Drugs to Treat Autoimmune Diseases Chelsea Wells
Outline <ul><li>Autoimmune diseases </li></ul><ul><ul><li>Types </li></ul></ul><ul><ul><li>Symptoms </li></ul></ul><ul><ul...
The Basics <ul><li>Autoimmunity occurs when the body is unable to differentiate “self” from “non-self” </li></ul><ul><ul><...
More Basics <ul><li>Both antibodies and effector T cells can be involved in the damage in autoimmune diseases. </li></ul><...
Common Autoimmune Diseases exocrine glands Sjögren's syndrome bone joints Rheumatoid arthritis central nervous system Mult...
Symptoms <ul><li>Tiredness </li></ul><ul><li>Depression </li></ul><ul><li>Weight gain </li></ul><ul><li>Weight loss </li><...
Diagnosis <ul><li>Based on symptoms and detection of antibodies </li></ul><ul><li>Antibodies against cell/tissue associate...
Immunological Tolerance <ul><li>Three present theories to explain the loss of immunological tolerance </li></ul><ul><ul><l...
Pathogenesis of Autoimmunity <ul><li>Genetic predisposition and environmental factors relevant  </li></ul><ul><ul><li>Immu...
Treatments- Immunosuppression <ul><li>Reduce the activation or efficacy of the immune system </li></ul><ul><li>Leaves body...
Immunosuppression Cont. <ul><li>Cortisone </li></ul><ul><ul><li>1st immunosuppressant identified </li></ul></ul><ul><ul><l...
Immunosuppression Cont. <ul><li>Azathioprine </li></ul><ul><ul><li>2nd immunosuppressant identified </li></ul></ul><ul><ul...
Immunosuppression Cont. <ul><li>Cyclosporine </li></ul><ul><ul><li>3rd immunosuppressant identified </li></ul></ul><ul><ul...
Treatments- Anti-Inflammatory <ul><li>Remedy pain by reducing inflammation </li></ul><ul><li>Steroidal </li></ul><ul><ul><...
Anti-Inflammatory Cont. <ul><li>Prednisone </li></ul><ul><ul><li>Given orally, intravenously, intramuscularly </li></ul></...
Disease Modifying Drugs <ul><li>Improve symptoms </li></ul><ul><li>Alter disease course </li></ul><ul><li>Improve radiogra...
Disease Modifying Drugs Cont. <ul><li>Methotrexate </li></ul><ul><ul><li>Immunosuppressive effects due to inhibition of en...
Disease Modifying Drugs Cont. <ul><li>Etanercept (Enbrel) </li></ul><ul><ul><li>Recombinant DNA drug </li></ul></ul><ul><u...
Disease Modifying Drugs Cont. <ul><li>Abatacept </li></ul><ul><ul><li>Inhibits costimulation of T cells </li></ul></ul><ul...
New Research <ul><li>Discovered role of protein </li></ul><ul><ul><li>Naturally occurring chemical interleukin 17 </li></u...
New Research <ul><li>New pathways for autoimmune treatment identified </li></ul><ul><ul><li>Rare genetic defect can trigge...
Future <ul><li>Understanding the role of inflammation in the development of autoimmunity </li></ul><ul><li>Determine wheth...
Sources <ul><li>www.wikipedia.com </li></ul><ul><li>http://www.aarda.org </li></ul><ul><li>www.pubmed.com </li></ul><ul><l...
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  • Disease appears without warning or cause Hormone levels have been shown the affect severity of disease Low level autoimmunity- aid in recognition of neoplastic cells by T cells, reducing incidence of cancer - allows rapid immune response in early stages on infection when the availability of foreign antigens limits the response
  • agnosis : Diagnosis of autoimmune diseases is based on symptoms and detection of antibodies (and/or very early T cells) reactive against antigens of tissues and cells involved. Antibodies against cell/tissue associated antigens are detected by immunofluorescence. Antibodies against soluble antigens are normally detected ELISA or radioimmunoassay (see table above). In some cases, a biological /biochemical assay may be used ( e.g. , Graves diseases, pernicious anemia).
