Podcast
Questions and Answers
Which of the following immunosuppressive agents directly inhibits the interleukin-2 (IL-2) receptor on activated T cells?
Which of the following immunosuppressive agents directly inhibits the interleukin-2 (IL-2) receptor on activated T cells?
Which immunosuppressant, while being effective against organ rejection, also has a significant role in preventing restenosis after stent implantation?
Which immunosuppressant, while being effective against organ rejection, also has a significant role in preventing restenosis after stent implantation?
Which agent, used in combination therapy for organ transplantation, works by disrupting the synthesis of purine nucleotides, essential for lymphocyte proliferation?
Which agent, used in combination therapy for organ transplantation, works by disrupting the synthesis of purine nucleotides, essential for lymphocyte proliferation?
Which immunosuppressive agent is a macrolide that binds to FKBP-12, ultimately inhibiting calcineurin, similar to cyclosporine, but with higher potency and lower organ rejection rates?
Which immunosuppressive agent is a macrolide that binds to FKBP-12, ultimately inhibiting calcineurin, similar to cyclosporine, but with higher potency and lower organ rejection rates?
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Which immunosuppressant, primarily used for kidney transplantation, acts by competitively binding to CD80 and CD86 on antigen-presenting cells, inhibiting the activation of T lymphocytes?
Which immunosuppressant, primarily used for kidney transplantation, acts by competitively binding to CD80 and CD86 on antigen-presenting cells, inhibiting the activation of T lymphocytes?
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Which of the following immunosuppressants is associated with a higher risk of developing post-transplant lymphoproliferative disorder (PTLD) as an adverse effect?
Which of the following immunosuppressants is associated with a higher risk of developing post-transplant lymphoproliferative disorder (PTLD) as an adverse effect?
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Which immunosuppressant is a prodrug that is metabolized to 6-mercaptopurine, which then inhibits the synthesis of guanosine monophosphate, leading to impaired nucleic acid production in lymphocytes?
Which immunosuppressant is a prodrug that is metabolized to 6-mercaptopurine, which then inhibits the synthesis of guanosine monophosphate, leading to impaired nucleic acid production in lymphocytes?
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Which of the following immunosuppressants is administered intravenously (IV) and has a long half-life of 8-10 days, making it suitable for once-a-month administration in maintenance therapy?
Which of the following immunosuppressants is administered intravenously (IV) and has a long half-life of 8-10 days, making it suitable for once-a-month administration in maintenance therapy?
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Which class of drug is NOT directly involved in the immune activation cascade as described in the lecture?
Which class of drug is NOT directly involved in the immune activation cascade as described in the lecture?
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Which immunosuppressive agent has been shown to significantly increase the risk of developing post-transplant type 1 diabetes?
Which immunosuppressive agent has been shown to significantly increase the risk of developing post-transplant type 1 diabetes?
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Flashcards
Immunotherapy
Immunotherapy
Treatment using immune system modulation to fight diseases.
Calcineurin Inhibitors
Calcineurin Inhibitors
Medications like cyclosporine and tacrolimus that inhibit T cell activation.
IL-2
IL-2
Interleukin 2, a cytokine crucial for T cell growth and function.
Cyclosporine
Cyclosporine
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Tacrolimus
Tacrolimus
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Sirolimus
Sirolimus
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Belatacept
Belatacept
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Antimetabolites
Antimetabolites
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Basiliximab
Basiliximab
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Corticosteroids
Corticosteroids
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Study Notes
Immunotherapy
- Immunotherapy is used to prevent the immune system from recognizing self antigens as foreign, inducing inflammation and tissue damage.
- This also applies to organ transplantation to prevent rejection and maintain graft acceptance by suppressing the immune system.
- Pharmacological approaches are used to selectively eradicate immunocompetent cells or downregulate the immune response without deleting the target cell.
- Monotherapy can cause severe toxicities, so a synergistic combination of low-dose immunosuppressive agents with different mechanisms is ideal to improve clinical efficacy while preventing adverse effects.
Immune Activation Cascade
- Signal 1 triggers T-cell activation at the CD3 receptor complex on the surface of antigen-presenting cells (APCs) due to the presence of an antigen.
- Signal 2 (costimulation) occurs when CD80 and CD86 on APCs engage CD28 on T cells.
- Both signals activate intracellular signal transduction pathways, including the calcium-calcineurin pathway.
- These pathways stimulate the production of cytokines, such as IL-2, and promote T-cell dependent B-lymphocyte activation.
- IL-2 activates mammalian target of rapamycin (mTOR), stimulating T-cell proliferation.
Cyclosporine
- Cyclosporine is a calcineurin inhibitor.
- It binds to a cyclophilin in T cells and forms a complex that inhibits calcineurin action, inhibiting cytokine synthesis, specifically IL-2.
- It dephosphorylates NFATc (cytosolic nuclear factor of activated T cells).
- Cyclosporine is available orally and intravenously, metabolised by the liver and excreted via the biliary system.
Therapeutic Uses of Cyclosporine
- Used to prevent rejection of organ transplants (kidney, liver, cardiac, lung).
