This document summarizes immunomodulators, which are drugs that suppress or stimulate the immune system. It describes the innate and adaptive immune response and how immunomodulators can act as immunosuppressants or immunostimulants. Key immunosuppressants discussed include glucocorticoids, calcineurin inhibitors, antiproliferatives, antibodies, and their mechanisms and uses for conditions like transplantation and autoimmune diseases. Immunostimulants covered include levamisole, thalidomide, BCG, interferons, interleukin-2, and immunization through vaccines and immune globulins.

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