Immunology: Immunosuppressants Flashcards
A patient is given a recombinant form of IL-2. Which 2 types of cancer can this recombinant drug be used to treat?
Renal cell carcinoma, metastatic melanoma (both treated with aldesleukin)
Which 2 hematologic malignancies are glucocorticoids often used to treat?
Non-Hodgkin lymphoma and chronic lymphocytic leukemia
A patient with Crohn disease who is receiving natalizumab therapy develops rapidly progressive paralysis and hyperreflexia. What virus is the probable culprit?
JC virus, which can cause progressive multifocal leukoencephalopathy (PML); the risk of PML is increased in patients treated with natalizumab
Sirolimus (rapamycin) binds FKBP in the cell and subsequently inhibits what protein kinase?
mTOR (mechanistic target of rapamycin)
A man taking allopurinol for gout starts taking an immunosuppressive agent for Crohn disease. Pancytopenia develops rapidly. What happened?
Azathioprine’s metabolite, 6-MP, is metabolized by xanthine oxidase; allopurinol inhibits xanthine oxidase, resulting in toxic levels of 6-MP
Which 2 factors can amplify the nephrotoxicity of calcineurin inhibitors?
Administration at higher doses and poor baseline renal function
A patient scheduled for kidney transplantation receives a monoclonal antibody against IL-2R for immunosuppression. Which side effects should be monitored?
Edema, hypertension, tremor (the prescribed drug is basiliximab)
mTOR is responsible for driving the transcription of what types of genes?
Proliferation genes
An elderly patient is diagnosed with CLL. What are the 2 molecular targets of the therapeutic antibodies commonly used to treat this disease?
CD-20 (targeted by rituximab) and CD52 (targeted by alemtuzumab); think “alymtuzumab” for chronic lymphocytic leukemia and “ri2Ximab” to target CD20
6-Mercaptopurine (6-MP) inhibits what specific protein involved in nucleotide synthesis?
PRPP amidotransferase
A patient develops severe hirsutism while taking cyclosporine for post-transplant immunosuppression. Which alternative drug with a similar mechanism of action may be ideal for her?
Tacrolimus (which does not cause the hirsutism or gingival hyperplasia associated with cyclosporine)
What are the 2 main cancers that may be treated with trastuzumab?
Breast and gastric cancers (if positive for a HER2 mutation)
Long-term use of immunosuppressants increases the risk of which 2 conditions?
Cancers and infections (immunosuppressants such as cyclosporine disrupt lymphocyte activation and growth)
Apart from transplant rejection prophylaxis, what are the 3 main clinical indications for azathioprine?
Rheumatoid arthritis, glomerulonephritis, Crohn disease (and other autoimmune conditions)
A patient is receiving long-term prednisone therapy for severe SLE. What are 2 potential effects of this medication on the bone?
Osteoporosis (predisposing to vertebral fracture), avascular/ischemic osteonecrosis (often of femoral head)
Azathioprine inhibits proliferation of lymphocytes by blocking nucleotide synthesis. For which antimetabolite is azathioprine a precursor?
6-Mercaptopurine; “azathiopurine” interferes with nucleic acid synthesis (toxic to proliferating lymphocytes)
With which 2 CD markers is the T-helper cell receptor associated?
CD3 and CD4
Which 2 recombinant cytokines could be used to treat chemotherapy-induced leukopenia?
Filgrastim (G-CSF) and sargramostim (GM-CSF), which aid in the recovery of granulocyte and monocyte counts
Which immunosuppressant medication is synergistic with cyclosporine?
Sirolimus (rapamycin); although cyclosporine can be used alone, sirolimus is not nephrotoxic (the kidney “sirvives”) and can enhance its efficacy
A patient with NADPH oxidase deficiency has recurrent bacterial infections. What cytokine can be used to treat his condition?
IFN-γ (used to treat chronic granulomatous disease or CGD)
What 3 types of cancer is bevacizumab commonly used to treat?
Renal cell carcinoma, non–small cell lung cancer, and colorectal cancer
What recombinant antibody mimics the function of osteoprotegerin to prevent further bone loss in osteoporosis?
Denosumab (which, like osteoprotegerin, targets RANKL and inhibits osteoclast maturation)
What is the molecular target of abciximab?
Abciximab targets platelet glycoproteins IIb/IIIa (ABC is as easy as 123), preventing platelet aggregation
Both mycophenolate mofetil and azathioprine inhibit the de novo production of what type of nucleotides?
Purines (adenine, guanine)
What are 3 clinical indications for treatment with interferon-α (IFN-α)?
Chronic hepatitis B, chronic hepatitis C (not preferred), renal cell carcinoma
Which messenger, directly downstream from the T-cell receptor, is activated to promote inflammatory cytokine (eg, IL-2) gene transcription?
NFAT, which is generated from NFAT-P by calcineurin-mediated dephosphorylation (NFAT then enters the nucleus and promotes transcription)
Apart from transplant rejection, what are the 2 main clinical indications for cyclosporine?
