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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
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
Dephosphorylates to activate transcription factors
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
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?
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