This document provides an overview of immunomodulators. It begins with definitions of immunity and antigens. It describes the types of immunity and components of the immune system. It then discusses mechanisms of immunomodulation and how drugs can suppress or stimulate the immune response. The document focuses on clinically used immunomodulators, dividing them into immunosuppressants and immunostimulants. Several commonly used immunosuppressants are described in detail, including their mechanisms of action, uses, and toxicities.

1. IMMUNOMODULATO
RS
Dr. Swarnank Parmar
JR-3
Dept of Pharmacology
GMC, Nagpur

2. Overview
• Introduction
• Types of immunity
• Immunomodulators
• Clinically used immunomodulators
• Drugs affecting immune response
• Immunosuppressant
• Immunostimulants

3. Introduction
• The word immunity is derived from the Latin word
immunes which means “exempt from”.
• Immunity is usually defined as a state of relative
resistance to an infection.
• Substances capable of stimulating immune mechanism
are called as antigens.

4. • Components of immune system:
– Lymphocytes
– Cellular immunity
– Humoral immunity
– Immunoglobulin
– Lymph nodes
– Spleen
– Thymus

5. • There are 2 types of immunity:
• Active immunity.
• Passive immunity

6. • The important components of immune system
include:
Granulocytes
Complement synthesis & antibody formation
Cellular immunity
Mucocutaneous barriers

7. Mechanisms ofMechanisms of
immunomodulationimmunomodulation
• Drugs may modulate immune mechanism by either
suppressing or by stimulating one or more of the
following steps:
– Antigen recognition & phagocytosis
– Lymphocyte proliferation/differentiation
– Synthesis of antibodies
– Ag –Ab interaction
– Release of mediators due to immune response
– Modification of target tissue response

8. • The importance of immune system in protecting the
body against harmful molecules is well recognized
• However, in some instances, this protection can result
in serious problems
• E.g, the introduction of allograft can elicit a damaging
immune response causing rejection of the transplanted
tissue

9. • Benefits of immunomodulators stem from their ability
to stimulate natural & adaptive defence mechanisms,
such as cytokines, which enables the body to help itself
• Natural immunomodulators act to strengthen weak
immune systems & to moderate immune systems that
are overactive
• Plant sterols & sterolins are natural
immunomodulators found in some raw fruits &
vegetables & in the alga, spirulina

10. Phases of immune
response
Suppressants Enhancers
Antigen recognisation
& processing
Corticosteroids
Cyclophosphamide
BCG vaccine
Tetramisole
Amplification L- Asparaginase
Corticosteroids
Cyclophosphamide
5-fluorouracil
Concanavalin A
Tetramisole
Antibody formation Corticosteroids
Cyclophosphamide
Cyclosporin A
Lipopolysaccaride
Tetramisole

11. Phases of immune
response
Suppressants Enhancers
Immune affector
response
Corticosteroids
Cylcophosphamide
Cyclosporin A
Methotrexate
Tetramisole

12. Immunomodulators types
• All drugs which modify immune response generally
categorized as immunomodulators. These can either
function as:
– 1. Immunosuppressants
– 2. Immunostimulants
• Some of these can have both the properties depending
on which component of immune response they affect

13. Immunosupressants
• Glucocorticoids
• Calcineurin inhibitors
– Cyclosporine
– Tacrolimus
• Antiproliferative / antimetabolic agents
– Sirolimus
– Everolimus
– Azathioprine
– Mycophenolate Mofetil
– Others – methotrexate, cyclophosphamide, thalidomide &
chlorambucil

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

15. • Immunosupressants are the drugs which inhibit
cellular/humoral or both types of immune responses, &
have their major use in organ transplantation &
autoimmune disease
• Problems arising – Life long use
Infection, cancers
Nephrotoxicity
Diabetogenic

