Immunosuppression, Therapeutic Cytokines & Antibodies Flashcards
Why are immunosuppressants frequently administered in combination?
To achieve greater efficacy with ↓ toxicity
What risk is associated with chronic suppression with immunosuppressants?
↑ risk of infection
↑ malignancy
What is mechanism of action of cyclosporine?
Indications?
Toxicity?
Calcineurin inhibitor; binds cyclophilin
Blocks T-cell activation by preventing IL-2 transcription
Uses:
Psoriasis
Rheumatoid arthritis
Toxicity: Nephrotoxicity Hypertension Hyperlipidemia Neurotoxicity Gingival hyperplasia Hirsutism
What is mechanism of action of Tacrolimus?
Indications?
Toxicity?
Calcineurin inhibitor; binds FK506 binding protein (FKBP)
Blocks T-cell activation by preventing IL-2 transcription
Uses:
Immunosuppression after solid organ transplant
Toxicity: Nephrotoxicity Hypertension Hyperlipidemia Neurotoxicity No Gingival hyperplasia & no hirsutism like cyclosporine ↑ risk of diabetes and neurotoxicity
What are examples of calcineurin inhibitors?
What is the major side effect to consider with these immunosuppressants?
Cyclosporine
Tacrolimus
Both calcineurin inhibitors are highly NEPHROTOXIC, especially in higher doses or in patients with ↓ renal function
What is another name for rapamycin?
What is mechanism of action of rapamycin?
Indications?
Toxicity?
Sirolimus
- mTOR inhibitor; binds FKBP (fk gene cluster binding protein)
- Blocks T-cell activation and B-cell differentiation by preventing response to IL-2
Uses:
Kidney transplant rejection prophylaxis
Synergistic with cyclosporine
Also used in drug eluting stents
Toxicity: Pancytopenia Insulin resistance Hyperlipidemia Not nephrotoxic
*Mammalian target of rapamycin (mTOR) inhibitors block the activity of the mammalian target of rapamycin. Mammalian target of rapamycin is a protein kinase, which regulates growth factors that stimulate cell growth and angiogenesis. In certain cancers the mTOR pathway is more active.
What is mechanism of action of Basiliximab?
Indications?
Toxicity?
Monoclonal antibody
blocks IL-2R
Kidney transplant rejection prophylaxis
Toxicity:
Edema
Hypertension
Tremor
What is mechanism of action of Azathioprine?
Indications?
Toxicity?
Antimetabolite precursor of 6-mercaptopurine
Inhibits lymphocyte proliferation by blocking nucleotide synthesis
Uses: Rheumatoid arthritis Crohn disease Glomerulonephritis other autoimmune conditions
Toxicity:
Pancytopenia
Which drug ↑ the toxicity of Azathioprine?
Why?
Allopurinol (an inhibitor of xanthine oxidase)
Azathioprine is antimetabolite precursor of 6-mercaptopurine
6-MP is degraded by xanthine oxidase
What is mechanism of action of Mycophenolate Mofetil?
Indications?
Toxicity?
Reversibly inhibits IMP (inosine monophosphate) dehydrogenase, preventing purine synthesis of B and T cells
Uses:
- lower the body’s natural immunity in patients who receive organ transplants (eg, kidney, heart, or liver)
- Glucocorticoid-sparing agent in rheumatic disease
Toxicity: GI upset Pancytopenia Hypertension Hyperglycemia Less nephrotoxic and neurotoxic
Which immunosuppressant is less nephro- and neurotoxic but is associated with invasive CMV infection?
Mycophenolate Mofetil
What is mechanism of action of Glucocorticoids?
Indications?
Toxicity?
- Inhibit NF-κB
- Suppress both B- and T-cell function by ↓ transcription of many cytokines
- Induce T cell apoptosis
Uses: Many autoimmune and inflammatory disorders Adrenal insufficiency Asthma CLL Non-Hodgkin lymphoma
Toxicity: Cushing syndrome Osteoporosis Hyperglycemia Diabetes Amenorrhea Adrenocortical atrophy Peptic ulcers psychosis Cataracts Avascular necrosis (femoral head)
*NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells): protein complex; controls transcription of DNA, cytokine production & cell survival.
Found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. Regulates the immune response to infection.
Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development.
NF-κB has also been implicated in processes of synaptic plasticity and memory
What is a common finding when initiating treatment with glucocorticoids?
Artificial leukocytosis (↑ WBC count)
What causes artificial leukocytosis upon initiating glucocorticoid treatment?
Demargination of neutrophils:
Glucocorticoids ↓ gene transcription of L-selectin
so ↓ L-selectin produced and transferred to the surface to replace recently shed L-selectin.
Without this replacement, the neutrophil will detach (or undergo “demargination”) from intravascular areas & enter peripheral circulation.
*The neutrophil uses cell adhesion molecules called L-selectin to loosely attach itself to the endothelial lining of the blood vessel.
L-selectin adhesion molecules undergo constant turn over as it moves along the blood vessel.
As L-selectin is removed from the cell surface by the enzyme sheddase, it is replaced by newly produced L-selectin from within inside the neutrophil.
What may develop in patients who abruptly stop glucocorticoids after chronic use?
Adrenal insufficiency
glucocorticoid induced adrenal insufficiency; GI-AI
What is the recombinant cytokine agent for erythropoietin?
Clinical uses?
Epoetin alfa (EPO analog)
Anemias (especially in renal failure)
What are the recombinant cytokine agents for colony stimulating factors?
Clinical uses?
Filgrastim (G-CSF)
Sargramostim (GM-CSF)
Leukopenia
Recovery of granulocyte and monocyte counts
What is the recombinant cytokine agents for thrombopoietin?
Clinical uses?
Romiplostim (TPO analog)
Eltrombopag (TPO receptor agonist)
Autoimmune thrombocytopenia; Platelet stimulator
Which cytokine is associated with ↑ risk of hypertension & thromboembolic events?
Epoetin alfa (EPO analog) > Erythropoietin
