Dr. Dheeraj Mulchandani (Resident CMC, ludhiana)

1. IMMUNOMODULATORS
Dr. Dheeraj Mulchandani
Christian Medical College, Ludhiana
PG Resident

2. Overview
 Introduction
 History
 Types of immunity
 Immunosuppresant classification
 Types of immunosuppresant
 Types of immunostumulants
 Recent advances
 Summary
 Bibliography

3. Learning Objectives:
 Different types of immunity.
 Drugs used as immunosuppresants and there clinical
applications.
 Drugs used as immunostimulants and there
application

4. Introduction
 The word immunity is derived from latin word
immunes which means “ exempt from”.
 Immunity is usually defined as a state of relative
resistance to an infection.

5.  Immune system is important
To maintain normal healthy life.
Protect us from any invading organism.

6. History

9. Immunity Types :

10. IL-7
GM-CSF,
IL-3
APC

11. Who are involved ?
 Innate
 Complement
 Granulocytes
 Monocytes/macrophages
 NK cells
 Mast cells
 Basophils
 Adaptive:
 B and T lymphocytes

12. ABNORMAL IMMUNE
RESPONSE
Hypersensitivity reactions
Type 1 – Anaphylactic shock
Type 2 – cytotoxic antibody mediated
Type 3 – Immune complex
Type 4 – Delayed type
Immediate
Delayed

13. Autoimmunity
It occurs due to failure of the body to differentiate the tissues
of the body and foreign cells
Leading to formation of antibodies against self tissues leading to
tissue damage by activation of T and B lymphocytes
Rheumatoid Arthritis, S.L.E, Type 1 Diabetes Mellitus,
Multiple Sclerosis etc…

14.  Congenital or acquired
 Acquired – d/t infections, drugs
 Leading to increased susceptibiliy for infections with
increased severity of disease
 Ex – AIDS,
X linked agammaglobulnaemia
Immunodeficiency diseases

15. IMMUNOMODULATORS

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

17. Immunosuppressants
 Drugs which inhibit cellular / humoral or both type of
immune responses.
•
Prednisolone
• Azathioprine
• Mtx
• Mycophenolate mofetil
• Sirolimus
• Everolimus
• Cyclosporin
• Tacrolimus
Calcineurin
inhibitors
M-TOR inhibitors
Glucocorticoids
Antiproliferative
drugs

18. Biological
agents
IL-1 receptor
antagonist
Anakinra
IL-2 receptor
antagonist
Basiliximab
Daclizumab
Anti- CD3
antibody
Muromonab CD3
Polyclonal
antibodies
Antithymocyte
antibody (ATG)
Rho(D) immune
globulin
TNF apha
inhibitors
Etanercept
Infliximab

19. Calcineurin inhibitors
 Cyclosporine
 Tacrolimus
 Most effective immunosuppressive drugs
 Blocks Induction of cytokine genes

21. Cyclosporine
 More effective against T-cell dependent immune
mechanisms – transplant rejection, autoimmunity
 Suppress the CMI
Uses
 Organ transplantation: Kidney, Liver, Heart
 Rheumatoid arthritis, IBD, uveitis
 Psoriasis
 Aplastic anemia
 Skin Conditions- Atopic dermatitis, Pemphigus vulgaris,
Lichen planus.

22. Toxicity : Cyclosporine
 Renal dysfunction
 Infections
 Hirsuitism
 Hypertension
 Hyperlipidemia
 Gum hyperplasia
 Hyperuricemia – worsens gout
 Calcineurin inhibitors + Glucocorticoids = Diabetogenic

23. Drug Interaction : Cyclosporine
 CYP 3A4
 Inhibitors: Erythromycin, Ketoconazole
 Inducers: Rifampicin, Phenytoin
 Additive nephrotoxicity: NSAIDs
Dose :
 IV, Oral, 10-15mg/kg/day x 14days
 2-6mg/kg/day - maintenance

24. Tacrolimus (FK 506)
 Immunosuppresant which is a macrolide
 Same MOA
 100 times more potent

25.  Metabolized by CYP3A4
 t1/2 – 12hrs
 >Potency, easy to monitor ; Therapeutic uses &
toxicity similar
 Preferred for organ transplant

26. Toxicity - Tacrolimus
 Nephrotoxicity
 Hypertension
 Hirsutism
 Gum hyperplasia
 Hyperurecemia
 Hyperglycemia

27. Organ transplant Doses
Kidney 0.05-0.1 mg/kg BD oral
Liver 0.1-0.2 mg/kg BD
I.V preparation is not available in India.

28. m – TOR inhibitors
It regulates cell growth, cell proliferation, protein
synthesis and transcription.
 Sirolimus
 Everolimus

29. Sirolimus (Rapamycin)
 Potent immunosuppresant (macrolide antibiotic)
 Inhibits T-cell activation and proliferation
 Absorbed orally - t1/2 – 60 hrs .
 Elimination - biliary
Drug Interactions: CYP 3A4

30. Uses
 Prophylaxis of organ transplant rejection
along with other drugs.
 Not recommended for liver transplant
 Sirolimus coated stents - to reduce incidence
of coronary artery restenosis.

