Immunosupressants and Immunostimulants their pharmacology, uses etc. Basics of immunology, innate immune response, acquired immune response, role of complement in innate immune response. Major histocompatibility complex, antibody structure. classification of immunosupressants, their mechanism of action, uses and adverse effects.

1. Dr Naser Ashraf Tadvi
Associate Professor
Department of Pharmacology
IMMUNOPHARMACOLOGY

2. Immunology
_ Physiology of self-non-self discrimination
_ The Latin term “IMMUNIS” means
EXEMPT, referring to protection against
foreign agents.

3. TYPES OF IMMUNE RESPONSES OF BODY
Innate immune response (IIR) Adaptive immune response (AIR)
Response is non-specific Pathogen and antigen specific
response
Exposure leads to immediate
maximal response
Lag time between exposure and
maximal response
No immunological memory Exposure leads to immunological
memory
Found in nearly all forms of life Found only in jawed vertebrates

4. Innate Immune response

5. Innate immune cells function
• Phagocytosis to kill offending organism
• Proteolytic digestion and presentation of
processed pathogen fragments, with MHC-
II proteins on surface of APC to activate T-
cells of AIR
• Secrete cytokines

6. Phagocytosis
Opsonin dependent Opsonin independent
Coating of invading
organisms by opsonins
• IgG/IgE
• C3b
• Lectin
Toll like receptors
• Pattern recognition receptors
which recognize generic
molecular pattern related to
bacteria or virus
• Example of recognized
components
• Bacterial cell wall component
• Viral DNA
• LPS of Gm –ve bacteria
• Techoic acid of Gm +ve bacteria

7. Role of complement system in IIR

8. Role of other components in IIR
Cell Function / role
1 Neutrophils Endocytosis & destruction of invading
bacteria (Myeloperoxidase & defensins)
2 Eosinophils Defense against parasites, pathogenesis of
allergic responses
3 Basophils &
mast cells
IgE mediated anaphylaxis
4 Macrophages APC to T cells
5 Dendritic cells Act as APC
6 Natural killer
cells
Intrinsic ability to kill invading microbes &
malignant cells
Killer activated receptors

9. Adaptive immune response (AIR)
Antigen mediated immunity
Production of circulating
immunoglobulin by plasma cells
derived from B-lymphocytes.
Cellular immunity
Mediated by sensitized T-
lymphocytes
CD8 cytotoxic: directly attack
invading organism
CD4: Aid in CMI (TH1) & AMI
(th2)
Particularly useful against
intracellular pathogens,
cancer cells and tissue
transplants
Particularly useful against
antigens dissolved in body
fluids and extracellular
pathogens

10. Major histocompatibility complex (MHC)
• Located in plasma membrane of most body cells
• Help T cells to recognize foreign antigen
• MHC1: on all nucleated human cells
• Identify and display self proteins to be ignored by
immune system as well as endogenous protein
fragments of an infected cell.
• MHC II: B-cells, macrophages, dendritic cells
• Identifies and displays the peptide fragments of an
exogenous infectious agent

11. CMI involving TH mediated activation
of T-lymphocytes

12. CMI involving direct role of CD8+ T
Lymphocyte

13. Activation, proliferation and differentiation of
B cell during Humoral Immunity

14. Antibodies
Antibody Function
1. IgG • Most abundant (80%),
• Protect against bacteria/virus by enhancing
phagocytosis or activating complement
• Cross placenta
2. IgA • 15%
• Provide localized protection on mucus membrane
3. IgM • 5-10%, first to be secreted
• Agglutination and lysis of microbes
• Antigen receptors on B Cells
4. IgD • 0.2%
• Antigen receptors on B Cells
5. IgE • 0.1%
• Located on mast cells, involved in allergic reactions
• Provide protection against parasitic worms

15. ANTIBODY
STRUCTURE
Fab
Fc

16. Fate of antigen antibody complex

17. Types of Drugs
_ Immunosuppressants
_ Immunostimulants

18. Classification of immunosupressants

19. Mechanism of action of cyclosporine, tacrolimus, sirolimus

20. Cyclosporine
Binds with cyclophilin to form complex which inhibits calcineurin.
Calcineurin induced dephosphorylation required for proteins like NFAT (nuclear factor of
activated ‘T’ cells) which help cytokine genes for production of IL2, TNF, interferon etc.
Mechanism of action

