Immunopharmacology of Autoimmunity PDF

Bana What are the 2 types of autoimmune diseases? what is the mechanism of action of methotrexate (MTX) when its used in oncology (high dose)? 1. Organ specific 2. Non-organ specific Inte...

Bana What are the 2 types of autoimmune diseases? what is the mechanism of action of methotrexate (MTX) when its used in oncology (high dose)? 1. Organ specific 2. Non-organ specific Interferes with dihydrofolate reductase (DHFR)→ reduced DNA synthesis What are the solutions to autoimmune diseases? what is the mechanism of action of methotrexate (MTX) 1. Reduce the immune response → by using when it’s used in autoimmunity (low dose)? Immunosuppressants 2. Block the consequences of the immune response involve blockade of AICAR transformylase → increased → by using anti-inflammatories adenosine levels & signaling → multiple anti-inflammatory 3. Replace / bypass function (if feasible and less effects via adenosine receptors toxic) / MTX inhibits DHFR → preventing purine and pyrimidine What are the management principles for autoimmune biosynthesis → Inability to make DNA and RNA blocking patients? protein synthesis MTX also blocks AICAR transformylase → accumulation of 1. Control long-term disease AICAR → AICAR gets broken down to adenosine → 2. Manage disease flare-ups adenosine act on A3 receptors → leading to inhibition of 3. Limit toxicity of immune-targeting drugs neutrophil degranulation What are the groups of drugs used in autoimmune Role of methotrexate (MTX)? patients? 1. Inhibits replication of B cells and T cells 1. Anti-proliferative agents → Anti-proliferative 2. Used in combination with cyclosporine to prevent 2. Immune cell-depleting agents → Anti- GvHD in RA and psoriasis proliferative 3. Cytokine inhibitors → anti-inflammatory What are the side effects of methotrexate (MTX)? 4. Inhibitors of cell signalling functions → anti- inflammatory 1. Alopecia 5. Precision medicine → anti-inflammatory 2. Bone marrow suppression Antiproliferative agents: Dose used of methotrexate for autoimmune patients is much lower than for cancer patients 1. Cyclophosphamide 2. Methotrexate What are the adenosine receptors? Cyclophosphamide is the inactive form of nitrogen 1. G-protein coupled receptors mustard that is metabolized in liver to active form and 2. A1, A2A, A2B, and A3 it’s an alkylating agent MTX is a teratogen (an agent or factor which causes What is the mechanism of action of cyclophosphamide? malformation of an embryo) Binds to DNA → DNA/RNA crosslinking → inhibition of Why are B cell-depleting agents used? protein synthesis Depletion used to treat B cell lymphoma or in certain What are the side effects of cyclophosphamide? autoimmune conditions (e.g. rituximab) 1. Alopecia 2. Nausea 3. bone marrow suppression Bana Why are T cell-depleting agents used? what is the main goal of the inhibitors of cell function? Depletion (via ATG or anti-CD25) usually for transplant to reduce pro-inflammatory signalling from immune cells patients to prevent organ rejection what is the mechanism of action of the inhibitors of cell Rituximab is used in RA function? Rituximab, a chimeric anti-CD20 monoclonal antibody Depend on the biological pathway being targeted (MAb), induces killing of normal and malignant B cells expressing the cell-surface molecule CD20. What is the main goal of precision medicine for treating autoimmunity? Rituximab mechanism of action: to target molecular pathways that drive disease in Causes B cell depletion via ADCC, complement activation individual patients/patient groups and apoptosis. Fewer B cells → fewer auto-antibodies autoimmune diseases are an extremely heterogeneous group of conditions What are the side effects of Rituximab? Natalizumab prevents activated T cells migrating 1. Reactivation of hepatitis B virus in infected hosts into and within the CNS of multiple sclerosis patients 2. Progressive multifocal leukoencephalopathy (PML) 3. Systemic Inflammatory Response Syndrome (SIRS) What is plasmapheresis (Plasma exchange)? Rituximab-opsonized B cells pathways to attack and kill: Plasmapheresis is the removal, treatment, and return or exchange of blood plasma or components thereof from 1. Complement-mediated cytotoxicity (membrane and to the blood circulation. (In autoimmune patients) attack complex) Exchanges blood plasma for donor plasma → 2. Antibody-dependent cellular cytotoxicity plasma exchange (macrophage) Exchanges blood plasma with other fluids → 3. Direct lysis (NK cells) plasmapheresis What are the Mechanisms of action to pharmacologically inhibit cytokines? What are the risks of plasma exchange and plasmapheresis? 1. Leakage or clotting 2. bleeding whilst on anti-coagulants what is Intravenous immunoglobulin (IVIG)? Purified, pooled, sterilised IgG from the plasma of >1,000 donors What is the main goal of inhibiting CKs? to reduce pro-inflammatory signalling from CKs like TNF- alpha, IL-1, IL-6 Bana What does IVIG do? What would u do if the drugs don’t work / stop working for RA? 1. Acts as an antibody replacement therapy (in immunodeficiency) Add additional DMARD(s) and continue anti-inflammatory 2. Used as an immunomodulator (in autoimmune or drugs inflammatory disease) Can use synthetic or biologic DMARDs Failure on combination of synthetic + biologic DMARDs → When is IVIG indicated? rituximab 1. Immune-mediated thrombocytopenia 2. Neurological conditions – Guillain-Barré Syndrome, some neuropathies 3. Kawasaki disease 4. Toxic epidermal necrolysis What are the mechanisms of action of IVIG? 1. Blockade of Fc receptors 2. interference with complement activation 3. inhibition of T and B cell function 4. alteration of immunoglobulin degradation → collectively anti-inflammatory What are the Immune mechanisms for RA? Multiple…but anti-rheumatoid factor, anti-CCP antibodies often detected. Immune complexes → inflammation, increased TNF- alpha production How do u manage RA? 1. Arrive at a diagnosis as early as possible 2. Ensure specialist care by a rheumatologist 3. Early initiation of treatment with DMARDs (Disease-Modifiying Anti-Rheumatic Drugs) 4. Achieve tight control – regularly monitor progression, adjust drug doses to reduce disease activity 5. Use NSAIDs and glucocorticoids as adjunct rather than main therapies How do u manage RA pharmacologically? Start monotherapy ASAP with oral methotrexate → then use anti-inflammatories (e.g., NSAIDs, glucocorticoids) to speed up disease control until the DMARDs are maximally effective → then treat disease flares with glucocorticoids