Transcript Drugs to Treat Autoimmune Diseases

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
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Tiredness
Depression
Weight gain
Weight loss
Muscle weakness
Cramps
Irritability
Sweating
Shaky
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Swelling
Rash
Body pains
Tremors
Numbness
Fatigue
Loss of appetite
Insomnia
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
TreatmentsImmunosuppression
• 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
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www.wikipedia.com
http://www.aarda.org
www.pubmed.com
http://pathmicro.med.sc.edu/ghaffar/tole
rance2000.htm
• Goodman and Gillman