Immunopharmacology Flashcards
What are the classes of drugs used for immune suppression in transplantation?
- Glucocorticoids (steroids)
- Calcineurin inhibitors
- Antimetabolites
- IL-2 receptor monoclonal antibodies (“mabs”)
- m-TOR (target of rapamycin) inhibitors
Which branch of the immune system is most affected by glucocorticoids?
Cell-mediated immunity
How do glucocorticoids function in immune suppression?
- Inhibit genes that code for cytokines, most importantly IL-2
- IL-2 is a proliferation signal for T cells, so its inhibition reduces T cell proliferation
- Glucocorticoids also suppress B cell expression of IL-2 and IL-2 receptors
- Anti-inflammatory effects (upregulates expression of lipocortin)
What are the side effects of glucocorticoids?
- Immunodeficiency
- Adrenal gland suppression (if used for over 21 days)
- Hyperglycemia and fat redistribution (characteristic moon face)
- Growth failure and delayed puberty
- Excitatory effects on CNS (euphoria, psychosis)
- Osteoporosis
- Cataracts
- Gastric ulcers (prevented with concurrent administration of omeprazole, misoprostol)
What are the calcineurin inhibitors?
- Cyclosporine
- Tacrolimus
What is the mechanism of action of the calcineurin inhibitors?
- Inhibit calcineurin, which phosphorylates and activates NF-AT
- NF-AT is a transcription factor involved in the synthesis of interleukins (e.g. IL-2) by activated T cells
- Therefore, the drugs decrease levels of IL-2 synthesis
What are the indications of calcineurin inhibitors?
- Human organ transplantation
- GVHD after hematopoietic stem cell transplantation
- Select autoimmune disorders
How are calcineurin inhibitors metabolized?
By P450 3A in the liver, with many drug–drug interactions
What are the adverse effects of calcineurin inhibitors?
- Very narrow therapeutic window
- If levels are too high: toxicities, e.g. nephrotoxicity, confusion, hyperglycemia (especially with tacrolimus), hypertension
- If levels are too low, transplant rejection may occur
- Increased risk of lymphoma and other cancers, e.g. Kaposi sarcoma, skin cancer, has been reported with cyclosporine (though recent evidence suggests this isn’t true)
What are the parameters that must be monitored while taking cyclosporine?
- Trough levels
- Serum electrolytes
- Kidney function
- Liver function
- Blood pressure
- Serum cholesterol
What are the indications of cyclosporine specifically?
- Ophthalmic solution is available for severe dry eye syndrome and ocular GVHD
- Cyclosporine is combined with methotrexate to prevent GVHD after allogeneic stem cell transplantation
- Used in a variety of autoimmune disorders, including uveitis, rheumatoid arthritis, psoriasis, and asthma
What are the indications of tacrolimus specifically?
Topical preparation is available for dermatologic diseases, e.g. atopic dermatitis, psoriasis
What is an example of an m-TOR inhibitor?
Sirolimus (rapamune)
What are the adverse effects of sirolimus?
- Narrow therapeutic window
- If levels are too high: toxicities, e.g. confusion, nephrotoxicity
- If levels are too low, transplant rejection may occur
What is the difference between the use of antimetabolites in anticancer chemotherapy and in immune suppression?
In immune suppression, the dose is lower
What cells do antimetabolites affect?
B cells and T cells
What are examples of antimetabolites?
- Methotrexate
- Azathioprine
- Mercaptopurine
- Mycophenolate
What is methotrexate?
A folic acid analogue that binds dihydrofolate reductase and prevents synthesis of tetrahydrofolate
What are the indications of methotrexate?
- Treatment of autoimmune diseases (e.g. rheumatoid arthritis, Behçet’s disease)
- Transplantations
What are the indications of azathioprine and mercaptopurine?
Transplant and rejection reactions
What is mycophenolate?
A reversible inhibitor of the enzyme inosine monophosphate dehydrogenase (IMPDH), leading to depletion of guanosine nucleotides
What are the indications of mycophenolate?
