Drugs to Treat Autoimmune Diseases

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Drugs to Treat Autoimmune Diseases

• Chelsea Wells

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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

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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

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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

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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
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Symptoms
Many different symptoms make autoimmune diseases
hard to diagnose

• Tiredness
• Depression
• Weight gain
• Weight loss
• Muscle weakness
• Cramps
• Irritability
• Sweating
• Shaky

• Swelling
• Rash
• Body pains
• Tremors
• Numbness
• Fatigue
• Loss of appetite
• Insomnia
• Coordination loss

Many times there are no symptoms!
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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

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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

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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

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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

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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

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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

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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

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Treatments- Anti-Inflammatory

• Remedy pain by reducing inflammation
• Steroidal
• Glucocorticoids- regulate gene transcription
• Bind to cortisol receptors
• Nonsteroidal
• Counteract cyclooxygenase enzyme
• Ibuprofen, aspirin, naproxen

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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

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Disease Modifying Drugs

• Improve symptoms
• Alter disease course
• Improve radiographic outcomes

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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

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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

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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

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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

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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

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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,

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Sources

• www.wikipedia.com
• http//www.aarda.org
• www.pubmed.com
• http//pathmicro.med.sc.edu/ghaffar/tolerance2000.
  htm
• Goodman and Gillman