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Drugs to Treat Autoimmune Diseas

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					Drugs to Treat Autoimmune
         Diseases


       Chelsea Wells
                  Outline
• Autoimmune diseases
   • Types
   • Symptoms
   • Diagnosis
• Immunological tolerance
   • Clonal Deletion Theory
   • Clonal Anergy Theory
   • Idiotype Network Theory
• Pathogenesis of autoimmunity
   • Mechanisms
• Treatments
   • Immunosuppressive
   • Anti-inflammatory
   • Disease modifying
• New research and Future
           The Basics
• Autoimmunity occurs when the body is
  unable to differentiate “self” from “non-self”
   • Results in overactive immune response
     against own cells and tissues
• Affects 5%-8% of the population
   • 78% affected are females
• Over 80 conditions linked to autoimmunity
   • 15 diseases directly linked to
     autoimmune response
• Low level autoimmunity is normal
         More Basics

• Both antibodies and effector T cells can
  be involved in the damage in
  autoimmune diseases.
• Organ specific
  • immune response is directed against
    antigen(s) associated with the target organ
    being damaged
• Non-organ specific
  • antibody is directed against an antigen not
    associated with the target organ
Common Autoimmune Diseases
  Name                                       Affects…
  Addison's disease                          adrenal cortex
  Ankylosing spondylitis                     spine and sacroiliac joints
  Antiphospholipid antibody syndrome (APS)   veins and/or arteries.
  Aplastic anemia                            bone marrow
  Diabetes mellitus type 1                   insulin-producing beta cells
  Goodpasture's syndrome                     kidneys and lungs
  Graves' disease                            hyperthyroidism
  Guillain-Barré syndrome (GBS)              peripheral nervous system
  Hashimoto's disease                        hypothyroidism
  Idiopathic thrombocytopenic purpura        platelets
  Lupus erythematosus                        All tissue
  Multiple sclerosis                         central nervous system
  Rheumatoid arthritis                       bone joints
  Sjögren's syndrome                         exocrine glands
             Symptoms
Many different symptoms make autoimmune
diseases hard to diagnose
•   Tiredness             •   Swelling
•   Depression            •   Rash
•   Weight gain           •   Body pains
•   Weight loss           •   Tremors
•   Muscle weakness       •   Numbness
•   Cramps                •   Fatigue
•   Irritability          •   Loss of appetite
•   Sweating              •   Insomnia
•   Shaky                 •   Coordination loss
Many times there are no symptoms!
            Diagnosis

• Based on symptoms and detection of
  antibodies
• Antibodies against cell/tissue associated
  antigens are detected by
  immunofluorescence
• Antibodies against soluble antigens are
  normally detected ELISA or
  radioimmunoassay
• Biological and biochemical assay also used
Immunological Tolerance

