immuno modulator s

7/30/2019 Immuno Modulator s

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IMMUNOMODULATORS

PURVI H KAKRANI

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The Immune Response - why and how ?

Discriminate: Self / Non self

Destroy:

Infectious invaders Dysregulated self (cancers)

Immunity:

Innate, Natural

Adaptive, Learned



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Who are involved ?

Innate

Complement

Granulocytes

Monocytes/macrophages NK cells

Mast cells

Basophils

Adaptive:

B and Tlymphocytes

B: antibodies T : helper,

cytolytic,suppressor.



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IMMUNE MODIFIERS

Immunosuppressants Immunostimulants

? Immune tolerance



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Immunosuppressants

Glucocorticoids

Calcineurin inhibitors Cyclosporine

Tacrolimus

Antiproliferative / antimetabolic agents Sirolimus

Everolimus

Azathioprine

Mycophenolate Mofetil Others methotrexate, cyclophosphamide,

thalidomide and chlorambucil



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Antibodies

Antithymocyte globulin

Anti CD3 monoclonal antibody Muromonab

Anti IL-2 receptor antibody

Daclizumab, basiliximab

Anti TNF alpha infliximab, etanercept



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Immunostimulants

Levamisole

Thalidomide

BCG Recombinant Cytokines

Interferons

Interleukin-2



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Immunosuppressants

Organ transplantation

Autoimmune diseases

Life long use

Infection, cancers

Nephrotoxicity

Diabetogenic

Problem



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Glucocorticoids

Induce redistribution of lymphocytes decrease in peripheral blood lymphocytecounts

Intracellular receptors regulate genetranscription

Down regulation of IL-1, IL-6

Inhibition of T cell proliferation

Neutrophils, Monocytes display poorchemotaxis

Broad anti-inflammatory effects onmultiple components of cellular immunity



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USES - Glucocorticoids

Transplant rejection

GVH BM transplantation

Autoimmune diseases RA, SLE,Hematological conditions

Psoriasis

Inflammatory Bowel Disease, Eye

conditions



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Calcineurin inhibitors

Cyclosporine

Tacrolimus

Most effective immunosuppressivedrugs

Target intracellular signalingpathways

Blocks Induction of cytokine genes



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Cyclosporine

More effective against T-cell dependentimmune mechanisms transplant rejection,autoimmunity

IV, Oral

Uses

Organ transplantation: Kidney, Liver, Heart Rheumatoid arthritis, IBD, uveitis

Psoriasis Aplastic anemia Skin Conditions- Atopic dermatitis, Alopecia

Areata, Pemphigus vulgaris, Lichen planus,Pyoderma gangrenosum



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Toxicity : Cyclosporine

Renal dysfunction

Tremor

Hirsuitism

Hypertension Hyperlipidemia

Gum hyperplasia

Hyperuricemia worsens gout

Calcineurin inhibitors + Glucocorticoids =Diabetogenic



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Drug Interaction : Cyclosporine

CYP 3A4

Inhibitors: CCB, Antifungals,Antibiotics, HIV PI, Grape juice

Inducers: Rifampicin, Phenytoin

Additive nephrotoxicity: NSAIDs



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Tacrolimus

Inhibits T-cell activation byinhibiting calcineurin

Use Prophylaxis of solid-organ allograft

rejection



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Toxicity - Tacrolimus

Nephrotoxicity

Neurotoxicity-Tremor, headache, motordisturbances, seizures

GI Complaints Hypertension

Hyperglycemia

Risk of tumors, infections

Drug interaction Synergistic nephrotoxicity with cyclosporine

CYP3A4



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Antiproliferative and Antimetabolic

drugs

Sirolimus

Everolimus

Azathioprine

Mycophenolate Mofetil Others:

Methotrexate

Cyclophosphamide

Thalidomide

Chlorambucil



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Sirolimus

Inhibits T-cell activation andProliferation

Complexes with an immunophilin,Inhibits a key enzyme in cell cycleprogression mammalian target ofrapamycin (mTOR)



