IMMUNOMODULATOR IMMUNOMODULATOR

Dr. V.K.GuptaSenior Scientist,Medicine Division

I.V.R.I.IZATNAGAR(UP)

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.

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.

History contd…..

The Immune Response - why and how ?

• Discriminate: Self / Non self• Destroy:– Infectious invaders– Dysregulated self (cancers)

• Immunity:– Innate, Natural– Adaptive, Learned

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.

SPECIFIC IMMUNOMODULATION : Limited to a single antigen

NON SPECIFIC IMMUNOMODULATION: Altered host reactivity to many different antigens

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)

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 itself Help the immune system and the body helps itself

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

bodyExcreted in milk or egg

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)

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.

Based on Source

1.Neuroendocrine hormonesOpioid peptidesAdrenocorticotropic hormoneGrowth hormone & ProlactinMelatonin

2.Thymic productsThymopoietinThymosin -1Thymosin fraction-5ThymulinThymic humoral factor

3.CytokinesInterleukin,Interferon,Colony stimulating factor,Chemokines,Growth factor.

4. Glucocorticoids CorticosteroidsAndrogens by adrenal cortex

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

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)

Propionibacterium acnesHeat killed or formaldehyde treatedsuspension 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 acnesHeat killed or formaldehyde treatedsuspension 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

LentinanFrom mycelia of Lentinus edodesAugment antigen specific cellular immune response.Anti tumor actionCytokine production including interferonActivate the complement pathwayIncreased activity on precursor effector cells,cytotoxic T-lymphocytes, NK cells, macrophage and antibody production

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

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)

Ocimum sanctum (Tulsi) (“Queen of plants” /“The mother medicine of nature”)Aqueous extract of O. sanctum showed immunotherapeutic potential in

bovine sub-clinical mastitisTulsi leaves are regarded as an 'adaptogen' or anti-stress agent It inhibit tumour development in miceEnhances survival of viral encephalitis patients

(Singh et al., 2010)

Allium sativumActive ingredient-allicinAugment NK cellsStimulates T cells and interleukin 2 productionInhibit tumour developmentGarlic boosts IL-10 and IL-4 and is useful in treating psoriasis

(Clement et al., 2010)

Withania somnifera (Ashwagandha)Adaptogen or vitalizerActive ingredient-alkoloides and saponinsAnti-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-phyllemblinPotent immunosuppressant in arthritis. Help to reduce

inflammation and oedemaFruit is considered as an adaptogenic that improves immunityImprove both cell mediated and humoral response

(Alamgir and Uddin, 2010)

Zingiber officinale (Ginger)Active ingredient-Terpenes, oleoresin, gingerolsAntioxidant, antibacterial propertyCombats travel sickness, helpful in cough and cold

Aloe VeraActive ingredient-Carboxy peptidase, salicylate and acemannanAnti-inflammatory,improves wound healingEnhance production IL-1 and TNFα from macrophagesBeneficial effect in antiretroviral therapy

Andrographis paniculataActive ingredient-Ethanol extract and diterpene andrographaloidesStimulate antibodyInhibit induction of NO synthase

Asparagus racemosus

Active ingredient-steroidal saponinsAnticancer activity

Curcuma longaActive ingredient-curcuminAnti-inflammatory effectChemopreventive effect against cancer.

Nyctanthes abortristisActive ingredient-lipidsHepatoprotectiveAntiviraal,antifungal,antileshmanial

Panax ginsengActive ingredient-saponins and glycosidesMacrophage migration, stimulate lymphocytes and cytokines

Picrorhiza kurroaActive ingredient-glucosideEnhance DTH response

Allium cepaActive ingredient-volatile sulfur compoundsHelpful in anaemia, skin disorder, stomach cancer,bacterial infection, eye

infectionCommonly used to treat cold cough and influenza

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)

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.”

http://www.americannutrition.com/store/Probiotics_Acidophilus.html

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)

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…………….

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…………….

