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Why are immunosuppressant drugs needed?
- 1. Suppress hosts response to organ transplant (host vs graft)
- 2. Suppress lymphocytes in graft's response to host (bone marrow vs host)
- 3. Treat autoimmune conditions (ulcerative colitis)
Characterise the 4 different type of immunosuppressants and give examples.
- 1. Inhibition of IL-2 production/action- Ciclosporin
- 2. Inhibition of cytokine gene expression- Corticosteroids
- 3. Inhibition of purine/pyrimidine synthesis- Cytotoxic agents
- 4. Blockage of T-cell surface molecules- Monoclonal antibodies against IL-2 receptor
What is ciclosporin and what is it used to treat?
- Cyclic peptide of 11 amino acids
- Found in fungus
- Potent immunosuppressant
- Drug of choice in organ transplantation
- Also used to treat autoimmune diseases
What is the normal series of events that occurs to cause IL-2 gene transcription?
- Antigen binds to Th cell
- Intracellular Ca2+ increases
- Phosphatase activated
- Dephosphorylates to activate transcription factors
- IL-2 transcribed
What is the role of IL-2 in the immune response?
IL-2 is necessary for the development of T cell immunological memory, which depends upon the expansion of the number and function of antigen-selected T cell clones.
What is the mechanism of action of ciclosporin?
- Ciclosporin binds to cyclophillin
- This complex binds to and inhibits the phosphatase
- IL-2 transcription is not initiated
- Th cells are not activated
What is the result of the use of ciclosporin?
- T-cell proliferation is inhibited
- The induction and effector phase of the immune response is inhibited
What are the side effects of ciclosporin?
Give a summary and example of glucocorticoids.
- Used in organ transplants and to treat autoimmune diseases.
- Prevents clonal proliferation of Th cells by downregulation of IL-2 transcription and other cytokines involved in the induction and effector phase of the immune response.
- Inflammatory actions also.
- Eg Hydrocortisone and Dexamethosone
What is the mechanism of action of the glucocorticoids?
- Steroid binds to intracellular receptor.
- Steroid-receptor complex acts as a transcription factor
- Induces transcription of genes, some of which inhibit IL-2 and other cytokine transcription
What are the side effects of glucocorticoids?
- Suppress response to infection
- Muscle wasting
What is the general action of cytotoxic agents?
- Cytotoxic agents inhibit the proliferation of cells within the body.
- They inhibit the proliferation of T and B cells in a specific immune response.
- They affect DNA synthesis to inhibit cell division and proliferation.
- Adverse effects include bone marrow depression.
What is the mechanism of the cytotoxic drug azathioprine?
It is metabolised in the body to form a purine analogue,mercaptopurine, which causes inhibition of DNA synthesis.
What is the mechanism of the cytotoxic drug cyclophosamide?
- It cross links DNA strands to inhibit DNA synthesis.
- This causes inhibition of T and B cell proliferation.
Give a summary of monoclonal antibodies against IL-2 receptors?
- Eg Basiliximab
- Blocks the IL-2 receptor
- Inhibits clonal expansion of T-cells in the specific immune response
- Side effect- hypersensitivity
Give an example of an inherited and aquired immunodeficiency disease?
- Leukocyte adhesion defieciency
- -defective leukocyte recruitment to infected tissue.
- -deletion of CD4 T-cells by HIV virus
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