agents affecting immune system
TRANSCRIPT
IMMUNOMODULATORS
The Immune Response - why and
how ?
• Discriminate: Self / Non self
• Destroy:
– Infectious invaders
–Dysregulated self (cancers)
• Immunity:
– Innate, Natural
–Adaptive, Learned
• Innate immune response– first line of defense against an antigenic insult.Includes
•defenses like physical (skin),• Biochemical (complement, lysozyme, interferons)•cellular components (neutrophils, monocytes,macrophages).
• Adaptive immune responsea) Humoral immunity - Antibody production –killing extracellular organisms.b) Cell mediated immunity – cytotoxic / killer Tcells – killing virus and tumour cells.
ABNORMAL IMMUNERESPONSE
• Hypersensitivity reactions
Type 1 – Anaphylactic shock
Type 2 –mismatched blood transfusion
Type 3 – Serum Sickness, glomerulonephritis
and arthritis.
Type 4 – TB
Autoimmunity
– Autoimmune diseases arise
when the body mounts an immune response
against itself as a result of failure to distinguishself tissues and cells from foreign antigens.
Rheumatoid Arthritis, Type 1 Diabetes Mellitus,Multiple Sclerosis etc….
• Immunodeficiency Diseases
Extrinsic – HIV causing AIDS.
IMMUNOMODULATORS
DEFINITION
Immunomodulators are drugs which
either suppress the immune system –
Immunosuppressants
orstimulate the immune system –
Immunostimulants
Immunosuppressant
Immunosuppressants
• Glucocorticoids - Prednisolone.• Calcineurin inhibitors
– Cyclosporine– Tacrolimus
• Antiproliferative / antimetabolic agents
– Sirolimus– Everolimus– Azathioprine–Mycophenolate Mofetil– Others –methotrexate, cyclophosphamide,thalidomide and chlorambucil , Interferon
• Antibodies
– Antithymocyte globulin
– Anti CD3 monoclonal antibody
• Muromonab
– Anti IL-2 receptor antibody –
• Daclizumab, basiliximab
– Anti TNF alpha – infliximab, etanercept
Problem
Life long use
Infection, cancers
Nephrotoxicity
Diabetogenic
Sites of Action of Selected ImmunosuppressiveAgents on T-Cell Activation
DRUG SITE OF ACTIONGlucocorticoid response elements inDNA (regulate gene transcription)CD3T-cell receptor complex (blocksantigen recognition)Calcineurin (inhibits phosphataseactivity)Calcineurin (inhibits phosphataseactivity)Deoxyribonucleic acid (falsenucleotide incorporation)Inosine monophosphatedehydrogenase (inhibits activity)IL-2 receptor (block IL-2-mediatedT-cell activation)Protein kinase involved in cell-cycleprogression (inhibits activity)
• Glucocorticoids
• Muromonab-
• Cyclosporine
• Tacrolimus
• Azathioprine
• Mycophenolate Mofetil
• Daclizumab, Basiliximab
• Sirolimus
Glucocorticoids
• Induce redistribution of lymphocytes –decrease in peripheral blood lymphocytecounts
• Intracellular receptors – regulate genetranscription
• Inhibition of T cell proliferation• Neutrophils, Monocytes display poorchemotaxis
• Broad anti-inflammatory effects on multiplecomponents of cellular immunity
USES - Glucocorticoids
• Transplant rejection
• Autoimmune diseases – RA , Hematologicalconditions
• Psoriasis
• Inflammatory Bowel Disease, Eye conditions
Toxicity
• Growth retardation
• Avascular Necrosis of Bone
• Risk of Infection
• Poor wound healing
• Cataract
• Hyperglycemia
• Hypertension
• Sirolimus
– inhibits protein kinase and inhibits T cellresponse to IL-2.
– Blocks cell cycle progression
Thalidomide – inhibits angiogenesis, reduces
phagocytosis, enhances cell mediated immunity
– Increases levels of IL-10.– Used in multiple myeloma, graft versus host
disease, colon and prostrate Cancer.
