The document discusses various aspects of immunopharmacology including the immune response, cells involved, immune modifiers, and immunization approaches. It describes several classes of immunosuppressive drugs like glucocorticoids, calcineurin inhibitors, antiproliferative agents, antibodies, and their mechanisms and uses. Some immunostimulants like levamisole, thalidomide, BCG, interferons, interleukin-2 are also mentioned along with their effects. The summary concludes with a brief overview of active and passive immunization approaches including vaccines, immune globulins, and Rho(D) immune globulin.

1. Chapter IV
Immunopharmacology
YEAR III Pharm.D
Dr. V. Chitra

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

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

5. IMMUNE MODIFIERS
Immunosuppressants Immunostimulants
? Immune tolerance

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

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

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

9. 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

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

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

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

14. 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

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

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

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

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

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

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

22. 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

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

24. 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

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

26. Mycophenolate Mofetil
{ Prodrug Æ 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

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

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

29. 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

30. Toxicity
{ Lymphopenia
{ Negative chronotropic effect
z S1P-receptor on human atrial myocytes

31. Antibodies
{ Against
lymphocyte cell-
surface antigens
{ Polyclonal /
Monoclonal

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

33. 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

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

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

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

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

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

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

42. 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

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

45. Moderate to severely active crohn’s disease
Adalimumab
Recombinant human anti-TNF mAb

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

47. 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)

48. Immunostimulants
{ Levamisole
{ Thalidomide
{ BCG
{ Recombinant Cytokines
z Interferons
z Interleukin-2

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

50. 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

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

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

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

54. 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

55. Immunization
{ Vaccines
{ Immune Globulin
{ Rho (D) Immune
Globulin

56. Immunization
{ Active – Stimulation with an Antigen
{ Passive – Preformed antibody

58. 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.

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

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

61. 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