16. Glucocorticoids
• Induce redistribution of lymphocytes – decrease in
peripheral blood lymphocyte counts
• Down regulation of IL-1, IL-2, IL-3, IL-6
• Inhibition of T cell proliferation
• Increase number of RBCs, platelets & neutrophils in
circulation
• Enhance rate of destruction of lymphoid cells

17. Uses
• Transplant rejection
• GVH – BM transplantation
• Autoimmune diseases – RA, SLE, Hematological
conditions
• Psoriasis
• Inflammatory Bowel Disease, Eye conditions

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

19. Calcineurin inhibitors
• Cyclosporine &Tacrolimus
• Most effective immunosuppressive drugs
• Target intracellular signaling pathways
• Blocks Induction of cytokine genes

20. Cyclosporin
• Cyclic peptide composed of 11 aa
• Extracted from a soil fungus
• Selectively inhibits T lymphocyte proliferation, IL-2
& other cytokine production & response of inducer
T cells to IL-1, without any effect on suppressor T
cells
• Lymphocytes are arrested at G0 or G1 phase

21. • Binds to the cytosolic protein cyclophilin
(immunophilin) of immunocompetent lymphocytes,
especially T-lymphocytes
• This complex of cyclosporine & cyclophilin inhibit
calcineurin, which, under normal circumstances, is
responsible for activating the transcription of IL-2
• It also inhibits lymphokine production & IL release,
leads to a reduced function of effector T-cells, does not
affect cytostatic activity

22. Uses
• Prevent rejection of kidney, liver, cardiac, BM & other
allogeneic transplants
• Can be used alone
• More effective when glucocorticoids are also
administered
• Most active when administered before antigen
exposure

23. • Useful in autoimmune disease as well
• Alternative to methotrexate for the treatment of
severe, active RA
• Selectively suppresses CMI
• 2nd
line drug for uveitis, bronchial asthma, etc.
• Free of toxic effects on BM & RE system

24. • For induction it is started orally 12 hrs before the
transplant & continued for as long as needed
• When graft rejection has started, it can be given i.v
• Concentrated in RBCs & WBCs
• Metabolized in liver excreted in bile
• Biphasic t1
/ : 4 -6hrs & 12 -18hrs

25. Toxicity : Cyclosporine
• Renal dysfunction
• Tremor
• Hirsuitism
• Hypertension
• Hyperlipidemia
• Gum hyperplasia
• Hyperuricemia – worsens gout
• Calcineurin inhibitors + Glucocorticoids =
Diabetogenic

26. Tacrolimus (FK506)Tacrolimus (FK506)
• Chemically different from cyclosporine, newer
immunosuppressant
• Macrolide that is isolated from soil fungus
• Binds to different cytoplasmic immunophilin
protein labelled FK506 binding protein(FKBP)

27. • Same MOA, 100 times more potent
• Orally as well as i.v infusion
• Metabolized by CYP3A4 & excreted in bile &
plasma t1
/2is 12hrs
• Clinical efficacy as well as toxicity profile are similar
to cyclosporine

28. Toxicity - Tacrolimus
• Nephrotoxicity
• Neurotoxicity-Tremor, headache, motor disturbances,
seizures
• GI Complaints
• Hypertension
• Hyperglycemia
• Risk of tumors, infections
• Drug interaction
– Synergistic nephrotoxicity with cyclosporine
– CYP3A4

29. Antiproliferative & Antimetabolic
drugs
• Sirolimus
• Everolimus
• Azathioprine
• Mycophenolate Mofetil
• Others:
– Methotrexate
– Cyclophosphamide
– Thalidomide
– Chlorambucil

30. Sirolimus
• Macrolide antibiotic
• Binds to same immunoglobulin FKBP as Tacrolimus
• Sirolimus-FKBP complex inhibits another kinase
called ‘mammalian target of rapamycin (mTOR)
(does not interact with calcineurin)
• Leads to proliferation & differentiation of T-cells
activated by IL-2

