IMMUNOMODULATORS

Ma. Stephanie Fay S. Cagayan, MD

The Immune Response

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

Immunity:
Innate, Natural Adaptive, Learned

Who are involved ?

Innate Adaptive:
Complement B and T lymphocytes Granulocytes B: antibodies Monocytes/macrophages T : helper, cytolytic, suppressor. NK cells Mast cells Basophils

IMMUNE MODIFIERS

Immunosuppressants

Immunostimulants

?Immune tolerance

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

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

Problem
Life long use Infection, cancers Nephrotoxicity Diabetogenic

This agent acts at multiple cellular sites to cause broad effects on inflammation and immune processes A. Tacrolimus B. Glucocorticoids C. Cyclophosphamide D. Azathioprine

This agent acts at multiple cellular sites to cause broad effects on inflammation and immune processes A. Tacrolimus B. Glucocorticoids C. Cyclophosphamide D. Azathioprine

Katzung Reviewer 7th ed. P 477

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

The following is/are true for Cyclosporine A. Acts by inhibiting a cytoplasmic phosphatase through binding with cyclophilin B. known to cause hyperglycemia C. Used in solid organ transplant D. All of the above

The following is/are true for Cyclosporine A. Acts by inhibiting a cytoplasmic phosphatase through binding with cyclophilin B. known to cause hyperglycemia C. Used in solid organ transplant

D. All of the above

Calcineurin inhibitors
Cyclosporine Tacrolimus

Most effective immunosuppressive drugs Target intracellular signaling pathways Blocks Induction of cytokine genes
bind to cyclophilin (for cyclosporine) or FKbinding protein (for tacrolimus) to inhibit calcineurin, a cytoplasmic phosphatase involved in signal transduction upon T-cell activation leading to gene transcription and consequently, cytokine expression.

Cyclosporine
More effective against T-cell dependent immune mechanisms transplant rejection, autoimmunity IV, Oral Erratic bioavailability 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 Liver and kidney transplant

Toxicity - Tacrolimus
Nephrotoxicity Neurotoxicity-Tremor, headache, motor disturbances, seizures GI Complaints Hypertension Hyperglycemia Risk of tumors, infections Drug interaction
Synergistic nephrotoxicity with cyclosporine CYP3A4

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

Sirolimus
Uses Prophylaxis of organ transplant rejection along with other drugs Toxicity Increase in serum cholesterol, Triglycerides Anemia Thrombocytopenia Hypokalemia Fever GI effects (hepatotoxicity, diarrhea) 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

Antiproliferative and Antimetabolic drugs

Azathioprine Mycophenolate Mofetil Others:
Methotrexate Cyclophosphamide Thalidomide Chlorambucil

The dose of this drug should be decreased if the patient is concomitantly taking allopurinol A. Glucocorticoid B. Cyclophosphamide C. Azathioprine D. Methotrexate

The dose of this drug should be decreased if the patient is concomitantly taking allopurinol A. Glucocorticoid B. Cyclophosphamide C. Azathioprine D. Methotrexate

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 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 coadministered with antacids Acyclovir, Gancyclovir compete with mycophenolate for tubular secretion

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 Tcell 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 Etanercept Infliximab Adalimumab

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

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

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
Glucocorticoids MuromonabCyclosporine Tacrolimus Azathioprine Mycophenolate Mofetil

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)

Daclizumab, Basiliximab
Sirolimus

Immunostimulants
Levamisole Thalidomide BCG Recombinant Cytokines
Interferons Interleukin-2

An immunostimulant drug which is currently used for bladder CA is A. Levimasole B. Imatinib C. BCG D. Interleukin alpha

An immunostimulant drug which is currently used for bladder CA is A. Levimasole B. Imatinib C. BCG D. Interleukin alpha

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

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 RBCs Hemolytic disease of newborn

Summary
Immunosuppresion
Calcineurin inhibitors Glucocorticoids Antimetabolites

Newer immunosuppresive agents

Effective control of rejection Glucocorticoid withdrawal

A drug indicated for treatment of moderate to severe rheumatoid arthritis but not appropriate for treating moderate to severe osteoarthritis is A. Acetaminophen B. Etanercept C.Ibuprofen D. Rofecoxib

A drug indicated for treatment of moderate to severe rheumatoid arthritis but not appropriate for treating moderate to severe osteoarthritis is A. Acetaminophen B. Etanercept C.Ibuprofen D. Rofecoxib