1. IMMUNOMODULATORIMMUNOMODULATOR
Dr. V.K.Gupta
Senior Scientist,
Medicine Division
I.V.R.I.IZATNAGAR(UP)

2. The prevention and control of disease in animals and man
is the primary concern of veterinarians and medicos.
The antibiotics will not be effective beyond 2020 as
estimated by WHO.
A novel alternative to antibiotics is the IMMUNO
MODULATION.
Herbal immunomodulators are the most effective without
causing any side effects.

3. The concept of immunomodulation emerged
in 1796 when Edward Jenner (the father of
immunology) undertook the first vaccination.
Since then, many attempts have been made to help the
immune system to face external (bacteria, viruses, etc.) or
internal (cancer and autoimmunity) attacks.

5. History contd…..

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

7. Who are involved ?
• Innate
– Complement
– Granulocytes
– Monocytes/macrophages
– NK cells
– Mast cells
– Basophils
• Adaptive:
– B and T lymphocytes
– B: antibodies
– T : helper, cytolytic,
suppressor.
• Adaptive:
– B and T lymphocytes
– B: antibodies
– T : helper, cytolytic,
suppressor.

9. SPECIFIC IMMUNOMODULATION : Limited to a single antigen
NON SPECIFIC IMMUNOMODULATION: Altered host reactivity to
many different antigens

10. An immunomodulator may be defined as a substance,
biological or synthetic, which can stimulate, suppress or
modulate any of the components of the immune system
including both innate and adaptive arms of the immune
response.
(Agarwal and Singh, 1999)

11. To induce effective and sustained immune response against
infections
Speed up the maturation of non specific & specific
immunity during neonatal period and in young animals
To enhance local immunity
Overcome the immunosuppressive effects of stress and
environmental pollution.
To maintain immune surveillance
Help the immune system and the body helps itselfHelp the immune system and the body helps itself

12. SHOULD BE
 Short withdrawal period with low
tissue residues
 Stimulate both specific and non
specific immune response
 Act as an adjuvant along with vaccine
 Active through oral route
 Compatible with other drugs
 Defined chemical composition and
Biological activity
 Inexpensive
SHOULD NOT
BE
Toxic
Antigenic
Pyrogenic
Long side effects in the
body
Excreted in milk or egg

13. Sl.No. Antimicrobials Immunomodulators
1 Problem of rapid emergence of
resistance
They circumvent the emergence of
resistance since they do not act on
microbes directly
2 In immunocompromised
animals, it work poorly
It is the treatment option for
immunocompromised animals
3 Specific therapy Broad spectrum of activity against viral and
fungal as well as bacterial diseases and may
provide nonspecific emergency-treatment
options in the event of the emergence of a
novel pathogen or a bio warfare attack
(Gallois et al., 2008)

14. Immuno stimulantsImmuno stimulants
ImmunosuppressentsImmunosuppressents
Based on Action
Immunosuppressants are the agents which suppress the immune system and are
used for the control of pathological immune response in autoimmune disease,
graft rejection etc.
Immunosuppressants are the agents which suppress the immune system and are
used for the control of pathological immune response in autoimmune disease,
graft rejection etc.
Immunostimulants are the agents which are used to enhance body's resistance
against infections , enhance the basal levels of immune response, and in
individuals with impairment of immune response as immunotherapeutic agent.
Immunostimulants are the agents which are used to enhance body's resistance
against infections , enhance the basal levels of immune response, and in
individuals with impairment of immune response as immunotherapeutic agent.

15. Based on
Source

16. 1.Neuroendocrine hormones
Opioid peptides
Adrenocorticotropic hormone
Growth hormone & Prolactin
Melatonin
2.Thymic products
Thymopoietin
Thymosin -1
Thymosin fraction-5
Thymulin
Thymic humoral factor
3.Cytokines
Interleukin,
Interferon,
Colony stimulating factor,
Chemokines,
Growth factor.
4. Glucocorticoids
Corticosteroids
Androgens by adrenal cortex

17. Sl.No Products Action on immune system
1 Opioid
substances
Immunosuppression
2 ACTH Immuno suppression, decrease blastogenic responses of
lymphocytes.
3 Growth hormone
& prolactin
Augment antibody synthesis, activity of cytotoxic T-
lymphocytes and natural killer cells.
Maintains the size of thymus & induces production of super
oxide anion
4 Melatonin Increases antibody production

