Thesis

The Impact of Everolimus on Wound Healing in Renal Transplant Patients

The major objective of immunosuppressive therapy is to mitigate graft rejection while retaining the ability of the immune system to fight pathogens and repair tissue. Immunosuppressant drugs that inhibit mammalian target of rapamycin (mTOR) signaling represent an important class of drugs, but they have been associated with adverse effects, including problems with wound healing, that detract from more extensive use. Derivatives of these drugs, such as everolimus, have been developed, however there have been no prospective studies to monitor wound closure in patients receiving this drug. The objective of this study was to determine whether everolimus impairs wound closure in kidney transplant recipients by monitoring the closure of 3-mm biopsy wounds over a period of 7-9 days and monitoring gene expression in the non-wounded skin. We did not observe a delay in wound closure in patients receiving everolimus and a standard immunosuppressant drug regimen as compared to the control group- patients only on standard immunosuppressant therapy. In addition, no significant changes in autophagy related 13, epidermal growth factor, insulin-like growth factor binding protein 3, interleukin 2, Kruppel-like factor 4, transforming growth factor, beta 1 expression were found. T cell activation and cytokine production were examined within the peripheral blood of the same patients. Interestingly cells isolated from patients receiving everolimus were more sensitive to cell death as compared to the control group. Upon mitogen stimulation, T cells isolated from the control and everolimus administered patients were able to become activated and upregulate CD 69, CD27, and IFN-γ. Together these data suggest that mTOR immunosuppression by everolimus does not independently delay wound closure.

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