31. • Extensively metabolized mainly by CYP3A4
• Elimination primarily by biliary route
• T1/2- approx 60 hours
Uses
• Prophylaxis of organ transplant rejection along
with other drugs(cyclosporin/tacrolimus)

32. Sirolimus
Toxicity
• Increase in serum cholesterol, Triglycerides
• Anemia
• Thrombocytopenia
• Hypokalemia
• Fever
• GI effects
• Risk of infection, tumors

33. Everolimus
• Similar to sirolimus in mechanism, clinical efficacy,
doses & drug interactions
• Better absorbed orally
• Shorter half life (approx 40 hours)
• Shorter time taken to reach steady state
• Similar uses & toxicity

34. Azathioprine
• Purine antimetabolite
• Selectively affects differentiation & function of T-
cells
• Inhibits cytolytic T-lymphocytes, CMI is primarily
depressed
Uses
• Prevention of renal & other graft rejections
• Rheumatoid arthritis(lower doses)

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

36. Mycophenolate Mofetil
• Newer immunosupressant
• Prodrug of Mycophenolic acid
• Inhibits Inosine Monophosphate Dehydrogenase –
enzyme in guanine synthesis
• Inhibits lymphocyte proliferation, antibody
production & CMI

37. Uses - Mycophenolate
Mofetil
• Prophylaxis of renal transplant rejection
• Mycophenolate mofetil+glucocorticoid+sirolimus –
non-nephrotoxic combination utilized in patients
developing renal toxicity with
cyclosporin/tacrolimus
• Toxicity
• GI, Hematological
– Diarrhea, Leucopenia
• Risk of Infection(CMV infections)

38. CyclophosphomideCyclophosphomide
• More marked effect on B cells & humoral immunity
• Used in BM transplantation in which short course
with high dose is given
• In other organ transplantations it is employed only as
a reserve drug
• In RA, it is rarely used
• Low doses are occasionally employed for
maintenance therapy in pemphigus, SLE & idiopathic
thrombocytopenic purpura

39. MethotrexateMethotrexate
• Folate antagonist, potent immunosupressant
• Markedly depresses cytokine production & cellular
immunity & has anti-inflammatory property
• Used as 1st
line drug in many autoimmune diseases
like rapidly progressing RA, severe psoriasis,
pemphigus, myasthenia gravis, uveitis, chronic active
hepatitis
• Low dose as maintenance therapy is relatively well
tolerated

40. Fingolimod(FTY720)
• Sphingosine 1 Phosphate Receptor agonist
• Reduce recirculation of lymphocytes from lymphatic
system to blood & peripheral tissues
• “Lymphocyte homing” – periphery into lymph node
• Protects graft from T-cell-mediated attack
Uses
• Combination immunosuppression therapy in

41. Toxicity
• Lymphopenia
• Bradycardia
• Macular edema

42. Antibodies
• Antithymocyte Globulin
• Monoclonal antibodies
– Anti-CD3 Monoclonal antibody (Muromonab-CD3)
– Anti-IL-2 Receptor antibody (Daclizumab, Basiliximab)
– Campath-1H (Alemtuzumab)
• Anti-TNF Agents
– Infliximab
– Etanercept
– Adalimumab

43. Anti-thymocyte Globulin
• Polyclonal antibody purified from horse or rabbits
immunized with human thymic lymphocytes
• Binds to T lymphocytes & depletes them
• Potent immunosupressant
Uses
• Induction of immunosuppression – transplantation
• To suppress acute allograft rejection episodes
Toxicity
• Hypersensitivity
• Risk of infection, Malignancy

44. Anti-CD3 Monoclonal
Antibody
• Murine monoclonal antibody against the CD3
glycoprotein expressed near to the T cell receptor on
helper T cell
• Binds to CD3, a component of T-cell receptor complex
involved in
– antigen recognition
– cell signaling & proliferation