21. Cyclosporine
• Pharmacokinetics: (Oral/ iv)
• Oral 30% BA, food decreases absorption
• Metabolized by CYP3A,
• Inactive metabolites excreted mainly in bile
• Plasma t ½ : 24 hours
• Indications:
• Prevent graft rejection in solid organs
• Second line drug in autoimmune diseases like RA, psoriasis
• Atopic dermatitis, uveitis, inflammatory bowel disease

22. Adverse effects
• Nephrotoxic, neurotoxic
• Hepatotoxic
• Hypertension
• Hyperuricemia
• Hyperlipidemia (LDL)
• Hyperplasia of gums
• Hirsutism

23. Tacrolimus
• Similar Mechanism, uses and adverse effects to
cyclosporine
• Binds FKBP-12
• Valuable in liver transplant
• Adverse effects
• Incidence of hirsutism, hyperuricemia, hyperlipidemia less
• More likely to precipitate diabetes
• neurotoxicity, alopecia and diarrhoea

24. Sirolimus
• Mechanism of action
• Binds to FKBP-12 & inhibits mTOR which plays key
role in cell cycle progression by activating Cdks
• T cells are arrested in G phase
• Uses
• Prevent acute graft rejection of solid organ transplant
• combination with Cyclosporine/ Mycophenolate mofetil
and Glucocorticoids
• Sirolimus eluted stents in Coronary angioplasty

25. Sirolimus
• Adverse effects
• Hyperlipidemia
• Anemia, thrombocytopenia, leukopenia
• Nephrotoxicity less than cyclosporine and
tacrolimus
• Delayed wound healing

26. Antiproliferatives
_ Azathioprine
_ Mycophenolate Mofetil
_ Methotrexate
_ Cyclophosphamide

27. Azathioprine
Azathioprine
6 – thioguanine
6 - mercaptopurine
Falsely incorporated in DNA of lymphocyte
Damage to the DNA (Dysfunctional lymphocytes)
Mechanism of Action

28. Azathioprine
Uses:
• To prevent renal graft rejection 3-5 mg/kg/day.
• Also used in rheumatoid arthritis (50-150 mg/day).
Adverse effects:
• Bone marrow depression, leukopenia, thrombocytopenia
• Alopecia
• Hepatotoxicity

29. Methotrexate
Mechanism of Immunosuppressant action
Increased adenosine levels
Potent endogenous anti-inflammatory
Inhibits superoxide anion generation in neutrophils
Also decreases cytokine production and enhances
apoptosis of activated T cells

30. Mycophenolate Mofetil
_ Prodrug of mycophenolic acid.
_ Inhibits inosine monophosphate dehydrogenase &
↓guanosine synthesis.
_ ↓ Humoral & cell mediated immunity.
_ Used in dose of 1-2 g/day in renal graft rejection
oral / i.v with cyclosporin & corticosteroid.

31. Cyclophosphamide
_ More marked effect on ‘B’ cells & humoral
immunity.
_ Rx of rheumatoid arthritis, S.L.E, pemphigus &
thrombocytopenic purpura.
_ Short course for preventing rejection of bone
marrow transplant.
_ Dose: 2-3 mg/kg/day orally.
_ Adverse effects: Cystitis, alopecia.

32. Glucocorticoids
_ More marked effect on C.M.I
_ Also have anti inflammatory action(↓arachidonic
acid synthesis, ↓ cytokine production).
_ To prevent graft rejection
• methyl prednisolone 0.5 to 1 g, i.v daily for 3 to 5 days.
_ Auto immune diseases
• Myaesthenia gravis, R.A etc (5-10 mg. Prednisolone or
equivalent for day with NSAID).

34. Adverse effects of Glucocorticoids
_ Glaucoma
_ Limb muscle atrophy
_ Ulcer peptic
_ Cushings syndrome
_ Osteoporosis
_ Cataract
_ Osteonecrosis (Avascular)
_ Renal Failure (C/I)
_ Tuberculosis (C/I)
_ Impair healing
_ CHF (C/I)
_ Oedema
_ Infections
_ Diabetes mellitus
_ Supress HPA

35. Biological Agents
_ TNF-α Inhibitors
_ Etanercept,
_ Infliximab,
_ Adalimumab
_ IL-1 receptor antagonists
_ Anakinra
_ IL-2 receptor antagonist
_ Daclizumab,
_ Basiliximab
_ IL-6 receptor inhibitor
_ Tocilizumab
_ Anti-CD3 antibody
_ Muromonab

36. Muromonab: OKT3
_ Monoclonal antibody to T3 (CD3) antigen near ‘T’ cell
receptor on human lymphocytes (helper ‘T’ cells).
_ Circulating ‘T’ lymphocytes bearing CD3 antigen are
removed from circulation within minutes after i.v.
Use: as induction therapy with corticosteroids and
azathioprine to prevent graft rejection.
Dose: 5mg/day/i.v
Adverse effects:
1. Flu like syndrome
2. Pulmonary Edema.