• Three present theories to explain the loss of
  immunological tolerance
  • Clonal Deletion Theory- self reactive lymphnoid
    cells destroyed during development of immune
    system
  • Clonal Anergy Theory- self reactive T or B cells
    become inactivated
  • Idiotype Network Theory- network of antibodies
    capable of neutralizing self reactive antibodies
    exist naturally within the body
Pathogenesis of Autoimmunity
  • Genetic predisposition and environmental factors relevant
      • Immunoglobulins, T cell receptors, major histocompatibilty
         complex
  • T Cell Bypass- The requirement of T cells to activate B cells in
    order to produce large amounts of antibodies is bypassed
  • Molecular Mimicry- An exogenous antigen shares structural
    similarities with host antigen and when an antibody is produced,
    it can bind to host antigen
  • Idiotype Cross Reaction- A cross reaction between the idiotype
    (molecule recognized by antigen) on an antiviral antibody and a
    host cell receptor for the virus in question
  • Cytokine Dysregulation- Certain cytokines have a role in the
    prevention of the exaggeration of pro-inflammatory immune
    response
  • Dendritic Cell Apoptosis- Defective dendritic cells can lead to
    inappropriate systemic lymphocyte activation and a decline in
    self tolerance
      Treatments-
   Immunosuppression
• Reduce the activation or efficacy of the
  immune system
• Leaves body very vulnerable to
  opportunistic infections
• Also used to prevent the body from
  rejecting an organ transplant
Immunosuppression Cont.
• Cortisone
  • 1st immunosuppressant identified
  • Steroid hormone
  • Discovered by Edward Calvin Kendall
    (1950)
  • Administered intravenously
  • Few side effects
     • Pain at injection site
     • Thinning of skin
     • Weight gain
Immunosuppression Cont.
• Azathioprine
   • 2nd immunosuppressant identified
   • Pro-drug
   • Discovered by Sir Roy Calne (1959)
   • Inhibits purine synthesis necessary for the
     proliferation of cells
   • Site of action-DNA (false nucleotide
     incorporation
   • Side effects
       • Carcinogen
       • Nausea
       • Rash
Immunosuppression Cont.
• Cyclosporine
  • 3rd immunosuppressant identified
  • Cyclic nonribosomal peptide
  • Discovered by Hartmann F. Stahelin (1972)
  • Site of action- calcineurin (inhibits phosphatase
    activity)
  • Side effects
     • Interacts with a wide variety of other drugs
       and substances
     • hyperplasia, convulsions, peptic ulcers, fever,
       vomiting, diarrhea, confusion, breathing
       difficulties, numbness and tingling, high blood
       pressure, kidney and liver dysfunction
Treatments- Anti-Inflammatory
  • Remedy pain by reducing inflammation
  • Steroidal
    • Glucocorticoids- regulate gene
      transcription
    • Bind to cortisol receptors
  • Nonsteroidal
    • Counteract cyclooxygenase enzyme
    • Ibuprofen, aspirin, naproxen
Anti-Inflammatory Cont.
• Prednisone
  • Given orally, intravenously,
    intramuscularly
  • Pro-drug
  • Also an effective immunosuppressant
  • Side effects
     • Weight gain
     • Increased blood pressure and blood
       sugar
     • Insomnia
Disease Modifying Drugs

• Improve symptoms
• Alter disease course
• Improve radiographic outcomes
Disease Modifying Drugs Cont.

  • Methotrexate
    • Immunosuppressive effects due to inhibition of
      enzyme involved in the metabolism of folic acid
    • Anti-inflammatory effects due to interruption of
      adenosine
    • Relatively rapid onset of action (4-6 weeks)
    • Side effects
       • Stomatitis
       • Oral ulcers
       • GI upset
Disease Modifying Drugs Cont.

  • Etanercept (Enbrel)
    • Recombinant DNA drug
    • binds TNF (tumor necrosis factor) in the circulation
      and in the joint, preventing interaction with cell
      surface TNF receptors thereby reducing TNF
      activity
    • Subcutaneous injection
    • Side effects
       • Susceptibility to opportunistic infection
Disease Modifying Drugs Cont.
  • Abatacept
     • Inhibits costimulation of T cells
        • Interferes with the process of turning T cells
          on which activate cells that cause
          inflammation and damage
     • Delays progression of structural damage
     • Side effects
        • Back pain
        • Cough
        • Dizziness
        • Headache
        • Susceptibility Infection
       New Research

• Discovered role of protein
  • Naturally occurring chemical
    interleukin 17
  • Plays role in autoimmune and
    inflammatory responses
  • Has commonly known effects within
    immunity
  • Future research will target unwanted
    actions and preserve benefits within
    the immune system
         New Research
• New pathways for autoimmune treatment
  identified
   • Rare genetic defect can trigger diseases
      • Mutation in Aire gene causes defect in iNKT
        cells-helps the immune system fight
        infections while suppressing T cells wanting
        to attack the body
   • manipulating the iNKT cell population is one
     possible way to cure autoimmune disease
              Future
• Understanding the role of inflammation in
  the development of autoimmunity
• Determine whether the trigger of disease
  is an infection itself
• Discover the role of apoptosis in the origin
  and development of autoimmunity
• Future treatments based on modern
  understanding of the immune system (e.g.,
  anti-idiotype antibodies, antigen peptides,
  anti-IL2 receptor antibodies, anti-CD4
  antibodies, antiTCR antibodies,
            Sources

• www.wikipedia.com
• http://www.aarda.org
• www.pubmed.com
• http://pathmicro.med.sc.edu/ghaffar/tole
  rance2000.htm
• Goodman and Gillman

				
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