Psoriasis, rheumatoid arthritis
A patient with psoriasis begins taking an immunosuppressant. After several months, she develops gingival hyperplasia and hirsutism. What drug is she taking?
Cyclosporine (tacrolimus has the same toxicity as cyclosporine but does not cause gingival hyperplasia or hirsutism)
What is the primary molecular target inhibited by mycophenolate?
IMP dehydrogenase, which promotes purine synthesis
A patient with optic neuritis and asymmetric neurologic deficits is treated with an antibody targeting α4-integrin. What immunosuppressive agent is she taking?
Natalizumab, which is used to treat multiple sclerosis (by targeting α4-integrin to impair leukocyte adhesion) is
What is the mechanism of action of mycophenolate mofetil?
Mycophenolate mofetil reversibly inhibits IMP dehydrogenase, preventing purine synthesis in T and B cells
A patient with severe persistent allergic asthma has frequent exacerbations despite high-dose inhaled steroid and long-acting β-agonist therapy. Which medication may be indicated?
Omalizumab, a recombinant antibody targeting IgE (used in treatment of refractory allergic asthma)
Which 2 medications must bind FKBP to inhibit cellular immunity?
Tacrolimus and sirolimus
A patient receiving a high maintenance dose of prednisone for several months runs out of her medication and cannot obtain a refill. For what complication is she at risk?
Adrenal insufficiency, which can develop as a result of abrupt steroid cessation (due to adrenal axis suppression in long-term steroid use)
What is the mechanism of action of tacrolimus (FK506)?
FK506 binds to FK506 binding protein (FKBP) and inhibits calcineurin, thereby preventing IL-2 transcription and thus inhibiting T-cell activation
Sirolimus (rapamycin) inhibits which target to exert its immunosuppressive effect?
mTOR
Which 2 immunosuppressants are commonly associated with drug-induced kidney failure?
Cyclosporine and tacrolimus (calcineurin inhibitors)
A patient presents with petechiae and is diagnosed with severe thrombocytopenia. Which 2 recombinant cytokines may be useful in treatment?
Romiplostim (thrombopoietin analog) and eltrombopag (thrombopoietin receptor agonist), which are platelet stimulators
A patient presents with intermittently red urine and anemia. Flow cytometry shows deficient CD55 and CD59 on RBCs. What recombinant antibody may be used to treat this condition?
Eculizumab (used to treat paroxysmal nocturnal hemoglobinuria)
A patient with an asthma exacerbation is treated with IV steroids. The next day, CBC shows a WBC count of 15,000. What is the mechanism behind this effect?
Glucocorticoids cause demargination of WBCs in the vasculature, producing an apparent (artificial) leukocytosis on blood testing
How does the inhibition of NF-κB by steroids lead to immune system suppression?
NF-κB inhibition decreases cytokine transcription, suppressing B- and T-cell function while inducing T-cell apoptosis
A premature infant has chronic lung disease. What is the target of the antibody that may be given to this infant to prevent RSV infection?
RSV F protein, which is targeted by palivizumab (paliVIzumab—VIrus) for RSV prophylaxis in high-risk infants
What are 2 adverse effects that are more pronounced with use of tacrolimus compared with use of cyclosporine?
Diabetes (metabolic side effects) and neurotoxicity
A patient experiences loss of vision and pain in her left eye. Brain MRI shows periventricular plaques. Which cytokine may be used in treatment?
IFN-β (often used to treat multiple sclerosis)
Glucocorticoids inhibit the transcription of what types of genes?
Inflammatory cytokine genes
A patient with high-risk unstable angina undergoes percutaneous coronary intervention. Which agent may be given to prevent additional ischemic complications?
Abciximab, an antiplatet agent targeting glycoproteins IIb/IIIa (ABC is as easy as 123)
A patient presents with right-sided flank pain and hematuria. CT of the abdomen shows a complex renal mass. Which 2 recombinant cytokines can treat this condition?
Aldesleukin (recombinant IL-2) and IFN-α (interferon-α), both of which treat renal cell carcinoma
Which immunosuppressant is often found in drug-eluting stents?
Sirolimus (rapamycin)
A liver transplant recipient develops a buffalo hump, hyperglycemia, striae, and acne. Which drug class can cause such symptoms?
Glucocorticoids
What are the 2 monoclonal antibodies that bind to and inhibit the IL-2 receptor (IL-2R)?
Daclizumab, basiliximab
Which 2 recombinant antibodies are notorious for increasing the risk of PML in patients with latent JC virus infection?
Natalizumab and rituximab
What are the 2 main indications for treatment with natalizumab?
Crohn disease and multiple sclerosis
What molecule does the antibody omalizumab target?
IgE (thus preventing IgE from binding to FcεRI), useful in patients with refractory allergic asthma
What are 3 benign ocular conditions that bevacizumab may be used to treat?
Macular edema, neovascular (“wet”) age-related macular degeneration, and proliferative diabetic retinopathy
A 65-year-old woman is found to have a T-score of -3.0 on a screening DEXA scan. Which therapeutic antibody would help to reduce her fracture risk?