18. Sl.No Products Action on immune system
1 Thymosin α 1 Increases lymphocyte and interferon production
2 Thymo poietin T cell differentiation
3 Thymulin Generates effector cytotoxic T-lymphocytes,
Increases NK cell activity
4 Thymosin
fraction 5
Increases cGMP, Induces T-cell markers on bone marrow,
enhances migration inhibitory factor,
increases antibody production & interferon
5 Thymic humoral
factor
Increases cytotoxic reactivity of lymphoid cells against synergic
tumors
Thymulin plays a role in the interaction between the immune system and the neuro-
endocrine system. (Garabedian et al., 1992)

19. Propionibacterium acnes
Heat killed or formaldehyde treated
suspension are used for immunotherapy.
Activate macrophage.
Clear particulate material from the
circulation.
Enhance humoral & cell mediated
immune response.
Alter liver enzyme levels.
Tumor regression.
Generalised stimulation of T & B
lymphocytes, NK cell & macrophage
Propionibacterium acnes
Heat killed or formaldehyde treated
suspension are used for immunotherapy.
Activate macrophage.
Clear particulate material from the
circulation.
Enhance humoral & cell mediated
immune response.
Alter liver enzyme levels.
Tumor regression.
Generalised stimulation of T & B
lymphocytes, NK cell & macrophage
Lentinan
From mycelia of Lentinus edodes
Augment antigen specific cellular
immune response.
Anti tumor action
Cytokine production including
interferon
Activate the complement pathway
Increased activity on precursor effector
cells,cytotoxic T-lymphocytes, NK cells,
macrophage and antibody production

20. Sl. No. Compound Immunomodulatory action
1 Levamisole Increases T cell and macrophage activity
2 Thiabendazole Enhances blastogenic responsiveness to
mitogens
3 Imuthiol Increases lymphocyte blastogenesis,IL-2
production
4 Avridine Increases bactericidal activity of neutrophils
5 Isoprinosine Increases T- helper cells
6 Glucan Enhances chemotaxis for neutrophils
7 Indomethacin Increases blastogenic responses to t- cells
8 Ascorbic acid T lymphocyte proliferation, lymphokine
production, Increases antibody production
9 Biostim Improves DTH reaction
10 Dihydroheptaptenol Increases number of neutrophils

21. Azadiracta indica (Neem)
Active ingredient-terpenoids
Stimulate phagocytic and antigen presenting ability of macrophages.
Effective in allergic disorders.
Enhances DTH in psoriasis patients, Having anti leprotic action.
The united nations declared neem as the tree of the 21st
century.
(Bhowmik et al., 2010)
Tinospora cordifolia
Active ingredient-tinosporone
Mainly using as a hepato protectant.
Increases the number of macrophages and its phagocytic activity
Inhibits myelosuppression induced by cyclophosphamide
Having anti neoplastic and anti tuberculosis activity (Aher and vahi, 2010)

22. Ocimum sanctum (Tulsi) (“Queen of plants” /“The mother medicine of nature”)
Aqueous extract of O. sanctum showed immunotherapeutic potential in
bovine sub-clinical mastitis
Tulsi leaves are regarded as an 'adaptogen' or anti-stress agent
It inhibit tumour development in mice
Enhances survival of viral encephalitis patients
(Singh et al., 2010)
Allium sativum
Active ingredient-allicin
Augment NK cells
Stimulates T cells and interleukin 2 production
Inhibit tumour development
Garlic boosts IL-10 and IL-4 and is useful in treating psoriasis
(Clement et al., 2010)

23. Withania somnifera (Ashwagandha)
Adaptogen or vitalizer
Active ingredient-alkoloides and saponins
Anti-carcinogenic effects in animal and cell cultures by decreasing the
expression of nuclear factor-kappaB, suppressing intercellular tumor necrosis
factor, and potentiating apoptotic signalling in cancerous cell lines.
(Ichikawa et al., 2006)
Emblica officinalis (Amla)
Active ingredient-phyllemblin
Potent immunosuppressant in arthritis. Help to reduce
inflammation and oedema
Fruit is considered as an adaptogenic that improves immunity
Improve both cell mediated and humoral response
(Alamgir and Uddin, 2010)

24. Zingiber officinale (Ginger)
Active ingredient-Terpenes, oleoresin, gingerols
Antioxidant, antibacterial property
Combats travel sickness, helpful in cough and cold
Aloe Vera
Active ingredient-Carboxy peptidase, salicylate and acemannan
Anti-inflammatory,improves wound healing
Enhance production IL-1 and TNFα from macrophages
Beneficial effect in antiretroviral therapy