  • Immunological tolerance- ability to differentiate self from nonself Leads to pathogenesis of autoimmune disease Theories proposed since mid twentieth century Evidence suggests that all these mechanisms actively contribute to immunological tolerance,
  • Genetic factors- The first two, which are involved in the recognition of antigens, are inherently variable and susceptible to recombination. These variations enable the immune system to respond to a very wide variety of invaders, but may also give rise to lymphocytes , which are capable of self-reactivity. strong evidence to suggest that certain MHC class II allotypes are strongly correlated with specific autoimmune diseases: Inverse relationship between infectious and autoimmune disease Antigen- molecule that stimulates an immune response, proteins or polysaccharides, may have entered from outside the body, or have been generated within the cell Antibody- proteins found in body that are used by the immune system to identify and neutralize foreign objects, produced by B cells, bind to antigens tcell bypass- Molec mimicry- this amplifies the immune response Idiotype cross rxn- - Idiotypes are antigenic epitopes (molecule recognized by immune system found in the antigen-binding portion (Fab) of the immunoglobulin molecule. In this case, the host-cell receptor is envisioned as an internal image of the virus, and the anti-idiotype antibodies can react with the host cells. Cytokine dysreg- Cytokines (signaling proteins used in cell communication) have been recently divided into two groups according to the population of cells whose functions they promote: Helper T-cells type 1 or type 2. The second category of cytokines, which include IL-4, IL-10 and TGF-β (to name a few), seem to have a role in prevention of exaggeration of pro-inflammatory immune responses. Dendritic cell apoptosis - immune system cells called dendritic cells present antigens to active lymphocytes . Dendritic cells that are defective in apoptosis can lead to inappropriate systemic lymphocyte activation and consequent decline in self-tolerance
  • Pain at injections site lasts 24-48 hours
  • Pro drug- administered in inactive form and is metabolized in vivo
  • Leads to reducted function of effector t cells which inhibits calcineurin, lymphokine production, interluekin release ADRs include
  • Tumor necrosis factor alpha (TNF) is a pro-inflammatory cytokine produced by macrophages and lymphocytes. It is found in large quantities in the rheumatoid joint and is produced locally in the joint by synovial macrophages and lymphocytes infiltrating the joint synovium.
  • Accordingly, the need is to develop a more relevant definition of inflammation at the molecular and cellular levels rather than the clinico-pathological level.  Infection has long been invoked as an underlying trigger for the induction of autoimmune disease. Usually infectious diseases are self-limited with full host recovery, with or without therapy.  Uncommonly, infections induce autoimmune disease in humans; For certain diseases, the basic research question is whether the &amp;quot;trigger&amp;quot; of the autoimmune disease is the infection itself by providing, say, an antigen mimic, or a failure of normal immuno-regulation to limit the immune response to infection.  infection or environmental exposures may raise the apoptotic burden to initiate autoimmune disease or even explain exacerbation and remissions.
