1. IMMUNITY, IMMUNOSUPPRESANT’S
NAVEEN KADIAN
DEPARTMENT OF
PJARMACHEMISTRY
KLE’S COLLEGE OF PHARMACY
BELGAUM-10

2. The Immune Response
 ABILITY TO RESIST ALMOST ALL TYPES OF
ORGANISMS OR TOXINS THAT TEND TO DAMAGE
THE TISSUES AND ORGANS
 Discriminate: Self / Non self
 Destroy:
 Infectious invaders
 Dysregulated self (cancers)
 Immunity:
 Innate, Natural
 Adaptive, Learned

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

4. ACQUIRED IMMUNITY
HUMORAL CELL
MEDIATED
IMMUNITY

5. FORMATION OF B
LYMPHOCYTE

6. ROLE OF MACROPHAGE IN
ACTIVATING LYMPHOCYTES
 MACROPHAGES ARE PRESENT IN
SINUSOIDS OF EPITHELIUM OF
LYMPHOIDAL ORGANS
 MOST ANTIGENS COME IN CONTACT
WITH MACROPHAGE
 PHAGOSITIZE THEM
 ANTIGENIC PRODUCTS ARE
LIBERATED IN CYTOSOL
 AND THEY STIMULATE B CELLS BY
CELL TO CELL CONTACT

7. ROLE OF T CELLS
 T HELPER CELLS SECRETE
SUBSTANCES (LYMPOKINES)
ACTIVATE B
CELLS

8. SPECIFIC ATTRIBUTES OF
HUMORAL IMMUNITY

9.  MEMORY
 A FEW OF LYMPHOBLAST DONOT
FORM PLASMA CELLS INSTEAD
BECOME B LYMPHOCYTES
 THEY REMAIN DORMANT UNTIL THEY
ARE ACTIVATED BY SAME ANTIGEN

10. RESPONSE

12. COMPLEMENT SYSTEM
 20 PROTEINS
 11 proteins are principle actors
 C1-C9,B,D
 CONSTANT PORTION ACTIVATES C1
AND A CASCADE OF REACTIONS
BEGIN


13. FUNCTIONS
 OPONISATION & PHAGOCYTOSIS
C3b
 LYSIS C5b6789
 AGGLUTINISTION
 NEUTALISATION OF VIRUSES
 CHEMOTAXIS C5a
 ACTIVATION OF MAST CELLS
C3a,C4a,C5a
 INFLAMMATORY EFFECTS

16. IMMUNE MODIFIERS
Immunosuppressants Immunostimulants
? Immune tolerance

17. Immunosuppressant's
 Glucocorticoids
 Calcineurin inhibitors
 Cyclosporine
 Tacrolimus
 Antiproliferative / antimetabolic agents
 Sirolimus
 Everolimus
 Azathioprine
 Mycophenolate Mofetil
 Others – methotrexate, cyclophosphamide,
thalidomide and chlorambucil

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

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

20. 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

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

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

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

25. 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

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

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

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

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

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

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

33. 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

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

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

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

37. 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

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

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

40. 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

41. Toxicity
 Lymphopenia
 Negative chronotropic effect
 S1P-receptor on human atrial myocytes

42. Antibodies
 Against
lymphocyte cell-
surface antigens
 Polyclonal /
Monoclonal

43. 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

44. 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

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

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

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

48. 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

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

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

54. 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

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

57. moderate to severely active crohn’s disease
AdalimumabAdalimumab
Recombinant human anti-TNF mAbRecombinant human anti-TNF mAb

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

59. 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)

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