9 immunosuppression Flashcards
What is immunosuppression?
It is the dampening (full or partial) of the immune response, which can occur naturally or via deliberate interventions.
What conditions often require immunosuppression?
Autoimmune diseases (e.g., rheumatoid arthritis, Crohn’s disease, SLE), allergies (e.g., hay fever, asthma, atopic dermatitis), and for organ transplantation/GVHD prevention.
What are the potential risks of immunosuppression?
Increased susceptibility to opportunistic infections and compromised tumor immune surveillance.
What are the main methods used to suppress the immune system?
Corticosteroids, cytotoxic drugs, non-cytotoxic drugs, trapping activated T cells, antibody-based therapies, and radiation.
What are corticosteroids?
Steroid hormones that are powerful anti-inflammatory and immunosuppressive agents produced naturally by the adrenal gland.
What are the two main classes of corticosteroids?
Glucocorticoids and mineralocorticoids.
Which natural glucocorticoid is commonly produced?
Cortisol (produced from cortisone).
What is an example of a synthetic corticosteroid?
Prednisone, which is a pro-drug converted in the liver to prednisolone.
How do corticosteroids work at the cellular level?
They bind to cytoplasmic steroid receptors complexed with Hsp90, the receptor-steroid complex then translocates to the nucleus, binds to specific gene regulatory sequences, and activates transcription.
What are some effects of corticosteroids on the immune system?
They reduce CD4⁺ T cell numbers, decrease macrophage activation, and inhibit mast cell degranulation (reducing histamine release).
What are common clinical uses of corticosteroids?
Treatment of autoimmune diseases (RA, SLE), allergies (asthma, hay fever), inflammatory conditions (Crohn’s disease, IBD), malignant diseases (lymphoma), and prevention of allograft rejection.
What are some side effects associated with prolonged corticosteroid use?
Hirsutism, weight gain (fat redistribution), increased bruising, abdominal striae, acne, cataracts, glucose intolerance (steroid-induced diabetes), hypertension, osteoporosis, mood swings, and increased risk of opportunistic infections.
What do cytotoxic drugs do?
They halt cell replication by targeting DNA synthesis, killing all dividing cells.
Name some examples of cytotoxic drugs used for immunosuppression.
Cyclophosphamide, methotrexate, mycophenolate mofetil, leflunomide, and azathioprine.
What is a key limitation of cytotoxic drugs?
Their non-specific toxicity affects all dividing cells, not just lymphocytes.
How does cyclophosphamide work, and what are its uses and side effects?
It is an alkylating agent that adds alkyl groups to DNA, disrupting replication. It’s used in autoimmune diseases (e.g., SLE, vasculitis) and cancers (e.g., lymphomas), but can cause bone marrow depression, alopecia, bladder irritation/cancer, sterility, skin tumors, and is teratogenic.
Describe methotrexate’s mechanism, uses, and side effects.
Methotrexate inhibits dihydrofolate reductase (DHFR), interfering with purine synthesis and causing T cell apoptosis. It is a first-line DMARD for RA, used in psoriasis, Crohn’s disease, and some cancers, with side effects including mucositis, nausea, bone marrow suppression, hepatic fibrosis, and pneumonitis.
What is mycophenolate mofetil, and what are its pros and cons?
It blocks de novo purine synthesis (via inhibition of IMPDH) in T and B cells, used to prevent kidney transplant rejection and treat autoimmune diseases; side effects include lymphopenia, opportunistic infections, lymphoma risk, and hepatotoxicity.
How does leflunomide work and what are its associated risks?
It inhibits dihydroorotate dehydrogenase (DHODH), blocking pyrimidine synthesis needed by T cells. It’s used in severe RA and psoriatic arthritis but can cause severe hepatotoxicity (especially with methotrexate) and is teratogenic.
What are non-cytotoxic immunosuppressive drugs?
They modulate T cell signaling without killing cells, thereby selectively reducing immune activation.
Provide examples of non-cytotoxic drugs.
Cyclosporin A, Tacrolimus (FK506), and Rapamycin (Sirolimus).
How do Cyclosporin A and Tacrolimus work?
They bind intracellular proteins (cyclophilin for CsA and FK-binding protein for tacrolimus) and inhibit calcineurin, preventing activation of NFAT and subsequent IL-2 production, thus blocking T cell proliferation.
What is the mechanism of Rapamycin (Sirolimus)?
It binds to FKBP, and the complex inhibits mTOR, blocking cell cycle progression in T cells and cytokine signal transduction.
What are some side effects of non-cytotoxic drugs?
They can be nephrotoxic, hepatotoxic, and may cause hypertension and diabetes.
What is the strategy of trapping activated T cells?
It involves preventing T cells from exiting the lymph nodes, thereby keeping them from reaching sites of inflammation.
What role does Sphingosine 1-phosphate (S1P) play in T cell migration?
S1P interacts with its receptor S1PR1 to create a gradient that guides T cells from lymph nodes to circulation.
How does Fingolimod (FTY720) work in immunosuppression?
Fingolimod binds to S1PR1, disrupting T cell migration and trapping them in lymph nodes; it is used in treating multiple sclerosis.
What are common side effects of Fingolimod?
Side effects include headache, colds, nausea, changes in heart rate, and macular oedema.
What are polyclonal antibodies in immunosuppression?
They are antibodies derived from animals (horse or rabbit sera) immunized with human T cells; they deplete T cells through complement-mediated lysis and ADCC, but have batch variability and risk of anaphylaxis.
What is OKT3 (Muromonab) and its function?
OKT3 is a mouse-derived monoclonal antibody targeting CD3ε on T cells, preventing T cell activation and inducing apoptosis; it was the first monoclonal antibody approved for clinical use in humans.
What is Basiliximab and how does it work?
Basiliximab is a chimeric mouse/human monoclonal antibody against CD25 (IL-2 receptor α-chain) that blocks IL-2 induced T cell proliferation; it is used in kidney transplants.
What is Daclizumab and what are its uses/concerns?
Daclizumab is a humanized anti-CD25 monoclonal antibody used to block IL-2-driven T cell proliferation, used in kidney transplants and MS; however, it was withdrawn in 2018 due to encephalitis.
What are the five main methods to suppress the immune system?
Corticosteroids, cytotoxic drugs, non-cytotoxic drugs, trapping activated T cells, and antibody-based immunosuppression (with radiation sometimes used).
Why is a combination of immunosuppressive drugs often used?
Combining drugs targets multiple pathways, reduces individual drug toxicity, and minimizes side effects.
What are the general risks associated with immunosuppression?
Increased risk of infections (opportunistic pathogens), potential increased cancer risk, and other unexpected side effects due to impaired immune surveillance.
