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.
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
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)
21.
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
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
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
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