25. Andrographis paniculata
Active ingredient-Ethanol extract and diterpene andrographaloides
Stimulate antibody
Inhibit induction of NO synthase
Asparagus racemosus
Active ingredient-steroidal saponins
Anticancer activity

26. Curcuma longa
Active ingredient-curcumin
Anti-inflammatory effect
Chemopreventive effect against cancer.
Nyctanthes abortristis
Active ingredient-lipids
Hepatoprotective
Antiviraal,antifungal,antileshmanial

27. Panax ginseng
Active ingredient-saponins and glycosides
Macrophage migration, stimulate lymphocytes and cytokines
Picrorhiza kurroa
Active ingredient-glucoside
Enhance DTH response

28. Allium cepa
Active ingredient-volatile sulfur compounds
Helpful in anaemia, skin disorder, stomach cancer,bacterial infection, eye
infection
Commonly used to treat cold cough and influenza

30. Enhances resistance of the body
 Makes body refractory to infections
Kamdhenu Ark - From the urine
of the cow
Protecting the DNA from oxidative
damage which is responsible for
ageing, cancer.
Cow urine was found to enhance
the humoral and cell mediated
immune response in mice, increases
B and T lymphocyte blastogenesis,
increases IgG and IgA antibody
titers in mice.
(Chauhan et al., 2001)
Both Panchagavya and Ark can help to reduce multiplication of the viruses such as
the one causing swine flu. (Satbir Singh Bedi, 2009)

31. The term “probiotic” was first used in 1965 by Lilly and Stillwell, to describe
substances secreted by one organism which stimulate the growth of the other.
The term “ probiotics” was derived from the greek word meaning “for life”.
(Reid et al., 2003)
An expert panel commissioned by FAO and WHO defined probiotics as “live
microorganisms which when administered in adequate amounts confer a
beneficial health effect to the host.”

33. a. Some strains can block pathogen
entry into the epithelial cell by
providing a physical barrier
b. Create a mucus barrier by causing
the release of mucus from goblet
cells.
(Melanie et al., 2010)

34. C. Other probiotics maintain intestinal
permeability by increasing the
intercellular integrity of apical tight
junctions, for example, by
pregulating the expression of zona-
occludens1 (a tight junction thereby
stopping the passage of molecules
into the lamina propria.
D. Some probiotic strains have
been shown to produce
antimicrobial factors
(Melanie et al., 2010)
Mechanism of action contd…………….Mechanism of action contd…………….

35. E. Other strains stimulate the innate
immune system by signaling dendritic
cells, which then travel to mesenteric
lymph nodes and lead to the induction
of T cells and the production of anti-
inflammatory cytokines, including IL-
10 and TGF-β.
F. Some probiotics may trigger innate
immune response by activitating NFκB
in Mφ and priming the host immune
response by influencing the production
of IL-8 and subsequent recruitment of
Nφ to sites of intestinal injury.
(Melanie et al., 2010)
Mechanism of action contd…………….Mechanism of action contd…………….

36. Adjuvants are the modulators of immune system.
Ramon (1926) - a substance when used in combination with
specific antigen vaccines enhanced levels of immunity beyond
those developed with the vaccine alone.
Jolles and Paraff,1973- any substance which acts
On a hapten or antigen enhancing its antigenic properties
On the cells involved in the immune response

37. During the past 70 years many adjuvants have been developed, but they were
never accepted for routine vaccination because of their immediate toxicity and fear of
delayed side effects.
Local acute or chronic inflammation with formation of painful abscess,
Persistant nodules, ulcers or draining lymphadenopathy
Influenza like illness with fever
IgE type immediate hypersensitivity to vaccine antigen including
anaphylaxis
Chemical toxicity to tissues or organs
Induction of hypersensitivity to host tissue producing autoimmune
arthritis, amyloidosis, anterior uveitis
Cross reaction with human tissue antigens causing glomerulonephritis
or meningoencephalitis
Immune suppression or oral tolerance
Carcinogenesis
Teratogenesis
(Edelman, 2002)

38. How to overcome-
Regulatory control over use of adjuvant
Development of relatively non-toxic synthetic immunoregulators
Safety and potency test standardization
How to overcome-
Regulatory control over use of adjuvant
Development of relatively non-toxic synthetic immunoregulators
Safety and potency test standardization
Sl. No Adjuvant used Animal
used
Adverse reaction References
1 Aluminium adjuvants Mice Motor neuron death (Petrik et al., 2007)
2 Oil in water emulsion Mice Increase the risk of
autoimmune disease
(Satoh et al., 2003)
3 Squalene Rat rheumatoid arthritis (Carlson et al., 2000)