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

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 feverIgE type immediate hypersensitivity to vaccine antigen including

anaphylaxisChemical toxicity to tissues or organsInduction of hypersensitivity to host tissue producing autoimmune

arthritis, amyloidosis, anterior uveitisCross reaction with human tissue antigens causing glomerulonephritis

or meningoencephalitisImmune suppression or oral toleranceCarcinogenesisTeratogenesis

(Edelman, 2002)

How to overcome-

Regulatory control over use of adjuvantDevelopment of relatively non-toxic synthetic immunoregulatorsSafety and potency test standardization

How to overcome-

Regulatory control over use of adjuvantDevelopment of relatively non-toxic synthetic immunoregulatorsSafety 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)

ThalidomideIsoprinosine . Immunocynin

ThalidomideIsoprinosine . Immunocynin

Recombinant Cytokines-Interferons, Interleukins, Colonystimulatingfactors

Recombinant Cytokines-Interferons, Interleukins, Colonystimulatingfactors

Bacillus Calmette-Guerin (BCG)

Bacillus Calmette-Guerin (BCG)

Levamisole Levamisole Other drugs– inosiplex, azimexon, imexon, thymosin, methylinosine monophosphate

Other drugs– inosiplex, azimexon, imexon, thymosin, methylinosine monophosphate

Immunization -Vaccines , Immune Globulin

Immunization -Vaccines , Immune Globulin

Immunostimulants

USES:

• immunodeficiency disorders• Chronic infections • cancer

Live, attenuated culture of BCG strain of Mycobacterium Bovis

MOAInduction of a granulomatous reaction at the site of

administration. It causes activation of macrophages to make them more effective killer cells

Therapeutic usesTreatment and prophylaxis of carcinoma of the urinary bladder,Prophylaxis of primary and recurrent stage of

papillary tumors after transurethral resection.

Adverse effectsHypersensitivity, shock, chills, fever, malaise, and immune complex disease.

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 .

Thalidomide

MOAEnhanced 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 usesSevere, refractory rheumatoid arthritis . Multiple myeloma

Adverse effects Teratogenicity

•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

Cytokines : PropertiesCytokines : Properties

Cytokine: ActionCytokine: Action

• Autocrine

• Paracine

• Endocrine

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

IL-15 Mononuclear cells Stimulation of activated B, T & NK cell, chemoattractant

Antitumor, in rheumatoid arthritis

IL-16 Tc cell, eosinophil Chemotaxis for CD4 cells antiHIV

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

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.

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.

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 andIL-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

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.

Isoprinosine(Inosiplex)

complex of the pacetamidobenzoate saltof N,N-dimethylamino-2- propanol: inosine in a 3:1 molar ratio

MOAaugment 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

Therapeutic usesHerpes simplex infections, subacute sclerosing

panencephalitis,acute viral encephalitis caused by herpes simplex, Epstein-Barr and measles viruses

Adverse effectsMinor CNS depressant, transient nausea and rise of uric acid

in serum and urine

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

Immunization

• Active – Stimulation with an Antigen

• Passive – Preformed antibody

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)

Immune Globulin

Indications• Individual is deficient in antibodies –

immunodeficiency• Individual is exposed to an agent, inadequate time

for active immunization– Rabies– Hepatitis B

• Nonspecific immunoglobulins–Antibody-deficiency disorders

• Specific immune globulins–High titers of desired antibody–Hepatitis B, Rabies, Tetanus