31. Toxicity
 Increase in serum cholesterol, Triglycerides
 Depress bone marrow ( thrombocytopenia, anaemia)
 Diarrhoea
 Liver damage

32. Everolimus
 Newer congener
 Shorter half life compared to sirolimus (40hrs)
 Shorter time taken to reach steady state
 Similar toxicity, drug interactions

33.  Use :
1. Prophylaxis of kidney and liver transplant rejections
2. Advanced RCC
3. Pancreatic NET

34. Anti – proliferative drugs
 Azathioprine
 Methotrexate
 Mycophenolate mofetil

35. Azathioprine
 Purine antimetabolite
 This purine synthase inhibitor acts after getting converted to 6-MP.
 Immunosuppresant action – by preventing clonal expansion of T and
B lymphocytes.
 Potent suppressant of CMI
Uses
 Prevention of organ transplant rejection (3-5mg/kg/day) – combined
with cyclosporin
 Autoimmune disease (1mg/kg/day)

37. Toxicity
 Bone marrow suppression- leukopenia,
thrombocytopenia, anemia
 Increased susceptibility to infection
 Hepatotoxicity
 Alopecia
 GI toxicity
 Drug interaction: Allopurinol

38. Methotrexate
 Folate antagonist
 Potent immunosuppresant
 Depresses cytokine production, chemotaxis and CMI
 Use :
1. NHL
2. Bladder, breast, head and neck cancers
3. Autoimmune diseases

39. Mycophenolate Mofetil
 Prodrug 
Mycophenolic acid
 Inhibits IMPDH

40.  T, B cells are highly dependent on this pathway for cell
proliferation
 Inhibits lymphocyte proliferation, Antibody formation,
CMI
 MMF + glucocorticoids + sirolimus= non nephrotoxic
combination.
 Can be used in patients developing cycl/Tacrolimus
toxicity.

41. Uses - Mycophenolate Mofetil
 Prophylaxis of transplant rejection (1gm BD oral)
 Add on: Glucocorticoids +
Calcineurin Inhibitors
 Toxicity
 Vomiting
 Diarrhea, Leucopenia
 Risk of Infection – CMV
 G.I bleed

42. Glucocorticoids
 Potent immunosuppressant and anti inflammatory action.
 Down regulation of IL-1, IL-2 &IL-6, TNF-alpha
Inhibition of T cell proliferation, chemotaxis is interfered
 Also, decrease production of ac. Phase reactants from
macrophages and endothelial cells
Complement function is interfered.
Inhibits NF-KB (Nuclear Factor
Kappa light chain enhancer of
activated B cells)

43. USES
 Transplant rejection
 Autoimmune diseases – RA, SLE,MG Psoriasis
 Inflammatory Bowel Disease, Eye conditions

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

45. Biological agents
 Recombinant proteins or poly/momoclonal antibodies
directed towards cytokines or lymphocyte antigens
which play role in immune response.
 Supplementary or reserve drugs for autoimmune or
GVHD patients.

46. TNF alpha inhibitors
 TNF – Amplifies immune system by releasing other
cytokines.

47. Uses of Anti-TNFα agents
 Rheumatoid arthritis
 Crohn’s disease – fistulae
 Psoriasis
 Psoriatic arthritis
 Ankylosing spondylosis
Toxicity
 Infusion reaction – fever, urticaria, hypotension, dyspnoea
 Opportunistic infections – TB, RTI, UTI

48. IL-1 Receptor Antagonist
 IL-1 Levels increased in pts with active inflammation.
 Anakinra
 Rilonacept
 Use – refractory RA ( not controlled by conventional
DMARDS)

49. Anti-IL-2 Receptor Antibodies
 Daclizumab
 Basiliximab
 CD25 acts as a high affinity receptor for IL-2 through which
cell proliferation and differentiation takes place
 Bind to IL-2 receptor on surface of activated T cells  Block IL-
2 mediated T-cell activation
Uses
 Prophylaxis of Acute organ rejection
Toxicity
 Anaphylaxis, Opportunistic Infections

50. Anti-CD3 Monoclonal Antibody
 Muromonab-CD3
 Binds to CD3 glycoprotein, a component of T-cell
receptor complex involved in :
 antigen recognition
 cell signaling & proliferation

51. Uses
 Acute organ transplant rejection ( Steroid resistant
cases)
Toxicity
 “Cytokine release syndrome” with flu like symptoms
 High fever, Chills, Headache, Tremor, myalgia,
arthralgia, weakness
 Prevention: Corticosteroids

52. Anti-thymocyte Globulin (ATG)
 Produced by gamma globulin fractions of serum
obtained from rabbits or horse after immunization with
human thymocytes.
 It binds to T lymphocytes
Cause depletion of circulating T cells and apoptosis of
activated T cells – Potent immunosppresant

53. Uses
 Induction of immunosuppression – transplantation
 Treatment of acute transplant rejection (esp. in steroid
resistant cases)
Toxicity
 Anaphylaxis
 Risk of infection

54. Anti – D immune globulin
 Its human IgG having high titer of antibodies against
Rh(D) antigen.
 It binds to Rho antigens and does not allow them to
induce antibody formation in Rh negative individuals.