39. Thalidomide
Isoprinosine .
Immunocynin
Thalidomide
Isoprinosine .
Immunocynin
Recombinant
Cytokines-
Interferons,
Interleukins,
Colonystimulating
factors
Recombinant
Cytokines-
Interferons,
Interleukins,
Colonystimulating
factors
Bacillus
Calmette-
Guerin (BCG)
Bacillus
Calmette-
Guerin (BCG)
LevamisoleLevamisole Other drugs–
inosiplex,
azimexon,
imexon,
thymosin,
methylinosine
monophosphate
Other drugs–
inosiplex,
azimexon,
imexon,
thymosin,
methylinosine
monophosphate
Immunization
-
Vaccines ,
Immune
Globulin
Immunization
-
Vaccines ,
Immune
Globulin

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

41. Live, attenuated culture of BCG strain of Mycobacterium Bovis
MOA
Induction of a granulomatous reaction at the site of
administration. It causes activation of macrophages to make
them more effective killer cells

42. Therapeutic uses
Treatment and prophylaxis of carcinoma of the urinary
bladder,Prophylaxis of primary and recurrent stage of
papillary tumors after transurethral resection.
Adverse effects
Hypersensitivity, shock, chills, fever, malaise, and immune
complex disease.

43. Levamisole /Ergamisol
 synthesized originally as an anthelmintic but appears
to restore depressed immune function of B
lymphocytes, T lymphocytes, monocytes and
macrophages
Therapeutic uses: Adjuvant therapy with 5-
fluorouracil colon cancer, agranulocytosis. Used to
treat immunodeficiency associated with Hodgkins
disease
Adverse effects :Flu-like symptoms, allergic
manifestation, nausea and muscle pain .

44. Thalidomide
MOA
Enhanced T-cell production
of cytokines – IL-2, IFN-γ
NK cell-mediated
cytotoxicity against tumor
cells. Decrease circulating
TNF-α in patients with
erythema nodosum
leprosum, but increase in
HIV-seropositive patients, It
affects angiogenesis also.
Therapeutic uses
Severe, refractory rheumatoid
arthritis . Multiple myeloma
Adverse effects
Teratogenicity

45. •Hormone like, small low molecular weight polypeptides.
•Maintain communication among cells to co-ordinate immune
response.
•Act synergistically or antagonistically thereby enhancing or
supressing their own production
•Autocrine, paracrine or endocrine in action.
•Causes tissue repair and provide resistance to infection
•Hormone like, small low molecular weight polypeptides.
•Maintain communication among cells to co-ordinate immune
response.
•Act synergistically or antagonistically thereby enhancing or
supressing their own production
•Autocrine, paracrine or endocrine in action.
•Causes tissue repair and provide resistance to infection

46. Cytokines : PropertiesCytokines : Properties

47. Cytokine: ActionCytokine: Action
• Autocrine
• Paracine
• Endocrine

48. NAME SOURCE FUNCTION THERAPEUTIC AGENT
IL-1 Monocyte, lymphocyte,
endothelium
Hematopoesis, co-stimulation of T cell, fibroblast
proliferation, acute phase response
Blockage of IL-1 activity
IL-2 Activated T cell T cell proliferation and differentaiation, B cell
proliferation and Ig secretion, proliferation and
cytolytic activity
Treatment of cancer &
infectious diseases, bone
marrow transplantation
IL-3 Activated T cell, mast cell,
NK cell
Proliferation & differentiation of myeloid progenitor
stem cell, prevention of apoptosis induction in
macrophages
Bone marrow
transplantation
IL-4 T cell, mast cell,
eosinophil, basophil
B cell proliferation and differentaiation, Ig switching, Antitumor agent, immune
stimulator
IL-6 T cell, monocyte,
endothelial cells, mast
cells
Stimulate B cell for antibody production & T cell
growth
Antitumor
IL-8 Monocyte, lymphocyte,
endothelial cells
Neutrophil chemotaxis & activation, chemokine
function
None
IL-10 Monocyte, lymphocyte,
endothelial cells
Inhibition of proinflamatory cytokines by monocyte,
granulocytes, inhibition of IL-2 production by T cell,
inhibition of antigen specific T cell activation
Antiinflamatory &
immunosupressive. used in
autoimmune disease
IL-12 Monocyte, Bcells Proliferation of T & NK cell, CTL response to tumor
cell, ↑ IFN γ production by T & NK cell, inhibit Ig E
production
Antimetastatic, antitumor,
vaccine adjuvant
IL-13 Activated T , B cell Bcell growth & differentaiation factor, stimulate
chemotaxis
Antitumor,anti
inflammatory agent