- Used in combination therapy regimens with corticosteroids or antimetabolites to prevent rejection.
- Used in the treatment of recalcitrant psoriasis.
- Used in the treatment of rheumatoid arthritis resistant to other medications .
Adverse Effects of Cyclosporine
- Nephrotoxicity (common).
- Hypertension.
- Hyperlipidemia.
- Hyperkalemia.
- Tremor.
- Hirsutism.
- Gum hyperplasia.
Tacrolimus
- Tacrolimus is a calcineurin inhibitor, a macrolide.
- It has a similar mechanism of action to cyclosporine.
- It binds to FKBP-12 (FK-binding protein).
- In terms of potency and its effect on organ rejection, tacrolimus is similar to cyclosporine.
- It is available orally and intravenously.
- It is absorbed orally variably and excreted via the biliary system.
Therapeutic Uses of Tacrolimus
- Used to prevent liver and kidney rejections.
- Used as combination therapy with glucocorticoids.
- Used as a topical ointment in treating atopic dermatitis (eczema).
Adverse Effects of Tacrolimus
- Nephrotoxicity.
- Development of post-transplant type 1 diabetes .
Sirolimus & Everolimus
- Sirolimus and Everolimus bind to FK-binding protein and then to mTOR.
- They inhibit the progression of activated T cells from the G1 to the S phase of the cell cycle.
- This inhibits T-cell proliferation.
- Sirolimus has a longer half-life (57-62 hours) than Everolimus.
- Sirolimus-coated stents are used to inhibit restenosis of blood vessels.
Adverse Effects of Sirolimus & Everolimus
- Hyperlipidemia.
- Anemia.
- Thrombocytopenia.
Belatacept
- Belatacept is a costimulation blocker binding to CD80 and CD86 on APCs and inhibits CD28-mediated costimulation of T lymphocytes.
- It prevents downstream stimulatory signals that promote T-cell survival, proliferation, and IL-2 production.
- It is the first IV maintenance immunosuppressant with a long half-life (8-10 days).
- First phase: high-dose followed by reduced dose, once-monthly administration.
Therapeutic Uses of Belatacept
- Used in kidney transplantation (combined with basiliximab, mycophenolate mofetil, and corticosteroids).
- Replaces calcineurin inhibitors for long-term maintenance immunosuppressive therapy.
Adverse Effects of Belatacept
- Post-transplant lymphoproliferative disorder.
- Anemia.
- Diarrhea.
- Urinary tract infections.
- Edema.
Azathioprine
- Azathioprine is a prodrug, that converts to 6-mercaptopurine (6-MP) a purine analogue.
- It incorporates into DNA, disrupting endogenous purines and impacting lymphocytes.
- It is well absorbed orally.
Therapeutic Uses of Azathioprine
- It is combined with corticosteroids and cyclosporine/tacrolimus to prevent rejection of kidney and other organ allografts.
Adverse Effects of Azathioprine
- Bone marrow suppression.
Mycophenolate Mofetil
- This drug replaced azathioprine due to its safety and effectiveness in prolonging graft survival.
- Mycophenolate mofetil (MMF) inhibits inosine monophosphate dehydrogenase, halting guanosine monophosphate production and thereby preventing nucleic acid synthesis in rapidly proliferating T and B cells.
Pharmacokinetics of Mycophenolate Mofetil
- It is well absorbed orally and excreted renally (through the kidneys).
- Drug is used in combination with sirolimus, tacrolimus, and prednisone to prevent acute organ rejection.
Adverse Effects of Mycophenolate Mofetil
- Diarrhea, nausea, vomiting, and abdominal pain.
Antithymocyte Globulins (ATG)
- Polyclonal antibodies that can prevent early allograft rejection in organ transplantation.
- They mediate complement-mediated destruction, antibody-dependent cell-mediated cytotoxicity, and apoptosis of T lymphocytes.
- Administered intravenously, and have a short half-life (2-3 days).
Adverse Effects of ATG
- Infusion reactions (chills and fever), leukopenia, thrombocytopenia, infections, and skin rashes.
Basiliximab
- A monoclonal antibody against the alpha chain of the IL-2 receptor that interferes with activated T-cell proliferation.
- It is administered intravenously with a half-life of 7 days.
- Usually administered in two doses: one at 2 hours before transplantation, and another 4 days afterward.
- It is combined with cyclosporine and corticosteroids for prophylaxis of acute renal transplant rejections.
Adverse Effects of Basiliximab
- Arrhythmias and hypersensitivity reactions.
Corticosteroids (Prednisone/Methylprednisolone)
- Binds to glucocorticoid-responsive elements on the DNA leading to reduced pro-inflammatory gene expression and increased anti-inflammatory gene expression.
- Used to suppress acute rejection of solid organ allografts and in chronic graft-versus-host disease (bone marrow transplant).
Adverse Effects of Corticosteroids
- Diabetogenic.
- Cataracts.
- Osteoporosis.
- Hypertension.
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Description
This quiz explores the principles of immunotherapy and the immune activation cascade. It covers how immunotherapy is applied in organ transplantation and the mechanisms that activate T-cells. Test your knowledge on these crucial immunological concepts.