55. Given to Rh negative mothers within 72hrs of delivery/abortion to
prevent HDNB

56. Immunosuppressants
 Organ transplantation
 Autoimmune diseases
 Life long use
 Infection, cancers
 Nephrotoxicity
 Diabetogenic
Problem

57. IMMUNOSTIMULANTS

58. Levamisol,
Thalidomide
BCG
Recombinat
Cytokines –
GMCSF, G-CSF
Interferons
Immunoglobulins

59. Levamisole
 Antihelminthic
 Restores depressed immune function of B, T cells,
Monocytes, Macrophages
 Adjuvant therapy with 5FU in colon cancer
- Aphthous ulcers
Not used now
Toxicity
 Agranulocytosis

60. Thalidomide
 Its an antiinflammatory, cytokine (TNF alpha, IL,
interferon) modulating drug with anxiolytic and antiemetic
property.
 Teratogenic
USE:
 Erythema nodusum leprosum
 cancer associated cachexia
 Multiple myeloma

61. Bacillus Calmette-Guerin
 Live, attenuated culture of BCG strain of
Mycobacterium Bovis
 Enhances immunity by stimulating the
reticuloendothelial cells
 Use – as ajuvant in cancer patients.
Adverse Effects
 Hypersensitivity
 Shock
 Chills

62. GMCSF
 Can stimulate prloiferation, differentiation and function
of myeloid stem lineages.
 Rx- Sargomostin
 It stimulates myelopoiesis
 Use –
1. neutropenia induced in cancer chemotherapy
2. Myeloid reconstitution after BMT

63.  Route – i.v/s.c
 ADR – Bone pain
- Dyspnea, Rash
- SVT arrhthmias
- Inc hepatic enzymes.

64. G-CSF
 The activity is restricted to neutrophils and their
stimulation, proliferation and fucntion.
 RX- Filgrastin, Pegfilgrastim
 Use : 1. treatment of severe neutropenia after
chemotherapy
2. Congential neutropenias

65.  Route – I.V/S.C
ADR –Bone pain
skin reaction
splenomegaly

66. Interferons
 Low molecular weight glycoproteins cytokines.
 They have antiviral and complex immunomodulatory
activity
 3 types IFN alpha, beta, gamma.
 Bind to cell surface receptors – initiate intracellular
events.
 Inhibition of cell proliferation
 Enhancement of immune activities
 Increased Phagocytosis

67. Interferon alpha – Ch. Hepatitis B,C
Gential warts
Chronic myeloid leukemia
 Interferon Beta – MS
 Interferon gamma – CGD

68. Adverse reactions:
 Flu-like symptoms – fever, chills, headache
 CVS- hypotension, Arrhythmia
 CNS- depression, confusion
 Thyroid dysfunction
 Alopecia

69. Immune Globulin
• Also known as antibodies, are glycoprotein molecules
produced by plasma cells (white blood cells).
• They act as a critical part of the immune response by
specifically recognizing and binding to particular antigens,
such as bacteria or viruses, and aiding in their destruction
Types - IgM, IgG, IgA, IgE and IgD

70. Uses – GBS
Myasthenia Gravis
Common variable immunodefiency
SLE

71. Recent Advances
 Voclosporin: semisynthetic analog of cyclosporin.
More potent & less nephrotoxic. (phase2b clinical
trials)
 CC-122 (avadomide) - Derivative of thalodimide
- Clinical potential for multiple
myeloma and NHL

72.  SCIG (Subcutaneous Ig) – FDA approved for CIDP
(Chronic inflammatory demyelinating polyneuropathy)

73. Summary
 What is Immunity
 Types of immunity – Auquired and innate
 Abnormal immune responses – HSR, autoimmunity,
immunodefieciency
 Various types of Immunosuppressants
 Various types of Immunostimulants

74. References
1. Krensky A.M, Azzi J.R, Hafler D.A. Immunosuppresants and
tolerogens. In : Goodman & Gilman The pharmacological
basis of therapeutics, 13th ed, p 637-652.
2. Jebrock J, Revollo J. Immunosuppresants. In: Lippincott
illustrated reviews pharmacology, South Asian edition,
p663-972
3. Bascones-Martinez A, Mattila R, Gomez-Font R, Meurman
JH. Immunomodulatory drugs: Oral and systemic adverse
effects. Medicina oral, patologia oral y cirugia bucal. 2014
Jan;19(1):e24.

75. 5. Shin HS, Grgic I, Chandraker A. Novel Targets of
Immunosuppression in Transplantation. Clinics in
laboratory medicine. 2019 Mar 1;39(1):157-69.
4. Farmakidis C, Dimachkie MM, Pasnoor M, Barohn RJ.
Immunosuppressive and immunomodulatory therapies
for neuromuscular diseases. Part II: New and novel
agents. Muscle & nerve. 2020 Jan;61(1):17-25.
6. Tripathi KD, In: Essentials of medical
pharmacology, 8th ed, p 937-945

76.  Thank you