49. NAME SOURCE FUNCTION THERAPEUTIC AGENT
IFN-α Leucocyte Antiproliferative action, immunoregulatory
action
Cancers, hepatitis B,
hepatitis C, AIDS, Kaposi
sarcoma, multiple
sclerosis
IFN-β Fibroblast,
epithelial cell,
endothelial cell
Antiviral, MHC antigen upregulation, NK cell
enhanced cytotoxicity, antimicrobial
Cancer, multiple
sclerosis
IFN-γ Monocyte,
macophage,
dendritic cell, T cell,
B cell
MHC class II expression, macrophage & NK cell
activation, Ig isotype selection
Infection with
Leishmania &
Toxoplasma. Used as
adjuvant
G-CSF Stromal cell,
endothelial cell,
fibroblast
Proliferation & differentiation of macrophage
progenitor cell, emergency granulopoesis
After bone marrow
transplantation
M-CSF Fibroblast,
endothelial cell, T
cell, monocyte,
neutrophil
Monocyte proliferation, differentiation &
activation
Antitumor, anti-
infection, myelo-
supression
GM-
CSF
T cell, macrophage,
endothelial cell, B
cell
Inhibit apoptosis of taget, proliferation ,
differentiation & activation of granulocyte,
macophage lineage
Recruitment of
peripheral blood stem
cell, stimulation of APC
for immunotherapy,
adjuvant action

50. NAME SOURCE FUNCTION THERAPEUTIC AGENT
α
chemokines
Monocyte,
neutrophil,
endothelial cell,
epithelial cell
Neutrophil chemotaxis & adherence, IL-6
secretion
None yet
β
chemokines
Monocyte,
fibroblast,
epithelial cells,
melanocytes
Monocyte activation, basophil activation, T
cell chemotaxis, NK cel cytolysis
None yet
RANTES T cell monocyte,
NK cell,
Fibroblast,
epithelial cell,
Endothelial cell
T cell chemotaxis & proliferation, monocytic
chemotaxis & activation, NK cell chemotaxis,
modulation of macrophages, eosinophils, T
cells
Supression of HIV
replication
TNF-α Macrophages, T
cell
Cytotoxic for tumor cell, antiviral,
antibacterial, antiparasitic activity, growth
stimulation, immunomodulation
Cancer & autoimmune
disease
TNF-β Mast cell,
platelet,
fibroblast
Wound repair, cell growth regulation, tissue
remodelling, immunosupression,
Inhibition of
inflammatory cell,
treatment of breast
cancer.

51. Cytokines-based therapies in clinical useCytokines-based therapies in clinical use
S.N. AGENT NATURE APPLICATION
1. Enbrel Chimeric TNF-receptors/
IgG cont. region
Rheumatoid Arthritis
2. Remicade/Humira Mab against TNF-α receptors Rheumatoid arthritis,
cronh’s dis.
3. Roferon INF-α Hepatitis B ,kaposi’s
sarcoma, Feline leukemia
4. Avonex INF -β Multiple sclerosis
5. Actimmune INF-γ CGD, Osteopetrosis
6. Neupogen G-CSF Increase Nphils,reduce
Infection in Cancer&AIDS
Patients
7. Epogen Erythropoietin Increase RBC Production
Kuby immunology,6th
ed.

52. Sl.
No
Cytokine Veterinary use Reference
1 IFN γ For the trteatment of circo virus
infection in grey parrots
Stanford, 2004
2 TNFα For the diagnosis of E.coli mastitis Alluwaimi , 2004
3 TNFα and
IL-6
For the early diagnosis of MMA in
swine
szczubiał and urban-chmiel,
2008.
4 IFN γ Reduces severity and mortality to
BHV-1 infection.
For the diagnosis of Bovine listeriosis
and Bovine tuberculosis
Sordille and Babuk, 1991
Barbuddhe et al., 1998
5 IL -11 For treating Pseudomonas aeruginosa
in immuno compromised animals
Opal et al., 1998
6 IL-1β, IL-
2, GM-CSF
Prevents S.aureus mastitis Williams et al., 1993

53. Cytokines based therapies-limitationsCytokines based therapies-limitations
• Maintain effective dose at local level.
• Repeated administration may be required.
• Can cause unpredictable and undesirable side
effects.
• Fever, diarrhea, anaemia, shock etc.

