33. Antibodies Antithymocyte Globulin Monoclonal antibodies
Anti-CD3 Monoclonal antibody (Muromonab-CD3)
Anti-IL-2 Receptor antibody (Daclizumab, Basiliximab)
Campath-1H (Alemtuzumab)
Anti-TNF Agents
Infliximab
Etanercept
Adalimumab
LFA-1 Inhibitor (lymphocyte function associated)
Efalizumab

34. Anti-thymocyte Globulin
Purified gamma globulin from serum of rabbits immunized with human thymocytes
Cytotoxic to lymphocytes & block lymphocyte function
Uses
Induction of immunosuppression – transplantation
Treatment of acute transplant rejection
Toxicity
Hypersensitivity
Risk of infection, Malignancy

35. Anti-CD3 Monoclonal Antibody
Muromonab-CD3
Binds to CD3, a component of T-cell receptor complex involved in
antigen recognition
cell signaling & proliferation

36. Muromonab-CD3 Antibody treatment
Rapid internalization of T-cell receptor
Prevents subsequent antigen recognition

37. Uses Treatment of acute organ transplant rejection Toxicity
“Cytokine release syndrome”
High fever, Chills, Headache, Tremor, myalgia, arthralgia, weakness
Prevention: Steroids

38. Anti-IL-2 Receptor Antibodies
Daclizumab and Basiliximab
Bind to IL-2 receptor on surface of activated T cells  Block IL-2 mediated T-cell activation
Uses
Prophylaxis of Acute organ rejection
Toxicity
Anaphylaxis, Opportunistic Infections

39. Campath-1H (Alemtuzumab)
Targets CD52 – expressed on lymphocytes, monocytes, Macrophages
Extensive lympholysis – Prolonged T & B cell depletion
Uses
Renal transplantation

41. Anti-TNF Agents TNF – Cytokine at site of inflammation Infliximab
Etanercept
Adalimumab

45. Infliximab Uses Rheumatoid arthritis Chron’s disease – fistulae
Psoriasis
Psoriatic arthritis
Ankylosing spondylosis
Toxicity
Infusion reaction – fever, urticaria, hypotension, dyspnoea
Opportunistic infections – TB, RTI, UTI

46. Etanercept Fusion protein
Ligand binding portion of Human TNF-α receptor fused to Fc portion of human IgG1
Uses
Rheumatoid arthritis

48. moderate to severely active crohn’s disease
Adalimumab
Recombinant human anti-TNF mAb
moderate to severely active crohn’s disease

49. LFA-1 Inhibitor - Efalizumab
Monoclonal Ab Targeting Lymphocyte Function Associated Antigen
Blocks T-cell Adhesion, Activation, Trafficking
Uses
Organ transplantation
Psoriasis

50. Sites of Action of Selected Immunosuppressive Agents on
Sites of Action of Selected Immunosuppressive Agents on T-Cell Activation
DRUG SITE OF ACTION
Glucocorticoids Glucocorticoid response elements in DNA (regulate gene transcription)
Muromonab- CD3T-cell receptor complex (blocks antigen recognition)
Cyclosporine Calcineurin (inhibits phosphatase activity)
Tacrolimus Calcineurin (inhibits phosphatase activity)
Azathioprine Deoxyribonucleic acid (false nucleotide incorporation)
Mycophenolate Mofetil Inosine monophosphate dehydrogenase (inhibits activity)
Daclizumab, Basiliximab IL-2 receptor (block IL-2-mediated T-cell activation)
Sirolimus Protein kinase involved in cell-cycle progression (mTOR) (inhibits activity)

51. Immunostimulants Levamisole Thalidomide BCG Recombinant Cytokines
Interferons
Interleukin-2

52. Immunization
Vaccines
Immune Globulin
Rho (D) Immune Globulin

54. Levamisole Antihelminthic
Restores depressed immune function of B, T cells, Monocytes, Macrophages
Adjuvant therapy with 5FU in colon cancer
Toxicity
Agranulocytosis

55. Thalidomide Birth defect
Contraindicated in women with childbearing potential
Enhanced T-cell production of cytokines – IL-2, IFN-γ
NK cell-mediated cytotoxicity against tumor cells
USE:
Multiple myeloma

56. Bacillus Calmette-Guerin
Live, attenuated culture of BCG strain of Mycobacterium Bovis
Carcinoma Bladder
Adverse Effects
Hypersensitivity
Shock
Chills

57. Interferons Antiviral Immunomodulatory activity
Bind to cell surface receptors – initiate intracellular events
Enzyme induction
Inhibition of cell proliferation
Enhancement of immune activities
Increased Phagocytosis

58. Interferon alfa-2b Hairy cell leukemia Malignant melanoma
Kaposi sarcoma
Hepatitis B
Adverse reactions
Flu-like symptoms – fever, chills, headache
CVS- hypotension, Arrhythmia
CNS- depression, confusion

59. Interleukin-2 (aldesleukin)
Proliferation of cellular immunity – Lymphocytosis, eosinophilia, release of multiple cytokines – TNF, IL-1, IFN-γ
Uses
Metastatic renal cell carcinoma
Melanoma
Toxicity
Cardiovascular: capillary leak syndrome, Hypotension

60. Immunization Active – Stimulation with an Antigen
Passive – Preformed antibody

61. Active immunization Vaccines
Administration of antigen as a whole, killed organism, or a specific protein or peptide constituent of an organism
Booster doses
Anticancer vaccines – immunizing patients with APCs expressing tumor antigen.

62. Immune Globulin Indications
Individual is deficient in antibodies – immunodeficiency
Individual is exposed to an agent, inadequate time for active immunization
Rabies
Hepatitis B

63. Nonspecific immunoglobulins Specific immune globulins
Antibody-deficiency disorders
Specific immune globulins
High titers of desired antibody
Hepatitis B, Rabies, Tetanus

64. Rho (D) Immune Globulin
Antibodies against Rh(D) antigen on the surface of RBC
Rh-negative women may be sensitized to “Foreign” Rh antigen on fetal RBC
Anti-RH Antibodies produced in mother can damage subsequent fetuses by lysing RBC’s
Hemolytic disease of newborn

65. Immune tolerance
Induction and maintenance of immunologic tolerance - active state of antigenic specific nonresponsiveness
Still experimental

66. Summary Immunosuppresion Newer immunosuppresive agents
Calcineurin inhibitors
Glucocorticoids
Antimetabolites
Newer immunosuppresive agents
Effective control of rejection
Glucocorticoid withdrawal