Alkylating AgentsChlorambucilMelphalanCyclophosphamideBusulfan

Alkylating AgentsChlorambucilMelphalanCyclophosphamideBusulfan

AntimetabolitesMethotrixateAzathioprine6-mercaptopurine

AntimetabolitesMethotrixateAzathioprine6-mercaptopurine

CortcosteroidsSelective immunosuppressorsCalcineurin InhibitorsCyclosporine

CortcosteroidsSelective immunosuppressorsCalcineurin InhibitorsCyclosporine

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

Adverse Effects

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

LymphocytopeniaMonocytopeniaImmunosuppressive

effects

Lymphocyte and monocyte function

Anti inflammatory effects

Complement level

ANTI INFLAMATORY AND IMMUNO SUPPRESSIVE EFFECTS OF CORTICOSTEROIDS

Leukocyteaccumulation

Leukocyte function

MonocytopeniaEosinopenia

Complement components

Histamine mediated reactions

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

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

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

Adverse effectsRenal dysfunction, tremor,

hirsutism, hypertension, hyperlipidemia,gum

hyperplasia, hyperuricemia, hyper-

cholesterolemia,nephrotoxicity, hypertension, diabetogenic,

Elevated LDL cholesterol

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.

Therapeutic UsesProphylaxis of solid-organ allograft rejection, kidney transplantation, pediatric liver transplantation.

Therapeutic UsesProphylaxis of solid-organ allograft rejection, kidney transplantation, pediatric liver transplantation.

Adverse effectsNephrotoxicity, neurotoxicity (tremor, headache, motor disturbances and seizures), GI complaints, hypertension,hyperkalemia, hyperglycemia, and diabetes

Adverse effectsNephrotoxicity, 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.

Sirolimus

Sirolimus (rapamycin) is a macrocyclic lactone produced by Streptomyces hygroscopicus

Plasma half life is 62 hrs.

MOAContrary 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.

Therapeutic UsesOrgan transplant inhibitor, graft rejection, incorporated into stents to inhibit local cell proliferation and blood vessel occlusion.

Adverse EffectsDose-dependent increase in serum cholesterol and triglycerides,impaired renal function, prolong delayed graft function, Lymphocele,anemia, leukopenia

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.

Therapeutic Uses Allogeneic kidney transplantation, organ transplant rejection

Adverse effectsBone marrow suppression including leukopenia

(common),thrombocytopenia, anemia (less common), increased susceptibility to infections (especially varicella andherpes simplex

viruses), hepatotoxicity, alopecia, GI toxicity

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.

Therapeutic Uses Prophylaxis of transplant rejection, renal transplantation

Adverse effectsLeukopenia, diarrhoea, and vomiting, sepsis associated with cytomegalovirus, in combination with mycophenolate mofetil has been associated with devastating viral infections including polyoma nephritis

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.

Therapeutic UsesAutoimmune 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 effectsPancytopenia and hemorrhagic cystitis, graftversus-host disease syndrome, nausea, vomiting, cardiac toxicity and electrolyte disturbances

Anti-TNF Agents

• TNF – Cytokine at site of inflammation

• Infliximab• Etanercept• Adalimumab

InfliximabThe 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.

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

Etanercept

• Fusion protein produced through expression of recombinant DNA.

• Ligand binding portion of Human TNF-α receptor fused to Fc portion of human IgG1Uses

• Rheumatoid arthritis

Uses :moderate to severely active crohn’s disease

Adalimumab Adalimumab

Recombinant human anti-TNF mAbRecombinant human anti-TNF mAb

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

Therapeutic UsesAcute renal transplant rejection, recovery from ischemic reperfusion injury.

Adverse effectsFever and chills, hypotension, Serum sickness, glomerulonephritis,leukopenia and thrombocytopenia, increased risk of infection and malignancy especially when multiple immunosuppressive agents are combined

Anti-CD3 Monoclonal Antibody

• Muromonab-CD3• Binds to CD3, a component of T-cell receptor

complex involved in– antigen recognition– cell signaling & proliferation

Muromonab-CD3

Antibody treatment

Rapid internalization of T-cell receptor

Prevents subsequent antigen recognition

Uses:• Treatment of acute organ transplant rejection

Toxicity• “Cytokine release syndrome”• High fever, Chills, Headache, Tremor, myalgia,

arthralgia, weakness

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 UsesSurvival of murine skin and heart allografts and monkey heartallografts, psoriasis, renal transplantation

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

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