54. Isoprinosine(Inosiplex)
complex of the pacetamidobenzoate saltof N,N-dimethylamino-
2- propanol: inosine in a 3:1 molar ratio
MOA
augment production of cytokines such as IL-1, IL-2 and IFN-γ
,increases proliferation of lymphocytes in response to mitogenic
or antigenic stimuli, increases active T-cell rosettes and induces
T-cell surface markers on prothymocytes

55. Therapeutic uses
Herpes simplex infections, subacute sclerosing
panencephalitis,acute viral encephalitis caused by herpes
simplex, Epstein-Barr and measles viruses
Adverse effects
Minor CNS depressant, transient nausea and rise of uric acid
in serum and urine

56. Immunocynin
stable form of
haemocynin, a non-
haeme, oxygen
carrying,copper-
containing protein
found in arthropods and
molluses
Therapeutic
uses:Urinary bladder
cancer.
Adverse effects:Rare-
mild fever

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

59. 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)

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

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

62. Alkylating Agents
Chlorambucil
Melphalan
Cyclophosphamide
Busulfan
Alkylating Agents
Chlorambucil
Melphalan
Cyclophosphamide
Busulfan
Antimetabolites
Methotrixate
Azathioprine
6-mercaptopurine
Antimetabolites
Methotrixate
Azathioprine
6-mercaptopurine
Cortcosteroids
Selective
immunosuppressors
Calcineurin Inhibitors
Cyclosporine
Cortcosteroids
Selective
immunosuppressors
Calcineurin Inhibitors
Cyclosporine

64. Glucocorticoids
MOA : Multiple mechanisms
• Induce redistribution of lymphocytes – decrease in peripheral
blood lymphocyte counts
• Intracellular receptors – regulate gene transcription
• Down regulation of IL-1, IL-6
• Inhibition of T cell proliferation
• Neutrophils, Monocytes display poor chemotaxis
• Broad anti-inflammatory effects on multiple components of
cellular immunity

67. Adverse Effects
Growth retardation in
children, avascular necrosis
of bone,osteopenia,
increased risk of infection,
poor wound healing,
cataracts, hyperglycemia
and hypertension.

68. Lymphocytopenia
MonocytopeniaImmunosuppressive
effects
Lymphocyte and
monocyte function
Anti inflammatory
effects
Complement level
ANTI INFLAMATORY AND IMMUNO SUPPRESSIVE EFFECTS OF CORTICOSTEROIDS
Leukocyte
accumulation
Leukocyte function
Monocytopenia
Eosinopenia
Complement components
Histamine mediated reactions

69. Calcineurin inhibitors
• Calcineurin (CN) is a protein phosphatase ,
activates the T cells of the immune system and can
be blocked by drugs.
– Cyclosporine
– Tacrolimus
• Most effective immunosuppressive drugs
• Target intracellular signaling pathways
• Blocks Induction of cytokine genes

70. Cyclosporine
Cyclosporine (A), cyclic polypeptide consisting of 11 amino acids ,
produced by the fungus species Beauveria nivea
Cyclosporine (A), cyclic polypeptide consisting of 11 amino acids ,
produced by the fungus species Beauveria nivea
Cyclosporine can be given orally or I.V. Plasma half life
is about 24 hrs

71. MOA
 Bind to the cytosolic protein cyclophilin (an
immunophilin) of immunocompetent lymphocytes,
especially T-lymphocytes. This complex of ciclosporin
and cyclophilin inhibits the phosphatase calcineurin,
which under normal circumstances induces the
transcription of interleukin-2
The drug also inhibits lymphokine production and
interleukin release, leading to a reduced function of
effector T-cells

72. Adverse effects
Renal dysfunction, tremor,
hirsutism, hypertension,
hyperlipidemia,gum
hyperplasia, hyperuricemia,
hyper-
cholesterolemia,nephrotoxicity,
hypertension, diabetogenic,
Elevated LDL cholesterol

73. Tacrolimus
MOA
 Like cyclosporine, tacrolimus inhibits T cell activation by
inhibiting calcineurin
 Tacrolimus binds to an intracellular protein FK506-binding
protein-12 (FKBP-12) an immunophilin structurally related to
cyclophilin. A complex of tacrolimus-FKBP-12, Ca2+, calmodulin,
and calcineurin then forms, and calcineurin phosphatase activity is
inhibited
 inhibition of phosphatase activity prevents dephosphorylation
and nuclear translocation of NFAT and inhibits T-cell activation.
MOA
 Like cyclosporine, tacrolimus inhibits T cell activation by
inhibiting calcineurin
 Tacrolimus binds to an intracellular protein FK506-binding
protein-12 (FKBP-12) an immunophilin structurally related to
cyclophilin. A complex of tacrolimus-FKBP-12, Ca2+, calmodulin,
and calcineurin then forms, and calcineurin phosphatase activity is
inhibited
 inhibition of phosphatase activity prevents dephosphorylation
and nuclear translocation of NFAT and inhibits T-cell activation.