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Sirolimus

Uses Prophylaxis of organ transplant rejection

along with other drugs

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

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Everolimus

Shorter half life compared tosirolimus

Shorter time taken to reach steadystate

Similar toxicity, drug interactions



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Azathioprine

Purine antimetabolite

Incorporation of false nucleotide

6 Thio-IMP 6Thio-GMP 6Thio-GTP

Inhibition of cell proliferation

Impairment of lymphocyte function

Uses

Prevention of organ transplantrejection

Rheumatoid arthritis



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Toxicity - Azathioprine

Bone marrow suppression-leukopenia, thrombocytopenia,anemia

Increased susceptibility to infection

Hepatotoxicity

Alopecia

GI toxicity

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Mycophenolate Mofetil

Prodrug Mycophenolic acid

Inhibits IMPDH enzyme in guanine

synthesis T, B cells are highly dependent on

this pathway for cell proliferation

Selectively inhibits lymphocyteproliferation, function Antibodyformation, cellular adhesion,migration



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Uses - Mycophenolate Mofetil

Prophylaxis of transplant rejection

Combination: Glucocorticoids

Calcineurin Inhibitors

Toxicity

GI, Hematological Diarrhea, Leucopenia

Risk of Infection



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Drug Interaction

Decreased absorption when co-administered with antacids

Acyclovir, Gancyclovir compete withmycophenolate for tubular secretion



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FTY720

S1P-R agonist sphingosine 1 receptor

Reduce recirculation of lymphocytes fromlymphatic system to blood and peripheral

tissuesLymphocyte homing periphery into

lymph node

Protects graft from T-cell-mediated attack

Uses Combination immunosuppression therapy

in prevention of acute graft rejection



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Toxicity

Lymphopenia

Negative chronotropic effect

S1P-receptor on human atrial myocytes



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Antibodies

Againstlymphocyte cell-surface antigens

Polyclonal /Monoclonal



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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

LFA-1 Inhibitor (lymphocyte function associated) Efalizumab



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Anti-thymocyte Globulin

Purified gamma globulin from serum ofrabbits immunized with human thymocytes

Cytotoxic to lymphocytes & block lymphocytefunction

Uses Induction of immunosuppression

transplantation Treatment of acute transplant rejection

Toxicity Hypersensitivity Risk of infection, Malignancy



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Anti-CD3 Monoclonal Antibody

Muromonab-CD3

Binds to CD3, a component of T-cell

receptor complex involved in antigen recognition

cell signaling & proliferation



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Muromonab-CD3

Antibody treatment

Rapid internalization of T-cellreceptor

Prevents subsequent antigenrecognition



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Uses

Treatment of acute organ transplantrejection

Toxicity

Cytokine release syndrome

High fever, Chills, Headache,Tremor, myalgia, arthralgia,weakness

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Anti-IL-2 Receptor Antibodies

Daclizumab and Basiliximab

Bind to IL-2 receptor on surface ofactivated T cells Block IL-2 mediated

T-cell activationUses

Prophylaxis of Acute organ rejection

Toxicity

Anaphylaxis, Opportunistic Infections



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Campath-1H (Alemtuzumab)

Targets CD52 expressed onlymphocytes, monocytes, Macrophages

Extensive lympholysis Prolonged T &B cell depletion

Uses

Renal transplantation



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Anti-TNF Agents

TNF Cytokine at site of inflammation

Infliximab Etanercept

Adalimumab



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Infliximab

Uses Rheumatoid arthritis Chrons disease fistulae Psoriasis Psoriatic arthritis Ankylosing spondylosis

Toxicity

Infusion reaction fever, urticaria,hypotension, dyspnoea

Opportunistic infections TB, RTI, UTI



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Etanercept

Fusion protein

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

IgG1

Uses

Rheumatoid arthritis



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moderate to severely active crohns disease