Antibodies
• Against lymphocyte cell-surface antigens
• Polyclonal / Monoclonal
•Mycophenolate Mofetil –mycophenolic acid
– Inhibits inosine monophosphate
dehydrogenase which is a key enzyme in
guanine nucleotide synthesis.
– Used in steroid refractory diseases, RA.Leflunomide – it inhibits pyrimidine synthesis.
Used in RA.
• Cyclophosphamide – alkylating agent which
destroys proliferating lymphoid cells. Used inautoimmune haemolytic anaemia, multiplesclerosis.
•Muromonab CD3 – T cell receptorcomplex
( blocks Ag recognition ).
– Used in steroid resistant rejection.
• Daclizumab, Basiliximab – IL-2receptor (blocks IL-2 mediated T cellactivation ).
– Used in acute organ rejection inrenal transplant patients.
Azathioprine ( Mercaptopurine )– interferes with purine nucleic acidmetabolism and incorporates falsenucleotide.
–Used in Renal allograft, RA ,glomerulonephritis
Interferons
- IFN alpha- immune enhancing action -melanoma.
– IFN beta - multiple sclerosis
– IFN gamma - chronic granulomatousdisease.
Immunostimulants
Immunostimulants
USES:
• immunodeficiency disorders
• Chronic infections
• cancer
specific Immunostimulants
• Levamisole• Thalidomide• BCG• Recombinant Cytokines
InterferonsInterleukin-2
• Other drugs– inosiplex, azimexon, imexon, thymosin,methylinosine monophosphate
• ImmunizationVaccines , Immune Globulin , Rho (D) Immune Globulin
Levamisole
• Antihelminthic
• Restores depressed immune function of B, Tcells, Monocytes, Macrophages
USES:
• Adjuvant therapy in colon cancer
• Used to treat immunodeficiency associated withHodgkins disease.
Toxicity
• Agranulocytosis
Thalidomide
• Birth defect• Contraindicated in women with childbearingpotential
• Enhanced T-cell production of cytokines – IL-2
• Cell-mediated cytotoxicity against tumor cells
USE:• Multiple myeloma
Bacillus Calmette-Guerin
• Live, attenuated culture of BCG strain ofMycobacterium Bovis
• It causes activation of macrophages to make themmore effective killer cells.
• used as intravesical therapy for superficial bladdercancer.
Adverse Effects
– Hypersensitivity
– Shock
– Chills
Interferons
• Antiviral
• Immunomodulatory activity
• Bind to cell surface receptors – initiate intracellularevents
– Enzyme induction
– Inhibition of cell proliferation
– Enhancement of immune activities
– Increased Phagocytosis
Interferon
• Hairy cell leukemia• Malignant melanoma• sarcoma• Hepatitis B
Adverse reactions• Flu-like symptoms – fever, chills, headache• CVS- hypotension, Arrhythmia• CNS- depression, confusion
Interleukin-2 (aldesleukin)
• Proliferation of cellular immunity –Lymphocytosis, eosinophilia, release of multiplecytokines .
Uses• Metastatic renal cell carcinoma• MelanomaToxicity
• Cardiovascular: capillary leak syndrome,Hypotension
Capillary leak syndrome
• (systemic capillary leak syndrome or Clarksonsyndrome)
• A rare medical condition where the numberand size of the pores in the capillaries areincreased which leads to a leakage of fluidfrom the blood to the interstitial fluid,resulting in dangerously low blood pressure(hypotension), edema and multiple organfailure due to limited perfusion.
Immunization
• Active – Stimulation with an Antigen
• Passive – Preformed antibody
Active immunization
Vaccines• Administration of antigen as a whole, killedorganism, or a specific protein or peptideconstituent of an organism
• Booster doses
• Anticancer vaccines:
Vaccinating patients with autologous antigenpresenting cells (APC) expressing tumor-associated antigens (TAA)
Immune Globulin
Indications
• Individual is deficient in antibodies –immunodeficiency
• Individual is exposed to an agent, inadequate timefor active immunization
– Rabies
– Hepatitis B
• Nonspecific immunoglobulins
–Antibody-deficiency disorders
• Specific immune globulins
–Hepatitis B, Rabies, Tetanus