BackgroundMammalian target of rapamycin (mTOR) inhibitors are approved to prevent allograft rejection and control malignancy. Unfortunately, they are associated with adverse effects, such as wound healing complications that detract from more extensive use. There is a lack of prospective wound healing studies to monitor patients treated with mTOR inhibitors, such as everolimus or sirolimus, especially in nondiabetics.MethodsPatients receiving everolimus with standard immunosuppressant therapy or standard immunosuppressant therapy without everolimus were administered 3-mm skin biopsy punch wounds in the left scapular region. Homeostatic gene expression was examined in the skin obtained from the biopsy and wound surface area was examined on day 7. Peripheral blood mononuclear cells were examined for cytokine production.ResultsThere are no significant changes in autophagy related 13, epidermal growth factor, insulin-like growth factor binding protein 3, IL-2, kruppel-like factor 4, and TGFB1 gene expression in the skin suggesting that there is little impact of everolimus on these genes within nonwounded skin. Peripheral blood T cells are more sensitive to cell death in everolimus-treated patients, but they retain the ability to produce proinflammatory cytokines required for efficient wound repair. Importantly, there is no delay in the closure of biopsy wounds in patients receiving everolimus as compared to those not receiving mTOR inhibition.ConclusionsEverolimus treatment is not associated with impaired closure of skin biopsy wounds in kidney transplant recipients. These data highlight the importance of exploring whether larger surgical wounds would show a similar result and how other factors, such as diabetes, impact wound healing complications associated with mTOR suppression.
The kidney is an essential organ necessary for the human body to discharge harmful toxins and is imperative for filtering blood. According to the Centers for Disease Control and Prevention, kidney disease is the eighth leading cause of death in the United States. Diabetes and hypertension are two major factors that influence kidney function, which can consequently lead to end-stage renal disease. The primary method of treatment for end-stage renal disease is kidney transplantation, which requires a regimen of immunosuppressant drugs to prevent allograft rejection. Previously, our lab has shown that administration of the immunosuppressant drug, sirolimus a mammalian target of rapamycin inhibitor, also known as mTOR, impairs skin homeostasis and wound repair. To further understand the mechanism behind this adverse effect of mTOR suppression, we examined renal transplant recipients who were administered the sirolimus derivative everolimus. The number and activation of αβ and γδ T cells in the blood of patients administered everolimus were compared to a control group of patients not administered everolimus. Several of these T cell populations, including Vγ9Vδ2 T cells, have been previously displayed to home to sites of tissue damage to improve wound repair. This data explores which T lymphocyte populations require mTOR to maximize function in transplant recipients with implications in tissue repair and graft rejection.
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