IMMUNOMODULATORS

Dr. Manjunath

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.

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 Anti IL-2 receptor antibody –

Daclizumab, basiliximab Anti TNF alpha – infliximab, etanercept

Immunostimulants

Levamisole Thalidomide BCG Recombinant Cytokines

Interferons Interleukin-2

Immunosuppressants

Organ transplantation Autoimmune diseases

Life long use Infection, cancers Nephrotoxicity Diabetogenic

Problem

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 6 Thio-IMP 6Thio-GMP 6Thio-GTP Inhibition of cell proliferation Impairment of lymphocyte functionUses Prevention of organ transplant

rejection Rheumatoid arthritis

Toxicity - Azathioprine

Bone marrow suppression- leukopenia, 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 co-administered 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 cell-surface antigens

Polyclonal / Monoclonal

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

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 Chron’s 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-α

receptor fused to Fc portion of human IgG1

Uses Rheumatoid arthritis

moderate to severely active crohn’s disease

Adalimumab Adalimumab Recombinant human anti-TNF mAbRecombinant human anti-TNF mAb

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 Glucocorticoids Glucocorticoid response elements in

DNA (regulate gene transcription) Muromonab- CD3T-cell receptor complex

(blocks antigen recognition) Cyclosporine Calcineurin (inhibits phosphatase

activity) Tacrolimus Calcineurin (inhibits phosphatase

activity) Azathioprine Deoxyribonucleic acid (false

nucleotide incorporation) Mycophenolate Mofetil Inosine monophosphate

dehydrogenase (inhibits activity) Daclizumab, Basiliximab IL-2 receptor (block IL-2-mediated

T-cell activation) Sirolimus Protein kinase involved in cell-

cycle progression (mTOR) (inhibits activity)

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-γ 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-γ

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

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

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 RBC’s

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

Newer immunosuppresive agents Effective control of rejection Glucocorticoid withdrawal