  • AutoimmuneDisorders_ChelseaWells

    1. 1. Drugs to Treat Autoimmune Diseases Chelsea Wells
    2. 2. Outline <ul><li>Autoimmune diseases </li></ul><ul><ul><li>Types </li></ul></ul><ul><ul><li>Symptoms </li></ul></ul><ul><ul><li>Diagnosis </li></ul></ul><ul><li>Immunological tolerance </li></ul><ul><ul><li>Clonal Deletion Theory </li></ul></ul><ul><ul><li>Clonal Anergy Theory </li></ul></ul><ul><ul><li>Idiotype Network Theory </li></ul></ul><ul><li>Pathogenesis of autoimmunity </li></ul><ul><ul><li>Mechanisms </li></ul></ul><ul><li>Treatments </li></ul><ul><ul><li>Immunosuppressive </li></ul></ul><ul><ul><li>Anti-inflammatory </li></ul></ul><ul><ul><li>Disease modifying </li></ul></ul><ul><li>New research and Future </li></ul>
    3. 3. The Basics <ul><li>Autoimmunity occurs when the body is unable to differentiate “self” from “non-self” </li></ul><ul><ul><li>Results in overactive immune response against own cells and tissues </li></ul></ul><ul><li>Affects 5%-8% of the population </li></ul><ul><ul><li>78% affected are females </li></ul></ul><ul><li>Over 80 conditions linked to autoimmunity </li></ul><ul><ul><li>15 diseases directly linked to autoimmune response </li></ul></ul><ul><li>Low level autoimmunity is normal </li></ul>
    4. 4. More Basics <ul><li>Both antibodies and effector T cells can be involved in the damage in autoimmune diseases. </li></ul><ul><li>Organ specific </li></ul><ul><ul><li>immune response is directed against antigen(s) associated with the target organ being damaged </li></ul></ul><ul><li>Non-organ specific </li></ul><ul><ul><li>antibody is directed against an antigen not associated with the target organ </li></ul></ul>
    5. 5. Common Autoimmune Diseases exocrine glands Sjögren's syndrome bone joints Rheumatoid arthritis central nervous system Multiple sclerosis All tissue Lupus erythematosus platelets Idiopathic thrombocytopenic purpura hypothyroidism Hashimoto's disease peripheral nervous system Guillain-Barré syndrome (GBS) hyperthyroidism Graves' disease kidneys and lungs Goodpasture's syndrome insulin-producing beta cells Diabetes mellitus type 1 bone marrow Aplastic anemia veins and/or arteries. Antiphospholipid antibody syndrome (APS) spine and sacroiliac joints Ankylosing spondylitis adrenal cortex Addison's disease Affects… Name  
    6. 6. Symptoms <ul><li>Tiredness </li></ul><ul><li>Depression </li></ul><ul><li>Weight gain </li></ul><ul><li>Weight loss </li></ul><ul><li>Muscle weakness </li></ul><ul><li>Cramps </li></ul><ul><li>Irritability </li></ul><ul><li>Sweating </li></ul><ul><li>Shaky </li></ul><ul><li>Swelling </li></ul><ul><li>Rash </li></ul><ul><li>Body pains </li></ul><ul><li>Tremors </li></ul><ul><li>Numbness </li></ul><ul><li>Fatigue </li></ul><ul><li>Loss of appetite </li></ul><ul><li>Insomnia </li></ul><ul><li>Coordination loss </li></ul>Many different symptoms make autoimmune diseases hard to diagnose Many times there are no symptoms!
    7. 7. Diagnosis <ul><li>Based on symptoms and detection of antibodies </li></ul><ul><li>Antibodies against cell/tissue associated antigens are detected by immunofluorescence </li></ul><ul><li>Antibodies against soluble antigens are normally detected ELISA or radioimmunoassay </li></ul><ul><li>Biological and biochemical assay also used </li></ul>
    8. 8. Immunological Tolerance <ul><li>Three present theories to explain the loss of immunological tolerance </li></ul><ul><ul><li>Clonal Deletion Theory- self reactive lymphnoid cells destroyed during development of immune system </li></ul></ul><ul><ul><li>Clonal Anergy Theory- self reactive T or B cells become inactivated </li></ul></ul><ul><ul><li>Idiotype Network Theory- network of antibodies capable of neutralizing self reactive antibodies exist naturally within the body </li></ul></ul>