75. Therapeutic Uses
Prophylaxis of solid-organ allograft rejection,
kidney transplantation, pediatric liver
transplantation.
Therapeutic Uses
Prophylaxis of solid-organ allograft rejection,
kidney transplantation, pediatric liver
transplantation.
Adverse effects
Nephrotoxicity, neurotoxicity (tremor, headache, motor
disturbances and seizures), GI complaints,
hypertension,hyperkalemia, hyperglycemia, and diabetes
Adverse effects
Nephrotoxicity, neurotoxicity (tremor, headache, motor
disturbances and seizures), GI complaints,
hypertension,hyperkalemia, hyperglycemia, and diabetes
Tacrolimus can be given orally or I.V. plasma half life of 7-8 hrs.Tacrolimus can be given orally or I.V. plasma half life of 7-8 hrs.

76. Sirolimus
Sirolimus (rapamycin) is a macrocyclic lactone produced by
Streptomyces hygroscopicus
Plasma half life is 62 hrs.

77. MOA
Contrary to ciclosporin and tacrolimus, drugs that affect
the first phase of T lymphocyte activation, sirolimus
affects the second one( namely signal transduction and
lymphocyte clonal proliferation).
It binds to FKBP1A like tacrolimus, however the
complex does not inhibit calcineurin but another protein,
mTOR (mammalian target of rapamycin ). It indirectly
inhibits several T lymphocyte-specific kinases and
phosphatases, hence preventing their transition from G1 to
S phase of the cell cycle.
Sirolimus prevents B cell differentiation into plasma
cells, reducing production of IgM, IgG, and IgA
antibodies.

79. Therapeutic Uses
Organ transplant inhibitor, graft rejection, incorporated
into stents to inhibit local cell proliferation and blood
vessel occlusion.
Adverse Effects
Dose-dependent increase in serum cholesterol and
triglycerides,impaired renal function, prolong delayed graft
function, Lymphocele,anemia, leukopenia

80. Azathioprine
purine antimetabolite and imidazolyl derivative of 6-
mercaptopurine
MOA
Following exposure to nucleophiles such as glutathione,
azathioprine is cleaved to 6-mercaptopurine, which in turn is
converted to additional metabolites that inhibit de novo purine
synthesis. 6-Thio-IMP, a fraudulent nucleotide,is converted to 6-
thio-GMP and finally to 6-thio-GTP, which is incorporated into
DNA. Cell proliferation is thereby inhibited impairing a variety of
lymphocyte functions.

81. Therapeutic Uses
Allogeneic kidney transplantation, organ transplant rejection
Adverse effects
Bone marrow suppression including leukopenia
(common),thrombocytopenia, anemia (less common), increased
susceptibility to infections (especially varicella andherpes simplex
viruses), hepatotoxicity, alopecia, GI toxicity

82. Mycophenolate Mofetil
MOA
 prodrug rapidly hydrolyzed to the active drug,
mycophenolic acid (MPA), a selective, noncompetitive and
reversible inhibitor of inosine monophosphate
dehydrogenase (IMPDH)- important enzyme in the de
novo pathway ofguanine nucleotide synthesis
B and T lymphocytes are highly dependent on this
pathway for cell proliferation ( other cell types can use
salvage pathways)
MPA therefore selectively inhibits lymphocyte
proliferation and functions including antibody formation,
cellular adhesion, and migration.

83. Therapeutic Uses
Prophylaxis of transplant rejection, renal transplantation
Adverse effects
Leukopenia, diarrhoea, and vomiting, sepsis associated
with cytomegalovirus, in combination with mycophenolate
mofetil has been associated with devastating viral
infections including polyoma nephritis

84. Cyclophosphamide
unique immunosuppressant as it suppresses B-lymphocyte
proliferation but can enhance T-cell responses
MOA
 introduce alkyl groups by form covalent bonds with
nucleophilic moieties such as phosphate, sulfhydryl, hydroxyl,
carboxyl, amino and imidazole groups present in DNA or RNA
 cross link in between the strands of DNA , prevent the cell
division and protein synthesis.
 most destructive to rapidly proliferating tissues and appear
to cause cell death when they divide
 cytotoxicity of the drugs correlates with the degree of DNA
alkylation.

