2017年12月，我所吴德沛教授课题组和刘海燕教授课题组在《European Journal of Immunology》杂志发表最新研究成果“IL-12/IL-18-preactivated donor NK cells enhance GVL effects and mitigate GvHD after allogeneic hematopoietic stem cell transplantation”。该研究成果证明IL-12/IL-18激活的“记忆样”供体NK细胞的过继性输注在异基因造血干细胞移植中发挥更为安全有效的抗白血病复发及减轻移植物抗宿主病的作用。吴德沛教授、刘海燕教授为该文的通讯作者。

如何有效促进移植物抗白血病(GVL)效应同时抑制移植物抗宿主病(GVHD),是提高异基因造血干细胞移植（allo-HSCT）疗效的关键。研究发现IL-12/15/18激活的“记忆样”供体NK细胞在过继输注后仍维持较强增殖活性和效应功能，发挥很好的GVL效应。然而供体NK细胞作为能够调控T细胞、树突状细胞及Treg细胞的“免疫调节者”，在急性GVHD（aGVHD）中具有“加重”或“减轻”病情的双重潜能，因此明确“记忆样”供体NK细胞在aGVHD中的作用及机制，对于其安全有效的应用于临床治疗非常重要。课题组研究结果证明IL-12/18及IL-12/15/18激活的供体NK细胞具有相似 “记忆样”特性，与未经细胞因子刺激处理的供体NK细胞相比均发挥较强的GVL效应。有趣的是，课题组发现虽然在“严重的”aGVHD小鼠模型中，IL-12/15/18及IL-12/18激活的供体NK细胞输注都能够显著抑制受体鼠的aGVHD病情，但是在较“缓和的”aGVHD模型中IL-12/15/18激活的供体NK细胞却具有加重aGVHD的风险，而IL-12/18激活的供体NK细胞则仍能够较好的抑制aGVHD病情。课题组进一步实验结果提示供者T细胞的异基因反应性、受体鼠体内的炎症情况、受体鼠的肿瘤负荷情况可能都影响了IL-12/15/18在aGVHD中作用的发挥，而在临床治疗中，患者体内的这些情况是错综复杂并很难实时明确的，因此IL-12/18激活的“记忆样”供体NK细胞的过继性输注有望在异基因造血干细胞移植中发挥更为安全有效的治疗作用。

原文摘要：Adoptive transfer of donor NK cells has the potential of mediating graft-versus-leukemia (GVL) effect while suppressing acute graft-versus-host-disease (aGVHD) during allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, these beneficial effects are limited by the transient function of adoptively transferred NK cells. Previous studies demonstrate that cytokine-induced memory-like NK cells that are preactivated by IL-12, IL-15, and IL-18 have enhanced effector functions and long life span in vivo. Here, we investigated the effects of IL-12/18-preactivated and IL-12/15/18-preactivated donor NK cells on GVL and aGVHD in a murine model of allo-HSCT. We found that both IL-12/18- and IL-12/15/18-preactivated NK cells mediated stronger GVL effect than control NK cells mainly due to their elevated activation/cytotoxicity and sustained proliferative potential. Interestingly, we observed that although both IL-12/18- and IL-12/15/18-preactivated NK cells significantly inhibited severe aGVHD, only the IL-12/18-preactivated NK cells maintained the beneficial effect of donor NK cells on mild aGVHD. The IL-12/15/18-preactivated NK cell infusion accelerated aGVHD in the fully-mismatched mild aGVHD model. Our results demonstrated that IL-12/18-preactivated NK cells displayed sustained and enhanced GVL functions, and could mitigate aGVHD despite the severity of the disease. IL-12/18-preactivated donor NK cell infusion may be an effective and safe adoptive therapy after allo-HSCT.