A 25-year-old man comes to the office due to a 1-month history of increasing abdominal girth and swollen extremities. His BMI is 32 kg/m2. Laboratory evaluation shows decreased serum albumin and hypercholesterolemia, and urinalysis reveals heavy proteinuria and fatty casts. A renal biopsy shows findings consistent with focal segmental glomerulosclerosis. Despite aggressive medical management, the patient requires a kidney transplant from his younger sister, who is a 5 out of 6 HLA antigen match. As a part of his posttransplant immunosuppressive regimen, he takes a medication that inhibits lymphocyte proliferation by directly blocking interleukin-2 signal transduction. This mechanism best describes which of the following drugs?
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Unless a transplanted kidney is obtained from a genetically identical donor (eg, identical twin), chronic immunosuppression therapy is needed to help prevent organ rejection. Sirolimus is commonly used as part of the immunosuppression regimen for solid organ transplants. It functions as a proliferation signal inhibitor by targeting the mTOR (mammalian target of rapamycin) signaling pathway, an important stimulator of cell growth and proliferation. Specifically, sirolimus binds to the immunophilin FK binding protein (FKBP), forming a complex that inhibits mTOR. This leads to interruption of IL-2 signal transduction, preventing G1 to S phase progression and lymphocyte proliferation.
Calcineurin inhibitors (eg, tacrolimus, cyclosporine) are other commonly used immunosuppression medications that function by blocking the translocation of nuclear factor of activated T-cells (NFAT), resulting in reduced transcription of IL-2.
(Choice A) Bortezomib binds and inhibits the 26S proteasome. In multiple myeloma, bortezomib can facilitate apoptosis of neoplastic cells by preventing degradation of proapoptotic factors.
(Choice B) Mycophenolate reversibly inhibits inosine monophosphate dehydrogenase. This blocks a critical step in the de novo synthesis of purine nucleotides that is required for proliferation of activated lymphocytes. Because most other cells have an alternative pathway for purine synthesis that lymphocytes lack, mycophenolate is relatively specific for suppression of B and T cells.
(Choice C) Prednisone and other glucocorticoids bind to cytoplasmic receptors, translocate to the nucleus, and then inhibit the transcription of genes that encode IL-2 and other inflammatory mediators.
(Choice D) Rituximab is a chimeric antibody directed against the CD20 antigen (specific to B lymphocytes). It depletes B cells (and reduces antibody production) through multiple pathways, including complement-mediated lysis, antibody-dependent cytotoxicity (via natural killer cells), and induction of lymphocyte apoptosis.
Educational objective:
Sirolimus binds to the immunophilin FK binding protein (FKBP) in the cytoplasm, forming a complex that binds and inhibits mTOR (mammalian target of rapamycin). Inhibition of mTOR signaling blocks IL-2 signal transduction and prevents cell cycle progression and lymphocyte proliferation.