Division of Transplantation, Department of Surgery, Clinical Science Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Transplantation. 2010 Apr 27;89(8):937-44. doi: 10.1097/TP.0b013e3181d05a58.
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.
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.
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.
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.
白细胞介素（IL）-15 是 T 细胞的趋化因子。它诱导增殖并促进激活的 T 细胞存活。在小鼠心脏和胰岛同种异体移植模型中，阻断 IL-15 受体导致长期移植物植入和调节性 T 细胞环境。本研究在非人类灵长类动物肾移植模型中使用 Mut-IL-15/Fc 研究了 IL-15 受体阻断的疗效。
根据 ABO 分型、主要组织相容性复合体 I 型分型和基于羧基荧光素二乙酸琥珀酰亚胺酯的混合淋巴细胞反应，选择雄性食蟹猴供体-受者对。一旦动物被分配到六个治疗组中的一个，它们就接受了肾移植和双侧原位肾切除术。每周监测两次血清肌酐水平，并根据需要进行协议活检。排斥反应定义为血清肌酐增加到 1.5mg/dL 或更高，并通过组织学确认。移植后定期进行全血细胞计数和流式细胞分析；评估 Mut-IL-15/Fc 的药代动力学参数。
与对照动物相比，尽管 Mut-IL-15/Fc 的血清水平充足，但 Mut-IL-15/Fc 治疗的动物并未显示移植物存活率增加。白细胞亚群的流式细胞分析显示 CD8 T 细胞和自然杀伤细胞数量减少，但这并未达到统计学意义。有趣的是，接受 Mut-IL-15/Fc 的两只动物发生了感染性并发症，但对照动物中没有感染。肾脏病理学差异很大。
移植前 IL-15 受体阻断并不能延长非人类灵长类动物肾移植中的同种异体移植物存活；然而，它减少了外周血中 CD8 T 细胞和自然杀伤细胞的数量。