45. Muromonab-CD3
Antibody treatment
Rapid internalization of T-cell receptor
Rapid T-cell depletion from blood
Prevents subsequent antigen recognition

46. Use
• Treatment of acute organ transplant
rejection
Toxicity
• “Cytokine release syndrome”
• Aseptic meningitis, life threatening
pulmonary edema(rare)

47. Anti-IL-2 Receptor Antibodies
• Daclizumab & Basiliximab
• Bind to IL-2 receptor with high affinity on surface of
activated T cells  Block IL-2 mediated T-cell activation
Uses
• Prophylaxis of Acute organ rejection & maintenance of
graft
Toxicity
• Anaphylaxis, Opportunistic Infections

48. Campath-1H
(Alemtuzumab)
• Monoclonal antibody binds CD52 – expressed on
lymphocytes, monocytes, macrophages
• Extensive lympholysis – Prolonged T & B cell depletion
Uses
• CLL, Bone marrow transplantation, Renal
transplantation
Toxicity
• Opportunistic infections

49. Anti-TNF Agents
• TNF – Cytokine at site of inflammation
• Infliximab
• Etanercept
• Adalimumab

50. Infliximab
• Chimeric monoclonal antibody against TNFα
Uses
• Rheumatoid arthritis
• Chron’s disease – fistulae
• Psoriasis
• Psoriatic arthritis
• Ankylosing spondylosis
Toxicity
• Infusion reaction – fever, urticaria, hypotension, dyspnoea
• Opportunistic infections – TB, RTI, UTI

51. Etanercept
• Fusion protein
• Ligand binding portion of Human TNF-α receptor fused
to Fc portion of human IgG1
• Neutralizes both TNFα & TNFß
• Prevents activation of macrophages & T-cells
Uses
• Rheumatoid arthritis
• Also approved for severe/refractory ankylosing
spondylitis, plaque psoriasis

52. LFA-1 Inhibitor - Efalizumab
• Recombinant humanized monoclonal Ab targeting
CD11a subunit of lymphocyte function associated
antigen 1
• Blocks T-cell adhesion, activation, trafficking
Uses
• Organ transplantation
• Psoriasis
• Withdrawn from market in 2009 due to fatal brain
infections(bacterial sepsis, invasive fungal disease)

53. Sites of Action of Selected
Immunosuppressive Agents on T-Cell
Activation
DRUG SITE OF ACTION
• Glucocorticoids Glucocorticoid response elements in
DNA (regulate gene transcription)
• Muromonab-CD3 T-cell receptor complex (blocks
antigen recognition)
• Cyclosporine Calcineurin (inhibits phosphatase
activity)
• Tacrolimus Calcineurin (inhibits phosphatase
activity)
• Azathioprine Deoxyribonucleic acid (false
nucleotide incorporation)
• Mycophenolate Mofetil Inosine monophosphate
dehydrogenase (inhibits activity)
• Daclizumab, Basiliximab IL-2 receptor (block IL-2-mediated
T-cell activation)
• Sirolimus Protein kinase involved in cell-cycle
progression (mTOR) (inhibits
activity)

54. Immunostimulants
• Levamisole
• Thalidomide
• BCG
• Recombinant Cytokines
– Interferons
– Interleukin-2

55. Immunization
• Vaccines
• Immune Globulin
• Rho (D) Immune
Globulin

56. TETRAMISOLE (LEVAMISOLE)
• Levamisole is orally active levo isomer of tetramisole,
restores depressed T-cell function
• Used as an adjunct in malignancies, aphthous ulcers &
recurrent herpes, also used as disease modifying drug
in Rheumatoid Arthritis
• Mainly acts by raising c-GMP levels through interaction
with thymopoietien receptor sites

57. • Leads to decrease in metabolic inactivation of c-
GMP accompanied with increased breakdown of c-
AMP
• Increase in c-GMP level induces lymphocyte
proliferation & augmentation of chemotactic
responses
• This reflects into increased antibody production,
lymphokine production, increased phagocytosis