Denosumab (denosumab helps make dense bones)
Aldesleukin is a recombinant form of which cytokine?
Interleukin-2 (IL-2)
A patient with end-stage renal disease presents with anemia and an MCV of 86 fL. What biologic agent can be used in treatment?
Epoetin alfa (an erythropoietin or EPO analog) which is useful in renal failure-associated anemias
What are the 2 main indications for treatment with ustekinumab?
Psoriasis and psoriatic arthritis
What is the mechanism of action of cyclosporine?
Cyclosporine inhibits calcineurin and binds cyclophilin, preventing IL-2 transcription and thus blocking T-cell activation
Cyclosporine has several adverse effects. Which of these is most common and concerning?
Nephrotoxicity is most concerning (others include hypertension, hyperlipidemia, neurotoxicity, hirsutism, and gingival hyperplasia)
What is the mechanism of action of sirolimus (rapamycin)?
Rapamycin inhibits mTOR, blocking T-cell activation and B-cell differentiation by inhibiting the cellular response to IL-2
After “doing some reading” about rituximab therapy, a patient diagnosed with T-cell lymphoma asks you whether he would qualify for it. How do you respond?
Tell the patient he is not a candidate for this therapy, as rituximab targets CD20 on B cells (and is therefore used to treat B-cell non-Hodgkin lymphoma and CLL)
Glucocorticoids inhibit what cellular protein complex implicated in DNA transcription and cytokine production?
NF-κB (nuclear factor κ-light chain enhancer of activated B cells)
Which 2 immunosuppressants are specifically preferred for kidney transplant rejection prophylaxis?
Sirolimus and Basiliximab (think Sir Basil’s kidney transplant)
Which immunosuppressant may be specifically preferred for the treatment of lupus nephritis?
Mycophenolate mofetil
A patient with Burkitt lymphoma is treated with a recombinant antibody targeting CD20. What is this agent?
Rituximab, which targets CD20 (“ri2Ximab”) on B cells
What 2 conditions may be treated with alemtuzumab?
CLL (“alymtuzumab” for chronic lymphocytic leukemia), multiple sclerosis (MS)
What 2 recombinant antibodies have been developed to treat autoimmune diseases by targeting soluble TNF-α?
Infliximab and adalimumab
A woman with progressive jaundice, ascites, and altered mental status tests positive for HBsAg and HBeAg. Which recombinant cytokine could help treat her condition?
Interferon-α (may be used in the treatment of chronic hepatitis B infection)
A woman has breast cancer that is positive for a HER2 mutation. Which monoclonal antibody can be used in treatment?
Trastuzumab (HER2—”tras2zumab”)
What is the mechanism of action of basiliximab?
Basiliximab is a monoclonal antibody that blocks the IL-2 receptor
What is the molecular target of eculizumab in the treatment of paroxysmal nocturnal hemoglobinuria (PNH)?
Complement protein C5
What drug is a decoy TNF-α receptor that may be used to treat rheumatoid arthritis, IBD, psoriasis, and ankylosing spondylitis?
Etanercept (not a monoclonal antibody)
What downstream messenger is activated by IL-2R signaling?
mTOR
What are the 2 molecular targets of ustekinumab?
IL-12 and IL-23
What are 2 key advantages associated with the use of mycophenolate mofetil for immunosuppression?
The drug is less nephrotoxic and less neurotoxic
A patient presents with melena. Barium enema reveals an “apple core” sign. Colon cancer is diagnosed. Which recombinant antibody may be used in the therapy for this disease?
Bevacizumab, which targets VEGF to treat malignancies such as colorectal cancer
What are 4 potential side effects of mycophenolate mofetil?
Hypertension, hyperglycemia, pancytopenia, gastrointestinal disturbance
A man is diagnosed with age-related macular degeneration. Fundoscopic exam shows neovascularization. Using antibodies to inhibit which target may help?
VEGF (targeted by bevacizumab)
What is the clinical advantage of combining different immunosuppressants?
Combining immunosuppressants increases their net efficacy while minimizing their individual toxicities
A patient with lupus nephritis begins taking mycophenolate mofetil and subsequently develops an invasive viral infection. Which virus is the likely pathogen?
Cytomegalovirus (CMV); mycophenolate mofetil is associated with invasive CMV infection
What is the molecular target of denosumab?
RANKL (like osteoprotegerin, denosumab inhibits osteoclast maturation by binding RANKL)
Which 3 toxicities should a patient who is taking sirolimus (rapamycin) be warned about?
Pancytopenia, insulin resistance, hyperlipidemia (sirolimus causes “pansirtopenia”)
What 3 autoimmune conditions can rituximab be used to treat?
ITP, multiple sclerosis, and rheumatoid arthritis
What are 4 clinical indications for treatment with adalimumab, infliximab, and etanercept?
Inflammatory bowel disease (Crohn disease or ulcerative colitis), rheumatoid arthritis, psoriasis, ankylosing spondylitis
