A 56-year-old woman with a history of heart failure is admitted to the hospital for orthotopic cardiac transplantation. The patient developed biventricular failure due to idiopathic myocarditis. She has had persistent New York Heart Association class IV symptoms refractory to maximal medical therapy and was placed on the transplant waiting list. An ABO-compatible cadaveric heart is available for transplant with partial human leukocyte antigen (HLA) mismatch. Cardiac transplantation is performed and the patient's T lymphocytes quickly recognize the foreign HLA molecules of the transplant cells. Inhibition of which of the following substances would specifically reduce the proliferation and differentiation of these T lymphocytes?

Question

A 56-year-old woman with a history of heart failure is admitted to the hospital for orthotopic cardiac transplantation.  The patient developed biventricular failure due to idiopathic myocarditis.  She has had persistent New York Heart Association class IV symptoms refractory to maximal medical therapy and was placed on the transplant waiting list.  An ABO-compatible cadaveric heart is available for transplant with partial human leukocyte antigen (HLA) mismatch.  Cardiac transplantation is performed and the patient's T lymphocytes quickly recognize the foreign HLA molecules of the transplant cells.  Inhibition of which of the following substances would specifically reduce the proliferation and differentiation of these T lymphocytes?

Quizplus · Accepted Answer

11ec160b_379d_2706_9249_8341ffa410da_MD0001_00 In normal T cells, calcineurin is a protein phosphatase that is activated upon stimulation of the appropriate cell receptor. Once activated, calcineurin dephosphorylates nuclear factor of activated T cells (NFAT), which allows NFAT to enter the nucleus and bind to an interleukin-2 (IL-2) promoter. IL-2 stimulates the growth and differentiation of T cells and is an important component of the immune response. Cyclosporine and tacrolimus, 2 of the more commonly used immunosuppressants in transplant patients, inhibit calcineurin activation. (Choice A) Bcl-2 is an apoptosis inhibitor. When Bcl-2 is overexpressed, cell death is delayed and an accumulation of indolent malignant cells occurs. Bcl-2 involvement has been implicated in follicular cell lymphomas, most of which have a characteristic t(14;18) translocation. Bcl-2 inhibition would not be specific to T cells. (Choice C) E-cadherin is a transmembrane glycoprotein that orchestrates epithelial cell adhesion. If this glycoprotein is lost, cell clusters may be disrupted. The loss of e-cadherin is associated with metastasis and is a predictor of disease progression in some cancers. (Choice D) Neurofibromin is a tumor suppressor protein encoded by the NF1 gene on chromosome 17. Neurofibromin can protect against cancer as it is a key suppressor of Ras, one of the more powerful activators of cell growth and proliferation. (Choice E) p53 is a tumor suppressor that causes cell cycle arrest and apoptosis. It is rendered ineffective in the majority of cancers. Educational objective: Calcineurin is an essential protein in the activation of interleukin-2, which promotes the growth and differentiation of T cells. Immunosuppressants such as cyclosporine and tacrolimus work by inhibiting calcineurin activation.

A 56-Year-Old Woman with a History of Heart Failure Is