    9. 9. Pathogenesis of Autoimmunity <ul><li>Genetic predisposition and environmental factors relevant </li></ul><ul><ul><li>Immunoglobulins, T cell receptors, major histocompatibilty complex </li></ul></ul><ul><li>T Cell Bypass- The requirement of T cells to activate B cells in order to produce large amounts of antibodies is bypassed </li></ul><ul><li>Molecular Mimicry- An exogenous antigen shares structural similarities with host antigen and when an antibody is produced, it can bind to host antigen </li></ul><ul><li>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 </li></ul><ul><li>Cytokine Dysregulation- Certain cytokines have a role in the prevention of the exaggeration of pro-inflammatory immune response </li></ul><ul><li>Dendritic Cell Apoptosis- Defective dendritic cells can lead to inappropriate systemic lymphocyte activation and a decline in self tolerance </li></ul>
    10. 10. Treatments- Immunosuppression <ul><li>Reduce the activation or efficacy of the immune system </li></ul><ul><li>Leaves body very vulnerable to opportunistic infections </li></ul><ul><li>Also used to prevent the body from rejecting an organ transplant </li></ul>
    11. 11. Immunosuppression Cont. <ul><li>Cortisone </li></ul><ul><ul><li>1st immunosuppressant identified </li></ul></ul><ul><ul><li>Steroid hormone </li></ul></ul><ul><ul><li>Discovered by Edward Calvin Kendall (1950) </li></ul></ul><ul><ul><li>Administered intravenously </li></ul></ul><ul><ul><li>Few side effects </li></ul></ul><ul><ul><ul><li>Pain at injection site </li></ul></ul></ul><ul><ul><ul><li>Thinning of skin </li></ul></ul></ul><ul><ul><ul><li>Weight gain </li></ul></ul></ul>
    12. 12. Immunosuppression Cont. <ul><li>Azathioprine </li></ul><ul><ul><li>2nd immunosuppressant identified </li></ul></ul><ul><ul><li>Pro-drug </li></ul></ul><ul><ul><li>Discovered by Sir Roy Calne (1959) </li></ul></ul><ul><ul><li>Inhibits purine synthesis necessary for the proliferation of cells </li></ul></ul><ul><ul><li>Site of action-DNA (false nucleotide incorporation </li></ul></ul><ul><ul><li>Side effects </li></ul></ul><ul><ul><ul><li>Carcinogen </li></ul></ul></ul><ul><ul><ul><li>Nausea </li></ul></ul></ul><ul><ul><ul><li>Rash </li></ul></ul></ul>
    13. 13. Immunosuppression Cont. <ul><li>Cyclosporine </li></ul><ul><ul><li>3rd immunosuppressant identified </li></ul></ul><ul><ul><li>Cyclic nonribosomal peptide </li></ul></ul><ul><ul><li>Discovered by Hartmann F. Stahelin (1972) </li></ul></ul><ul><ul><li>Site of action- calcineurin (inhibits phosphatase activity) </li></ul></ul><ul><ul><li>Side effects </li></ul></ul><ul><ul><ul><li>Interacts with a wide variety of other drugs and substances </li></ul></ul></ul><ul><ul><ul><li>hyperplasia, convulsions, peptic ulcers, fever, vomiting, diarrhea, confusion, breathing difficulties, numbness and tingling, high blood pressure, kidney and liver dysfunction </li></ul></ul></ul>
    14. 14. Treatments- Anti-Inflammatory <ul><li>Remedy pain by reducing inflammation </li></ul><ul><li>Steroidal </li></ul><ul><ul><li>Glucocorticoids- regulate gene transcription </li></ul></ul><ul><ul><li>Bind to cortisol receptors </li></ul></ul><ul><li>Nonsteroidal </li></ul><ul><ul><li>Counteract cyclooxygenase enzyme </li></ul></ul><ul><ul><li>Ibuprofen, aspirin, naproxen </li></ul></ul>
