IMMUNOMODULATORS

PURVI H KAKRANI

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The Immune Response - why and how ?

Discriminate: Self / Non self Destroy:

Infectious invaders Dysregulated self (cancers) Innate, Natural Adaptive, Learned

Immunity:

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Who are involved ?

Innate

Adaptive:

Complement Granulocytes Monocytes/macrophages NK cells Mast cells Basophils

B and T lymphocytes 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 Daclizumab, basiliximab

Anti IL-2 receptor antibody

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

Problem
Life long use Infection, cancers Nephrotoxicity Diabetogenic

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Glucocorticoids

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
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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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Toxicity

Growth retardation Avascular Necrosis of Bone Risk of Infection Poor wound healing Cataract Hyperglycemia Hypertension

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Calcineurin inhibitors

Cyclosporine Tacrolimus

Most effective immunosuppressive drugs Target intracellular signaling pathways Blocks Induction of cytokine genes

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Cyclosporine

More effective against T-cell dependent immune 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 by inhibiting calcineurin Use

Prophylaxis of solid-organ allograft rejection

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Toxicity - Tacrolimus

Nephrotoxicity Neurotoxicity-Tremor, headache, motor disturbances, 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 and Proliferation Complexes with an immunophilin, Inhibits a key enzyme in cell cycle progression mammalian target of rapamycin (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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Drug Interactions: CYP 3A4

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Everolimus

Shorter half life compared to sirolimus Shorter time taken to reach steady state Similar toxicity, drug interactions

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Azathioprine

Purine antimetabolite Incorporation of false nucleotide

6Thio-GMP 6Thio-GTP

6 Thio-IMP

Inhibition of cell proliferation Impairment of lymphocyte function Uses Prevention of organ transplant rejection Rheumatoid arthritis
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Toxicity - Azathioprine

Bone marrow suppressionleukopenia, thrombocytopenia, anemia Increased susceptibility to infection Hepatotoxicity Alopecia GI toxicity Drug interaction: Allopurinol
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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 lymphocyte proliferation, function Antibody formation, cellular adhesion, migration
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Uses - Mycophenolate Mofetil

Prophylaxis of transplant rejection Combination: Glucocorticoids Calcineurin Inhibitors Toxicity GI, Hematological

Diarrhea, Leucopenia

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Risk of Infection
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Drug Interaction

Decreased absorption when coadministered with antacids Acyclovir, Gancyclovir compete with mycophenolate for tubular secretion

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FTY720

S1P-R agonist sphingosine 1 receptor Reduce recirculation of lymphocytes from lymphatic system to blood and peripheral tissues Lymphocyte 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

Against lymphocyte cellsurface 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) Infliximab Etanercept Adalimumab Efalizumab
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Anti-TNF Agents

LFA-1 Inhibitor (lymphocyte function associated)

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Anti-thymocyte Globulin

Purified gamma globulin from serum of rabbits immunized with human thymocytes Cytotoxic to lymphocytes & block lymphocyte function

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-cell receptor Prevents subsequent antigen recognition
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Uses

Treatment of acute organ transplant rejection Toxicity Cytokine release syndrome High fever, Chills, Headache, Tremor, myalgia, arthralgia, weakness Prevention: Steroids
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Anti-IL-2 Receptor Antibodies

Daclizumab and Basiliximab Bind to IL-2 receptor on surface of activated T cells Block IL-2 mediated T-cell activation

Uses Prophylaxis of Acute organ rejection Toxicity Anaphylaxis, Opportunistic Infections

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Campath-1H (Alemtuzumab)

Targets CD52 expressed on lymphocytes, 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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Adalimumab Recombinant human anti-TNF mAb

moderate to severely active crohns disease

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LFA-1 Inhibitor - Efalizumab

Monoclonal Ab Targeting Lymphocyte Function Associated Antigen 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
Glucocorticoid response elements in DNA (regulate gene transcription) CD3T-cell receptor complex (blocks antigen recognition) Calcineurin (inhibits phosphatase activity) Calcineurin (inhibits phosphatase activity) Deoxyribonucleic acid (false nucleotide incorporation) Inosine monophosphate dehydrogenase (inhibits activity) IL-2 receptor (block IL-2-mediated T-cell activation) Protein kinase involved in cell-cycle progression (mTOR) (inhibits activity)

Glucocorticoids MuromonabCyclosporine Tacrolimus Azathioprine Mycophenolate Mofetil Daclizumab, Basiliximab Sirolimus

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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 immune function of B, T cells, Monocytes, Macrophages Adjuvant therapy with 5FU in colon cancer

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Toxicity Agranulocytosis
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Thalidomide

Birth defect Contraindicated in women with childbearing potential Enhanced T-cell production of cytokines IL-2, IFN- NK cell-mediated cytotoxicity against tumor cells USE: Multiple myeloma
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Bacillus Calmette-Guerin

Live, attenuated culture of BCG strain 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 of multiple 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 a whole, killed organism, or a specific protein or peptide constituent of an organism Booster doses Anticancer vaccines immunizing patients with APCs expressing tumor antigen.
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Immune Globulin
Indications Individual is deficient in antibodies immunodeficiency Individual is exposed to an agent, inadequate time for active immunization

Rabies Hepatitis B

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Nonspecific immunoglobulins

Antibody-deficiency disorders
High titers of desired antibody Hepatitis B, Rabies, Tetanus

Specific immune globulins

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Rho (D) Immune Globulin

Antibodies against Rh(D) antigen on the surface of RBC Rh-negative women may be sensitized to Foreign Rh antigen on fetal RBC Anti-RH Antibodies produced in mother can damage subsequent fetuses by lysing RBCs Hemolytic disease of newborn
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Immune tolerance

Induction and maintenance of immunologic tolerance - active state of antigenic specific nonresponsiveness Still experimental

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Summary

Immunosuppresion

Calcineurin inhibitors Glucocorticoids Antimetabolites

Effective control of rejection Glucocorticoid withdrawal

Newer immunosuppresive agents

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