IMMUNOMODULATORS

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IMMUNOMODULATORS

• Dr. Manjunath

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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 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
• 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

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
• 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
• 6 Thio-IMP 6Thio-GMP 6Thio-GTP
• Inhibition of cell proliferation
• Impairment of lymphocyte function
• Uses
• Prevention of organ transplant rejection
• Rheumatoid arthritis

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Toxicity - Azathioprine

• Bone marrow suppression- leukopenia,
  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
• Risk of Infection

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Drug Interaction

• Decreased absorption when co-administered 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 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 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-a 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 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
• 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)

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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
• 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
• 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
  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
• Newer immunosuppresive agents
• Effective control of rejection
• Glucocorticoid withdrawal

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