Drugs to Treat Autoimmune Diseases Chelsea Wells Outline
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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 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!
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 • 1 st 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 • 2 nd 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 • 3 rd 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 i. NKT cells-helps the immune system fight infections while suppressing T cells wanting to attack the body • manipulating the i. NKT 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-IL 2 receptor antibodies, anti-CD 4 antibodies, anti. TCR antibodies,
Sources www. wikipedia. com http: //www. aarda. org www. pubmed. com http: //pathmicro. med. sc. edu/ghaffar/tole rance 2000. htm • Goodman and Gillman • •
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