85. Therapeutic Uses
Autoimmune disorders (including systemic lupus
erythematosus), in patients with acquired factor XIII
antibodies and bleeding syndromes, autoimmune
hemolytic anemia, antibody-induced pure red cell aplasia,
and Wegener's granulomatosis
Adverse effects
Pancytopenia and hemorrhagic cystitis, graftversus-host
disease syndrome, nausea, vomiting, cardiac toxicity and
electrolyte disturbances

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

88. Infliximab
The drug cross links with membrane bound
TNF—α receptors on cell surface to inhibit T-
cell and macrophage function and to prevent
the release of other proinflammatory
cytokines (IL-1, IL-6 and 8 along with
collagenase and metalloproteinases). Though
it also has a longer half life, it does not bind
TNF-β.

89. Uses
• Rheumatoid arthritis
• Chron’s disease – fistulae
• Psoriasis
• Psoriatic arthritis
• Ankylosing spondylosis
Adverse effects
• Infusion reaction – fever, urticaria, hypotension,
dyspnoea
• Opportunistic infections – TB, RTI, UTI

90. Etanercept
• Fusion protein produced through expression
of recombinant DNA.
• Ligand binding portion of Human TNF-α
receptor fused to Fc portion of human IgG1
Uses
• Rheumatoid arthritis

91. Uses :
moderate to severely active crohn’s disease
AdalimumabAdalimumab
Recombinant human anti-TNF mAbRecombinant human anti-TNF mAb

92. Antithymocyte Globulin (ATG)
Antithymocyte globulin is a purified gamma globulin from the
serum of rabbits immunized with human thymocytes
MOA
 Antithymocyte globulin contains cytotoxic antibodies that bind to
CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, CD45, and HLA class
I and II molecules on the surface of human T lymphocytes.
deplete circulating lymphocytes by direct cytotoxicity(both
complement and cell-mediated) and block lymphocyte function by
binding to cell surface molecules involved in the regulation of cell
function

93. Therapeutic Uses
Acute renal transplant rejection, recovery from ischemic
reperfusion injury.
Adverse effects
Fever and chills, hypotension, Serum sickness,
glomerulonephritis,leukopenia and thrombocytopenia,
increased risk of infection and malignancy especially when
multiple immunosuppressive agents are combined

94. Anti-CD3 Monoclonal Antibody
• Muromonab-CD3
• Binds to CD3, a component of T-cell receptor
complex involved in
– antigen recognition
– cell signaling & proliferation

95. Muromonab-CD3
Antibody treatment
Rapid internalization of T-cell receptor
Prevents subsequent antigen recognition

96. Uses:
• Treatment of acute organ transplant rejection
Toxicity
• “Cytokine release syndrome”
• High fever, Chills, Headache, Tremor, myalgia,
arthralgia, weakness

97. Efalizumab
Efalizumab (LFA-1 Inhibitor) is a humanized IgG1 mAb targeting
the CD11a chain of LFA-1 (lymphocyte function associated
antigen).
MOA
Binds to LFA-1 and prevents the LFA-1-ICAM (intercellular
adhesion molecule) interaction to block T-cell adhesion,
trafficking, and activation.
Therapeutic Uses
Survival of murine skin and heart allografts and monkey heart
allografts, psoriasis, renal transplantation

98. Rho (D) Immune GlobulinRho (D) Immune Globulin
• It is a concentrated (15%)
solution of human IgG
containing a higher titer of
antibodies against the Rho
(D)antigen of the red cell
• prevent the immunological
condition known as Rhesus
disease (or hemolytic disease of
newborn).
• treating chronic idiopathic
thrombocytopenic purpura in
Rh-positive patients who have
not been splenectomized

99. Helping the body to help itself by optimising the immune
system is of central importance.
Unfortunately no immunomodulator is available which
fulfill all the standards
It needs extensive research and development of
compounds
Attention should directed towards patenting effective plant
products or preparations for the benefit of man kind and
animal welfare.
An ideal immunomodulator has yet to be discovered,
developed and validated
Helping the body to help itself by optimising the immune
system is of central importance.
Unfortunately no immunomodulator is available which
fulfill all the standards
It needs extensive research and development of
compounds
Attention should directed towards patenting effective plant
products or preparations for the benefit of man kind and
animal welfare.
An ideal immunomodulator has yet to be discovered,
developed and validated