58. Thalidomide
• Anxiolytic, antiemetic drug with antiinflammatory,
cytokine modulatory activity
• Enhanced T-cell production of cytokines – IL-2,
IFN-γ
• NK cell-mediated cytotoxicity against tumor cells
USE:
• Multiple myeloma, ENL

59. Bacillus Calmate Guerin(BCG)
Vaccine
• It is used as immunological enhancer to stimulate
intact immune system (i.e. a non-specific
immunoenhancer.) of the body.
• BCG & its methanol extracted residue (MER) contain
muramyl dipeptide as an active immunostimulant
ingredient
• T-lymphocytes are principle target cells for the action
of BCG vaccine.

60. • It causes stimulation of macrophage function, phagocytic
activity, lysosomal enzyme activity & chemotaxis
mechanisms
• It induces the production of lymphocyte-activity factor
resulting of phase I of immune response.
• Because of its activity against tumour antigen it is beneficial
in treatment of lung & breast cancer, acute lympholytic &
myelogeneous leukaemia.
• It is available as unlyophilized, live or killed lyophilized form.

61. Interferons
• Low molecular weight glycoprotein cytokines
produced by host cells in response to viral infections
• Immunomodulatory activity
• Bind to cell surface receptors – initiate intracellular
events
– Enzyme induction
– Inhibition of cell proliferation
– Affect viral replication
– Increased Phagocytosis

62. Interferon alfa-2b
• Hairy cell leukemia
• Malignant melanoma
• Kaposi sarcoma
• Chronic Hepatitis B
Adverse reactions
• Flu-like symptoms – fever, malaise, headache
• CVS- hypotension, Arrhythmia
• CNS- depression, altered behaviour

63. Interleukin-2 (aldesleukin)
• Proliferation of cellular immunity – Lymphocytosis,
eosinophilia, release of multiple cytokines – TNF, IL-1, IFN-γ
• Promotes differentiation of T-cells
Uses
• Metastatic renal cell carcinoma
• Malignant Melanoma
Toxicity
• Flu- like symptoms- fever, headache, fatigue
• Hypotension, drowsiness, confusion, loss of appetite

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

65. Active immunization
Vaccines
• Impart active immunity
• Active immunization more efficacious & longer
lasting than passive immunization
• Booster doses required at certain intervals
• Anticancer vaccines – immunizing patients with APCs
expressing tumor antigen

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

68. • Nonspecific immunoglobulins
– Antibody-deficiency disorders
• Specific immune globulins
– High titers of desired antibody
– Hepatitis B, Rabies, Tetanus

69. Rho (D) Immune Globulin
• Antibodies against Rh(D) antigen on the surface of
RBC
• Binds the Rho antigens & does not allow them to
induce antibody formation in Rh –ve individuals
• Used for prevention of postpartum/post-abortion
formation of antibodies in Rho-D –ve women
(Hemolytic disease of newborn)
• Given at 28th
week of pregnancy

70. Conclusion
• Immunology is one of the most rapidly developing
areas of medical biotechnology research
• Immunomodulators are going to be central part of 21st
centuary medicine
• Immunomodulation is a normalising process which
correct weak immune systems & temper immune
systems that are overactive
• Immunomodulators are becoming a viable adjunct to
established modalities offering a novel approach for
the treatment of infectious disease in coming decades

71. References
• Patil U.S, Jaydeokar A.V, Bandawane D.D,
immunomodulators : a pharmacological review,
international journal of pharmacy & pharmaceutical
sciences, vol 4, suppl 1, 2012
• Essentials of Medical Pharmacology: K.D. Tripathi, 7th
edition
• Rang.H.P, Dale.M.M, Ritter.J.M, FlouerR.J, Pharmacology,
Philadelphia, Churchil livingstone-elsevier, 7th
edition