IMMUNOMODULATORS

Dr. Manjunath

The Immune Response - why and how ?

Discriminate: Self / Non self Destroy:

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

Immunity:

Who are involved ?

Innate

Adaptive:

Complement Granulocytes Monocytes/macrophages NK cells Mast cells Basophils

B and T lymphocytes B: antibodies T : helper, cytolytic, suppressor.

IMMUNE MODIFIERS

Immunosuppressants

Immunostimulants

? Immune tolerance

Immunosuppressants

Glucocorticoids Calcineurin inhibitors

Cyclosporine Tacrolimus

Antiproliferative / antimetabolic agents

Sirolimus Everolimus Azathioprine Mycophenolate Mofetil Others methotrexate, cyclophosphamide, thalidomide and chlorambucil

Antibodies

Antithymocyte globulin Anti CD3 monoclonal antibody

Muromonab Daclizumab, basiliximab

Anti IL-2 receptor antibody

Anti TNF alpha infliximab, etanercept

Immunostimulants

Levamisole Thalidomide BCG Recombinant Cytokines

Interferons Interleukin-2

Immunosuppressants

Organ transplantation Autoimmune diseases

Problem
Life long use Infection, cancers Nephrotoxicity Diabetogenic

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

USES - Glucocorticoids

Transplant rejection GVH BM transplantation Autoimmune diseases RA, SLE, Hematological conditions Psoriasis Inflammatory Bowel Disease, Eye conditions

Toxicity

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

Calcineurin inhibitors

Cyclosporine Tacrolimus

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

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

Toxicity : Cyclosporine

Renal dysfunction Tremor Hirsuitism Hypertension Hyperlipidemia Gum hyperplasia Hyperuricemia worsens gout Calcineurin inhibitors + Glucocorticoids = Diabetogenic

Drug Interaction : Cyclosporine

CYP 3A4

Inhibitors: CCB, Antifungals, Antibiotics, HIV PI, Grape juice Inducers: Rifampicin, Phenytoin

Additive nephrotoxicity: NSAIDs

Tacrolimus

Inhibits T-cell activation by inhibiting calcineurin Use

Prophylaxis of solid-organ allograft rejection

Toxicity - Tacrolimus

Nephrotoxicity Neurotoxicity-Tremor, headache, motor disturbances, seizures GI Complaints Hypertension Hyperglycemia Risk of tumors, infections

Drug interaction

Synergistic nephrotoxicity with cyclosporine CYP3A4

Antiproliferative and Antimetabolic drugs

Sirolimus Everolimus Azathioprine Mycophenolate Mofetil Others:

Methotrexate Cyclophosphamide Thalidomide Chlorambucil

Sirolimus

Inhibits T-cell activation and Proliferation Complexes with an immunophilin, Inhibits a key enzyme in cell cycle progression mammalian target of rapamycin (mTOR)

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

Drug Interactions: CYP 3A4

Everolimus

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

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

Toxicity - Azathioprine

Bone marrow suppressionleukopenia, thrombocytopenia, anemia Increased susceptibility to infection Hepatotoxicity Alopecia GI toxicity Drug interaction: Allopurinol

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

Uses - Mycophenolate Mofetil

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

Diarrhea, Leucopenia

Risk of Infection

Drug Interaction

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

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

Toxicity

Lymphopenia Negative chronotropic effect

S1P-receptor on human atrial myocytes

Antibodies

Against lymphocyte cellsurface antigens Polyclonal / Monoclonal

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

Anti-TNF Agents

LFA-1 Inhibitor (lymphocyte function associated)

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

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 Prevention: Steroids

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

Campath-1H (Alemtuzumab)

Targets CD52 expressed on lymphocytes, monocytes, Macrophages Extensive lympholysis Prolonged T & B cell depletion Uses Renal transplantation

Anti-TNF Agents

TNF Cytokine at site of inflammation Infliximab Etanercept Adalimumab

Infliximab
Uses Rheumatoid arthritis Chrons disease fistulae Psoriasis Psoriatic arthritis Ankylosing spondylosis Toxicity Infusion reaction fever, urticaria, hypotension, dyspnoea Opportunistic infections TB, RTI, UTI

Etanercept

Fusion protein Ligand binding portion of Human TNF- receptor fused to Fc portion of human IgG1 Uses Rheumatoid arthritis

Adalimumab Recombinant human anti-TNF mAb

moderate to severely active crohns disease

LFA-1 Inhibitor - Efalizumab

Monoclonal Ab Targeting Lymphocyte Function Associated Antigen Blocks T-cell Adhesion, Activation, Trafficking Uses Organ transplantation Psoriasis

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

Immunostimulants

Levamisole Thalidomide BCG Recombinant Cytokines

Interferons Interleukin-2

Immunization

Vaccines Immune Globulin Rho (D) Immune Globulin

Levamisole

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

Toxicity Agranulocytosis

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

Bacillus Calmette-Guerin

Live, attenuated culture of BCG strain of Mycobacterium Bovis Carcinoma Bladder

Adverse Effects

Hypersensitivity Shock Chills

Interferons

Antiviral Immunomodulatory activity Bind to cell surface receptors initiate intracellular events

Enzyme induction Inhibition of cell proliferation Enhancement of immune activities Increased Phagocytosis

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

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

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 immunizing patients with APCs expressing tumor antigen.

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
High titers of desired antibody Hepatitis B, Rabies, Tetanus

Specific immune globulins

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

Immune tolerance

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

Summary

Immunosuppresion

Calcineurin inhibitors Glucocorticoids Antimetabolites

Effective control of rejection Glucocorticoid withdrawal

Newer immunosuppresive agents