Immunopharmacology

• Immunopharmacology


  The study of drugs that modulate the immune system

  
• Immune system

  • Evolved to protect multicellular organisms from pathogens
  • Highly adaptable, defends the body against a diverse range of pathogens

  
• Main parts of the immune system

  • White blood cells
  • Antibodies
  • Complement system
  • Lymphatic system
  • Spleen
  • Bone marrow
  • Thymus

  
• Active immunity

  Exposure to a disease organism triggers the immune system to produce antibodies to that disease

  
• Passive immunity

  Antibodies to a disease are provided rather than produced through the immune system

  
• Immune system's powerful destructive mechanisms can do more harm than good in certain instances

  
• Examples of when immune system causes harm

  • Hypersensitivity reactions
  • Autoimmune disorders
  • Rejection reactions to transplanted tissues

  
• Immunomodulators

  Drugs used to modulate immune response to various antigens

  
• Types of immunomodulators


  • Immunosuppressants
  • Immunostimulants

  
• Adaptive immune response

  1. Activation of T lymphocytes

  2. Production of antibodies by activated B lymphocytes

  
• Antigen-presenting cells (APCs)


  Process antigens into small peptides recognized by T-cell receptors
• 1. cell activation


  1. Signal 1: T-cell triggering at CD3 receptor complex

  2. Signal 2: CD80/CD86 on APCs engage CD28 on T cells

  3. Signal 3: IL-2 binds to IL-2 receptor, activating cell cycle
• Cell-mediated immunity

  • TH1 cells orchestrate, produce IFN-γ, IL-2, TNF-β to activate macrophages, CTLs, NK cells
  • CTLs recognize peptides bound to class I MHC, induce target cell death
  • NK cells kill virus-infected and neoplastic cells

  
• Humoral immunity


  • B lymphocytes differentiate into antibody-secreting plasma cells
  • Antibodies bind to pathogens, trigger precipitation of viruses and destruction of bacteria

  
• Abnormal immune responses

  • Hypersensitivity
  • Autoimmunity
  • Immunodeficiency

  
• Immunosuppressive agents

  Drugs that suppress immune mechanisms

  
• Corticosteroids


  • Decrease synthesis of inflammatory/immune signaling molecules
  • Inhibit proliferation of T lymphocytes, cytotoxic to certain T cell subsets
  • Impair cell-mediated and humoral immunity

  
• Immunophilin inhibitors


  Interfere with T-cell function by binding to immunophilins and inhibiting calcineurin or mTOR
• Mycophenolate mofetil


  • Inhibits inosine monophosphate dehydrogenase, suppressing B and T lymphocyte activation
• Sirolimus and everolimus


  Available only as oral drugs
• Temsirolimus


  Available as an intravenous agent
• Cyclosporine

  • Exhibits erratic bioavailability, serum levels are routinely monitored
  • Undergoes slow hepatic metabolism by the cytochrome P450 system and has a long half-life
  • Its metabolism is affected by a host of other drugs
• Toxicity of cyclosporine and tacrolimus

  • Renal dysfunction
  • Hypertension
  • Neurotoxicity
  • Hyperglycemia
  • Hyperlipidemia
  • Cholelithiasis
• Toxicity of sirolimus and its analogs

  • Hypertriglyceridemia
  • Hepatotoxicity
  • Diarrhea
  • Myelosuppression
• Mycophenolate mofetil

  • Rapidly converted into mycophenolic acid, which inhibits inosine monophosphate dehydrogenase, an enzyme in the de novo pathway of guanosine triphosphate (GTP) synthesis
  • Suppresses both B- and T-lymphocyte activation
• Lymphocytes

  • Particularly susceptible to inhibitors of the de novo pathway because they lack the enzymes necessary for the alternative salvage pathway for GTP synthesis
• Calcineurin inhibitors: cyclosporine and tacrolimus


  Block signal transduction through the calcium-calcineurin pathway, activated downstream of signal 1, to impair T-cell activation
• One of the primary limitations to the use of calcineurin inhibitors is nephrotoxicity, which has led to the development of regimens using these agents in combination with other immunosuppressant drugs
• Belatacept


  Binds to CD80 and CD86, prevents CD28 from binding to those molecules and, thus, inhibits signal 2 of the T-cell activation pathway
• Sirolimus (also known as rapamycin) and everolimus

  • Inhibit the protein mTOR, blocking the signal transduction pathway
  • Prevent progression into the cell cycle and T-cell proliferation
• Azathioprine

  • A prodrug that is converted first to 6-mercaptopurine (6-MP) and then to the corresponding nucleotide analog, thioinosinic acid
  • The analog is incorporated into nucleic acid chains and blocks further elongation of the DNA
• Thalidomide


  Suppresses TNF-α production, increases IL-10, reduces neutrophil phagocytosis, alters adhesion molecule expression, and enhances cell-mediated immunity
• Adverse effects of immunosuppressive drugs

  • Azathioprine: medullar suppression, pancreatitis, hepatitis, myalgia, and dizziness
  • Methotrexate: flu-like syndrome, nausea, vomiting, fatigue, diarrhoea, medullar toxicity
  • Cyclosporine: hypertension, nephropathy, convulsions, hyperkalemia, shaking, and hepatitis
  • Corticosteroids: adrenal crisis, hypertension, hypercholesterolemia, glucose intolerance, insomnia, diabetes and cosmetic changes
• Antilymphocyte globulin (ALG) and antithymocyte globulin (ATG)

  Antibodies in these preparations bind to T cells involved in antigen recognition and initiate their destruction by serum complement
• Immune Globulin Intravenous (IGIV)

  Intravenous use of this immunoglobulin preparation (usually IgG) prepared from pools of thousands of healthy donors is believed to have a normalizing effect on an individual's immune networks

  
• Rho(D) Immune Globulin

  Contains antibodies against red cell Rho(D) antigens, administration blocks the primary immune response to the foreign cells

  
• Muromonab-CD3

  Binds to the CD3 antigen on the surface of human thymocytes and mature T cells, blocks the killing action of cytotoxic T cells and probably interferes with other T-cell functions
• Infliximab

  Humanized monoclonal antibody targeted against TNF-α, decreases formation of interleukins and adhesion molecules involved in leukocyte activation
• Daclizumab

  Highly specific monoclonal antibody that binds to the alpha subunit of the IL-2 receptor displayed on the surface of T cells and prevents activation by IL-2
• Aldesleukin

  Recombinant interleukin-2 (IL-2), promotes the production of cytotoxic T lymphocytes and activates NK cells