- More effective than azathioprine in preventing acute rejection
- Used in combination with cyclosporine and prednisolone
- Mycophenolate mofetil is used in solid organ transplant patients for refractory rejection
- Mycophenolate mofetil is combined with prednisonse as an alternative to cyclosporine or tacrolimus in patients who do not tolerate these drugs
- In renal transplants, it is used with low-dose cyclosporine to reduce cyclosporine-induced nephrotoxicity
What are the components of tacrolimus-led triple therapy?
- Tacrolimus (0.1 mg/kg/day) twice daily (every 12 hours)
- Prednisolone
- Azathioprine (1–2 mg/kg) once daily
What organ is tacrolimus-led triple therapy used for?
Kidney transplants
What are the monoclonal antibodies used in immune suppression?
- Muromonab-CD3
- Basiliximab (IL-2 receptor antagonist)
- Daclizumab (IL-2 receptor antagonist)
- Infliximab (anti-TNF-α)
- Adalimumab (anti-TNF-α)
- Rituximab (CD20 antagonist)
- Omalizunab (anti-IgE)
- Tocilizumab (anti-IL-6)
- Sarilumab (IL-6 receptor antagonist)
- Secukinumab (anti-IL-17)
Muromonab-CD3 is a monoclonal antibody used to block CD3 used in TCR signaling. However, initial binding of the drug causes a transient cytokine release and a cytokine storm. How are the negative effects of this action mitigated?
Concurrent administration of glucocorticoids and other anti-inflammatory drugs (methylprednisolone, diphenydramine, acetaminophen)
What are the indications of IL-2 receptor antagonist monoclonal antibodies
- Prophylaxis of acute renal transplant rejection, in combination with cyclosporine, tacrolimus, and glucocorticoids
- Treatment of the donor’s bone marrow before grafting
How are the IL-2 receptor antagonist monoclonal antibodies administered?
IV
Basiliximab is administered as two doses: one 2 hours prior to the surgery, one 4 days after the surgery
What is the half-life and duration of action of daclizumab?
- Half-life of 20 days
- Duration of blockade is 120 days
What is the half-life and duration of action of basiliximab?
7 days
What are the adverse effects of the anti-IL-2 monoclonal antibodies?
- Generally well tolerated
- The major toxicity is on the GI system
What are the indications of the anti-TNF-α monoclonal antibodies?
T cell-dependent rheumatoid arthritis
How are the anti-TNF-α monoclonal antibodies administered?
At a low dose alongside glucocorticoids to treat the flare-up of the autoimmune disease
What are the adverse effects of the anti-TNF-α monoclonal antibodies?
- Serious infections (namely tuberculosis) that may lead to death—treatment must be stopped if the patient develops a fever consistent with infection
- Neurologic: multiple sclerosis, seizures, inflammation of the ocular nerve
- Exacerbation of congestive heart failure
What are the indications of rituximab?
- B cell lymphoma
- Rheumatoid arthritis with a B cell component in its pathology
Which cytokine was most implicated in cytokine storm syndrome in COVID-19?
IL-6
What are the indications of tocilizumab?
- Cytokine release syndrome
- Giant cell arteritis
- Rheumatoid arthritis
When in the course of COVID-19 is tocilizumab administered?
After the acute mild disease, when moderate to severe symptoms begin to show
What are the indications of secukinumab?
Moderate-to-severe plaque psoriasis
What conditions are immune stimulants used for?
- Immunodeficiency disorders
- Chronic infectious diseases
- HIV/AIDS
- Cancer
What are the classes of immune stimulant drugs?
- Anti-PD-1 antibodies: nivolumab, tremelimumab
- Anti-CTLA-4 antibodies: ipilimumab, lambrolizumab, pidilizumab
- Interferons
- IL-2
What are the uses of interferons in immune stimulation?
- Antiviral (type I)
- Anticancer
- Immunomodulating effects (type II)
What are the adverse effects of interferons?
- Flu-like symptoms
- Fatigue
- Malaise
What are the uses of IL-2 in immune stimulation?
- T cell proliferation
- NK cell activation
- LAK cell activation
- Treatment of malignant melanoma, renal cell carcinoma, Hodgkin disease
What are the adverse effects of IL-2?
- Fever
- Anorexia