    15. 15. Anti-Inflammatory Cont. <ul><li>Prednisone </li></ul><ul><ul><li>Given orally, intravenously, intramuscularly </li></ul></ul><ul><ul><li>Pro-drug </li></ul></ul><ul><ul><li>Also an effective immunosuppressant </li></ul></ul><ul><ul><li>Side effects </li></ul></ul><ul><ul><ul><li>Weight gain </li></ul></ul></ul><ul><ul><ul><li>Increased blood pressure and blood sugar </li></ul></ul></ul><ul><ul><ul><li>Insomnia </li></ul></ul></ul>
    16. 16. Disease Modifying Drugs <ul><li>Improve symptoms </li></ul><ul><li>Alter disease course </li></ul><ul><li>Improve radiographic outcomes </li></ul>
    17. 17. Disease Modifying Drugs Cont. <ul><li>Methotrexate </li></ul><ul><ul><li>Immunosuppressive effects due to inhibition of enzyme involved in the metabolism of folic acid </li></ul></ul><ul><ul><li>Anti-inflammatory effects due to interruption of adenosine </li></ul></ul><ul><ul><li>Relatively rapid onset of action (4-6 weeks) </li></ul></ul><ul><ul><li>Side effects </li></ul></ul><ul><ul><ul><li>Stomatitis </li></ul></ul></ul><ul><ul><ul><li>Oral ulcers </li></ul></ul></ul><ul><ul><ul><li>GI upset </li></ul></ul></ul>
    18. 18. Disease Modifying Drugs Cont. <ul><li>Etanercept (Enbrel) </li></ul><ul><ul><li>Recombinant DNA drug </li></ul></ul><ul><ul><li>binds TNF (tumor necrosis factor) in the circulation and in the joint, preventing interaction with cell surface TNF receptors thereby reducing TNF activity </li></ul></ul><ul><ul><li>Subcutaneous injection </li></ul></ul><ul><ul><li>Side effects </li></ul></ul><ul><ul><ul><li>Susceptibility to opportunistic infection </li></ul></ul></ul>
    19. 19. Disease Modifying Drugs Cont. <ul><li>Abatacept </li></ul><ul><ul><li>Inhibits costimulation of T cells </li></ul></ul><ul><ul><ul><li>Interferes with the process of turning T cells on which activate cells that cause inflammation and damage </li></ul></ul></ul><ul><ul><li>Delays progression of structural damage </li></ul></ul><ul><ul><li>Side effects </li></ul></ul><ul><ul><ul><li>Back pain </li></ul></ul></ul><ul><ul><ul><li>Cough </li></ul></ul></ul><ul><ul><ul><li>Dizziness </li></ul></ul></ul><ul><ul><ul><li>Headache </li></ul></ul></ul><ul><ul><ul><li>Susceptibility Infection </li></ul></ul></ul>
    20. 20. New Research <ul><li>Discovered role of protein </li></ul><ul><ul><li>Naturally occurring chemical interleukin 17 </li></ul></ul><ul><ul><li>Plays role in autoimmune and inflammatory responses </li></ul></ul><ul><ul><li>Has commonly known effects within immunity </li></ul></ul><ul><ul><li>Future research will target unwanted actions and preserve benefits within the immune system </li></ul></ul>
    21. 21. New Research <ul><li>New pathways for autoimmune treatment identified </li></ul><ul><ul><li>Rare genetic defect can trigger diseases </li></ul></ul><ul><ul><ul><li>Mutation in Aire gene causes defect in iNKT cells-helps the immune system fight infections while suppressing T cells wanting to attack the body </li></ul></ul></ul><ul><ul><li>manipulating the iNKT cell population is one possible way to cure autoimmune disease </li></ul></ul>
    22. 22. Future <ul><li>Understanding the role of inflammation in the development of autoimmunity </li></ul><ul><li>Determine whether the trigger of disease is an infection itself </li></ul><ul><li>Discover the role of apoptosis in the origin and development of autoimmunity </li></ul><ul><li>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, </li></ul>
    23. 23. Sources <ul><li>www.wikipedia.com </li></ul><ul><li>http://www.aarda.org </li></ul><ul><li>www.pubmed.com </li></ul><ul><li>http://pathmicro.med.sc.edu/ghaffar/tolerance2000.htm </li></ul><ul><li>Goodman and Gillman </li></ul>

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