37. Other monoclonal antibodies
1 IL-12 Inhibitor Ustekinumab Psoriasis, Chrons disease,
Multiple sclerosis
2 Anti-CD3 Muromonab Graft rejection
3 Anti IgE Omalizumab Bronchial Ashthma
4 Anti CD-20 Rituximab CD20+ NHL, CLL
5 Anti CD 52 Alemtuzumab CLL
6 Alpha-4 integrin
inhibitor
Natalizumab Multiple sclerosis
7 Anti-CD80/ CD86 Abatacept Resistant Rheumatoid arthritis
8 CTLA-4 Inhibitor Ipilimumab Advanced Melanoma
9 PD-1 inhibitor Nivolumab Metastatic melanoma

38. Anti thymocyte globulin
_ Purified polyclonal antibody from horse/rabbit
immunized with thymic lymphocytes.
_ Used to prevent acute graft rejection in steroid
resistant cases.
Dosage & preparation:
_ (equine) 100mg/vial injection 10mg/kg/day/i.v
_ (rabbit) 25mg/vial injection 1.5 to 2.5 mg/kg/day.
Adverse effects: anaphylaxis, serum sickness.

39. Anti ‘D’ globulin [Rho(D) immune globulin]
_ Human immunoglobulin ‘G’.
_ High titer of antibodies against Rh (D) antigen.
_ Bind with Rh o antigen and inhibit induction of
antibodies in Rh negative individuals.
_ To be administered 72 hours of delivery/abortion.
Use: Prevents hemolytic disease in future off spring.
Prepn & Dose: 250 to 350 g/I.M

40. Regimens of immunosuppressants for
success of organ transplantation.
• Induction regimen
_ (Perioperative period – starting before
transplantation to 2 to 12 weeks after it)
_ Most common – triple regimen
Cyclosporine/tacrolimus/sirolimus + prednisolone
+ MMF/azathioprine.

41. II. Acute rejection regimen
_ To suppress an episode of acute rejection.
_ Methyl prednisolone – 0.5 to 1 g/I.V daily for
3-5 days or muromonab OKT3/ATG.
III. Maintenance regimen
_ For prolonged period or lifelong.
_ Triple regimen (nephrotoxicity of cyclosporine
limiting factor).
_ Cyclophosphamide/MMF in case of intolerance
to 1st line drugs.

42. Immunostimulants
_ BCG
_ Levamisole
_ Thalidomide
_ Lenalidomide
_ Human recombinant IL-2: Aldesleukin
_ GM-CSF: Sargograstim
_ G-CSF: Figrastim
_ Recombinant Interferons

43. BCG
_ Live attenuated culture of a strain of M Bovis
_ Indications
_ TB prophylaxis
_ Treatment and prophylaxis of cancer in situ of urinary
bladder
_ Action
_ Non specific stimulation of T cells and Natural killer
cells

44. Levamisole
_ Antihelmintic drug
_ Restores depressed T function also B cells,
macrophages
_ Use:
_ Adjuvant with 5-FU in colorectal cancer
_ Slow spreading vitiligo

45. Thalidomide
_ Actions
_ Inhibits angiogenesis
_ Inhibits TNF-α release from monocytes
_ Inhibits phagocytosis by neutrophils
_ Use:
_ Multiple myeloma
_ ENL

46. Aldesleukin
_ Human recombinant IL-2
_ Stimulates Th and Tc cells
_ Used in metastatic renal cell cancer &
melanoma
_ Adverse effects:
_ Capillary leak syndrome

47. Recombinant Interferons
_ Interferon α:
_ Activates T lymphocytes, NK cells & Macrophages
_ Uses
_ CML, NHL, Hairy cell leukemia
_ Malignant melanoma
_ Aids related Kaposis sarcoma
_ Hepatitis B and C Virus
_ Adverse effects
_ Flu like syndrome, nephro & neurotoxicity

48. Recombinant Interferons
_ Interferon β:
_ Used in multiple sclerosis
_ Interferon γ:
_ Restores macrophage cytotoxicity by generating
free radicals
_ Used in chronic granulomatous diseases