Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California 94305, USA.
J Heart Lung Transplant. 2011 Dec;30(12):1409-17. doi: 10.1016/j.healun.2011.08.017.
IL-16 promotes the recruitment of various cells expressing CD4, a receptor for IL-16. The precise role of IL-16 in transplant rejection remains unknown; therefore, the present study investigated the contribution of IL-16 to the development of chronic rejection in heart transplants.
C-H-2(bm12)KhEg (H-2(bm12)) donor hearts were transplanted into (1) IL-16-deficient (IL-16(-/-)) C57BL/6J or (b) wild type (WT) control recipients (MHC class II mismatch). Grafts were harvested at 52 days, parenchymal rejection was assessed by the ISHLT grading system, and CAV was examined morphometrically. Graft infiltrating cells were detected 10 and 52 days after transplantation. Intragraft cytokine and chemokine profiles were assessed. To confirm the role of IL-16 in CAV development, C-H-2(bm12)KhEg (H-2(bm12)) donor hearts were transplanted into C57BL/6J WT recipients treated with (1) anti-IL-16-neutralization monoclonal antibody or (b) control immunoglobulin G. Grafts were harvested at 52 days, and CAV was quantified morphometrically. Graft-infiltrating cells were examined histologically.
Parenchymal rejection and CAV was significantly attenuated in donor hearts transplanted into IL-16(-/-) recipient mice compared with WT controls. Donor hearts transplanted into IL-16(-/-) recipients had a significant reduction in coronary artery luminal occlusion, intima-to-media ratio, and percentage of diseased vessels. CAV was associated with decreased donor organ inflammation, as well as donor organ cytokine (IL-1β and IL-6) and chemokine (MCP-1 and KC) protein expression. Intimal proliferation and inflammatory cell infiltration were significantly reduced in hearts transplanted into recipients treated with an IL-16-neutralization antibody.
IL-16-deficiency reduced graft inflammatory cell recruitment, and allograft inflammatory cytokine and chemokine production. Therefore, IL-16 neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection.
IL-16 可促进表达 IL-16 受体 CD4 的各种细胞的募集。IL-16 在移植排斥反应中的确切作用尚不清楚；因此，本研究探讨了 IL-16 对心脏移植慢性排斥反应的发展的贡献。
将 C-H-2(bm12)KhEg（H-2(bm12)）供体心脏移植到（1）IL-16 缺陷（IL-16(-/-)）C57BL/6J 或（b）野生型（WT）对照受体（MHC Ⅱ类错配）中。在 52 天时收获移植物，通过 ISHLT 分级系统评估实质排斥反应，并通过形态计量学检查 CAV。在移植后 10 天和 52 天检测移植物浸润细胞。评估移植物内细胞因子和趋化因子谱。为了证实 IL-16 在 CAV 发展中的作用，将 C-H-2(bm12)KhEg（H-2(bm12)）供体心脏移植到用（1）抗 IL-16 中和单克隆抗体或（b）对照免疫球蛋白 G 处理的 C57BL/6J WT 受体中。在 52 天时收获移植物，并通过形态计量学定量 CAV。检查移植物浸润细胞的组织学。
与 WT 对照相比，移植到 IL-16(-/-)受体小鼠的供体心脏的实质排斥和 CAV 明显减轻。移植到 IL-16(-/-)受体的供体心脏的冠状动脉管腔闭塞、内膜-中膜比和病变血管百分比均显著降低。CAV 与供体器官炎症减少以及供体器官细胞因子（IL-1β 和 IL-6）和趋化因子（MCP-1 和 KC）蛋白表达减少有关。在接受 IL-16 中和抗体治疗的受体中移植的心脏，内膜增殖和炎症细胞浸润明显减少。
IL-16 缺乏减少了移植物炎症细胞的募集以及同种异体移植物炎症细胞因子和趋化因子的产生。因此，IL-16 中和可能为心脏同种异体移植排斥的新型治疗提供潜在靶点。