Adalimumab

Recombinant human anti-TNF mAb



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LFA-1 Inhibitor - Efalizumab

Monoclonal Ab TargetingLymphocyte Function AssociatedAntigen

Blocks T-cell Adhesion, Activation,Trafficking

Uses Organ transplantation

Psoriasis



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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- CD3T-cell receptor complex (blocksantigen recognition)

Cyclosporine Calcineurin (inhibits phosphataseactivity)

Tacrolimus Calcineurin (inhibits phosphataseactivity)

Azathioprine Deoxyribonucleic acid (falsenucleotide incorporation)

Mycophenolate Mofetil Inosine monophosphatedehydrogenase (inhibits activity)

Daclizumab, Basiliximab IL-2 receptor (block IL-2-mediatedT-cell activation)

Sirolimus Protein kinase involved in cell-cycleprogression (mTOR) (inhibits

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Immunostimulants

Levamisole

Thalidomide

BCG Recombinant Cytokines

Interferons

Interleukin-2



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Immunization

Vaccines

Immune Globulin

Rho (D) Immune

Globulin



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Levamisole

Antihelminthic

Restores depressed immunefunction of B, T cells, Monocytes,Macrophages

Adjuvant therapy with 5FU in coloncancer

Toxicity

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Thalidomide

Birth defect

Contraindicated in women withchildbearing potential

Enhanced T-cell production ofcytokines IL-2, IFN-

NK cell-mediated cytotoxicity againsttumor cells

USE:

Multiple myeloma



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Bacillus Calmette-Guerin

Live, attenuated culture of BCGstrain of Mycobacterium Bovis

Carcinoma Bladder

Adverse Effects

Hypersensitivity

Shock

Chills



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Interferons

Antiviral

Immunomodulatory activity

Bind to cell surface receptors initiate intracellular events

Enzyme induction

Inhibition of cell proliferation

Enhancement of immune activities

Increased Phagocytosis



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Interferon alfa-2b

Hairy cell leukemia Malignant melanoma

Kaposi sarcoma

Hepatitis B

Adverse reactions

Flu-like symptoms fever, chills,headache

CVS- hypotension, Arrhythmia

CNS- depression, confusion



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Interleukin-2 (aldesleukin)

Proliferation of cellular immunity Lymphocytosis, eosinophilia, release ofmultiple cytokines TNF, IL-1, IFN-

Uses

Metastatic renal cell carcinoma

Melanoma

Toxicity

Cardiovascular: capillary leak syndrome,Hypotension



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Immunization

Active Stimulation with an Antigen

Passive Preformed antibody



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Active immunization

Vaccines

Administration of antigen as awhole, killed organism, or a specificprotein or peptide constituent of anorganism

Booster doses

Anticancer vaccines immunizingpatients with APCs expressingtumor antigen.



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Immune Globulin

Indications

Individual is deficient in antibodies immunodeficiency

Individual is exposed to an agent,inadequate time for activeimmunization

Rabies Hepatitis B



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Nonspecific immunoglobulins

Antibody-deficiency disorders

Specific immune globulins

High titers of desired antibody

Hepatitis B, Rabies, Tetanus



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Rho (D) Immune Globulin

Antibodies against Rh(D)antigen on the surface ofRBC

Rh-negative women may be

sensitized to Foreign Rhantigen on fetal RBC

Anti-RH Antibodiesproduced in mother candamage subsequent fetusesby lysing RBCs

Hemolytic disease ofnewborn



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Immune tolerance

Induction and maintenance ofimmunologic tolerance - active stateof antigenic specific

nonresponsiveness

Still experimental



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Summary

Immunosuppresion

Calcineurin inhibitors

Glucocorticoids

Antimetabolites

Newer immunosuppresive agents

Effective control of rejection

Glucocorticoid withdrawal



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immuno modulator s

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