Interleukin-15 receptor blockade in non-human primate kidney transplantation.
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BACKGROUND: Interleukin (IL)-15 is a chemotactic factor to T cells. It induces proliferation and promotes survival of activated T cells. IL-15 receptor blockade in mouse cardiac and islet allotransplant models has led to long-term engraftment and a regulatory T-cell environment. This study investigated the efficacy of IL-15 receptor blockade using Mut-IL-15/Fc in an outbred non-human primate model of renal allotransplantation. METHODS: Male cynomolgus macaque donor-recipient pairs were selected based on ABO typing, major histocompatibility complex class I typing, and carboxy-fluorescein diacetate succinimidyl ester-based mixed lymphocyte responses. Once animals were assigned to one of six treatment groups, they underwent renal transplantation and bilateral native nephrectomy. Serum creatinine level was monitored twice weekly and as indicated, and protocol biopsies were performed. Rejection was defined as a increase in serum creatinine to 1.5 mg/dL or higher and was confirmed histologically. Complete blood counts and flow cytometric analyses were performed periodically posttransplant; pharmacokinetic parameters of Mut-IL-15/Fc were assessed. RESULTS: Compared with control animals, Mut-IL-15/Fc-treated animals did not demonstrate increased graft survival despite adequate serum levels of Mut-IL-15/Fc. Flow cytometric analysis of white blood cell subgroups demonstrated a decrease in CD8 T-cell and natural killer cell numbers, although this did not reach statistical significance. Interestingly, two animals receiving Mut-IL-15/Fc developed infectious complications, but no infection was seen in control animals. Renal pathology varied widely. CONCLUSIONS: Peritransplant IL-15 receptor blockade does not prolong allograft survival in non-human primate renal transplantation; however, it reduces the number of CD8 T cells and natural killer cells in the peripheral blood.
Drug Therapy, Combination
Immunoglobulin Fc Fragments
Killer Cells, Natural
Published Version (Please cite this version)10.1097/TP.0b013e3181d05a58
Publication InfoHaustein, Silke; Kwun, Jean; Fechner, John; Kayaoglu, Ayhan; Faure, Jean-Pierre; Roenneburg, Drew; ... Knechtle, Stuart J (2010). Interleukin-15 receptor blockade in non-human primate kidney transplantation. Transplantation, 89(8). pp. 937-944. 10.1097/TP.0b013e3181d05a58. Retrieved from https://hdl.handle.net/10161/10064.
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William R. Kenan, Jr. Distinguished Professor
During my career as an academic surgeon, I have had the privilege of leading and/or participating in a diverse portfolio of hypothesis-driven research projects. These projects have centered on the immunology of surgery and transplantation, including both cellular and antibody-mediated immune responses. During my training I studied the response of hyper-sensitized recipients to allogeneic liver transplantation, and am currently studying means of reducing immunologic memory that might
Assistant Professor of Surgery
Research interests include humoral tolerance to organ transplants in animal model and humans, developing a clinically relevant animal model to study the mechanisms of antibody-mediated rejection (AMR), and establishing a conceptual basis that will translate into therapeutic intervention of AMR.
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