Agents affecting immune system

1. IMMUNOMODULATORS

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

3. • 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 response
a) Humoral immunity - Antibody production –
killing extracellular organisms.
b) Cell mediated immunity – cytotoxic / killer T
cells – killing virus and tumour cells.

4. ABNORMAL IMMUNE
RESPONSE
• Hypersensitivity reactions
Type 1 – Anaphylactic shock
Type 2 – mismatched blood transfusion
Type 3 – Serum Sickness, glomerulonephritis
and arthritis.
Type 4 – TB

5. Autoimmunity
– Autoimmune diseases arise
when the body mounts an immune response
against itself as a result of failure to distinguish
self tissues and cells from foreign antigens.
Rheumatoid Arthritis, Type 1 Diabetes Mellitus,
Multiple Sclerosis etc….
• Immunodeficiency Diseases
Extrinsic – HIV causing AIDS.

6. IMMUNOMODULATORS

7. DEFINITION
Immunomodulators are drugs which
either suppress the immune system –
Immunosuppressants
or
stimulate the immune system –
Immunostimulants

8. Immunosuppressant

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

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

12. Problem
Life long use
Infection, cancers
Nephrotoxicity
Diabetogenic

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

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

15. USES - Glucocorticoids
• Transplant rejection
• Autoimmune diseases – RA , Hematological
conditions
• Psoriasis
• Inflammatory Bowel Disease, Eye conditions

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

17. • Sirolimus
– inhibits protein kinase and inhibits T cell
response 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.

18. Antibodies
• Against lymphocyte cell-surface antigens
• Polyclonal / Monoclonal

19. • 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 in
autoimmune haemolytic anaemia, multiple
sclerosis.

20. • Muromonab CD3 – T cell receptor
complex
( blocks Ag recognition ).
– Used in steroid resistant rejection.
• Daclizumab, Basiliximab – IL-2
receptor (blocks IL-2 mediated T cell
activation ).
– Used in acute organ rejection in
renal transplant patients.

21. Azathioprine ( Mercaptopurine )
– interferes with purine nucleic acid
metabolism and incorporates false
nucleotide.
–Used in Renal allograft, RA ,
glomerulonephritis
Interferons
- IFN alpha- immune enhancing action -
melanoma.
– IFN beta - multiple sclerosis
– IFN gamma - chronic granulomatous
disease.

22. Immunostimulants

23. Immunostimulants
USES:
• immunodeficiency disorders
• Chronic infections
• cancer

24. specific Immunostimulants
• Levamisole
• Thalidomide
• BCG
• Recombinant Cytokines
Interferons
Interleukin-2
• Other drugs
– inosiplex, azimexon, imexon, thymosin,
methylinosine monophosphate
• Immunization
Vaccines , Immune Globulin , Rho (D) Immune Globulin

25. Levamisole
• Antihelminthic
• Restores depressed immune function of B, T
cells, Monocytes, Macrophages
USES:
• Adjuvant therapy in colon cancer
• Used to treat immunodeficiency associated with
Hodgkins disease.
Toxicity
• Agranulocytosis

26. Thalidomide
• Birth defect
• Contraindicated in women with childbearing
potential
• Enhanced T-cell production of cytokines – IL-
2
• Cell-mediated cytotoxicity against tumor cells
USE:
• Multiple myeloma

27. Bacillus Calmette-Guerin
• Live, attenuated culture of BCG strain of
Mycobacterium Bovis
• It causes activation of macrophages to make them
more effective killer cells.
• used as intravesical therapy for superficial bladder
cancer.
Adverse Effects
– Hypersensitivity
– Shock
– Chills

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

29. Interferon
• Hairy cell leukemia
• Malignant melanoma
• sarcoma
• Hepatitis B
Adverse reactions
• Flu-like symptoms – fever, chills, headache
• CVS- hypotension, Arrhythmia
• CNS- depression, confusion

30. Interleukin-2 (aldesleukin)
• Proliferation of cellular immunity –
Lymphocytosis, eosinophilia, release of multiple
cytokines .
Uses
• Metastatic renal cell carcinoma
• Melanoma
Toxicity
• Cardiovascular: capillary leak syndrome,
Hypotension

31. Capillary leak syndrome
• (systemic capillary leak syndrome or Clarkson
syndrome)
• A rare medical condition where the number
and size of the pores in the capillaries are
increased which leads to a leakage of fluid
from the blood to the interstitial fluid,
resulting in dangerously low blood pressure
(hypotension), edema and multiple organ
failure due to limited perfusion.

32. Immunization
• Active – Stimulation with an Antigen
• Passive – Preformed antibody

34. 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:
Vaccinating patients with autologous antigen
presenting cells (APC) expressing tumor-
associated antigens (TAA)

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

36. • Nonspecific immunoglobulins
–Antibody-deficiency disorders
• Specific immune globulins
–Hepatitis B, Rabies, Tetanus