Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria.
Eur J Immunol. 2015 Sep;45(9):2470-9. doi: 10.1002/eji.201545494.
Establishing donor-specific immunological tolerance could improve long-term outcome by obviating the need for immunosuppressive drug therapy, which is currently required to control alloreactivity after organ transplantation. Mixed chimerism is defined as the engraftment of donor hematopoietic stem cells in the recipient, leading to viable coexistence of both donor and recipient leukocytes. In numerous experimental models, cotransplantation of donor bone marrow (BM) into preconditioned (e.g., through irradiation or cytotoxic drugs) recipients leads to transplantation tolerance through (mixed) chimerism. Mixed chimerism offers immunological advantages for clinical translation; pilot trials have established proof of concept by deliberately inducing tolerance in humans. Widespread clinical application is prevented, however, by the harsh preconditioning currently necessary for permitting BM engraftment. Recently, the immunological mechanisms inducing and maintaining tolerance in experimental mixed chimerism have been defined, revealing a more prominent role for regulation than historically assumed. The evidence from murine models suggests that both deletional and regulatory mechanisms are critical in promoting complete tolerance, encompassing also the minor histocompatibility antigens. Here, we review the current understanding of tolerance through mixed chimerism and provide an outlook on how to realize widespread clinical translation based on mechanistic insights gained from chimerism protocols, including cell therapy with polyclonal regulatory T cells.
建立供者特异性免疫耐受可以通过避免器官移植后对抗同种异体反应所需的免疫抑制药物治疗来改善长期结果。嵌合状态定义为供者造血干细胞在受者中的植入，导致供者和受者白细胞的共存。在许多实验模型中，通过预处理（例如通过照射或细胞毒性药物）将供者骨髓（BM）共移植到受者中，通过（混合）嵌合导致移植耐受。嵌合状态为临床转化提供了免疫优势；通过在人类中故意诱导耐受，初步临床试验已经证实了这一概念。然而，由于目前允许 BM 植入所必需的苛刻预处理，广泛的临床应用受到了阻碍。最近，实验性嵌合状态中诱导和维持耐受的免疫机制已经得到定义，揭示了调节作用比历史上认为的更为突出。来自鼠模型的证据表明，在促进完全耐受方面，删除和调节机制都是至关重要的，包括次要组织相容性抗原。在这里，我们综述了通过嵌合状态实现耐受的最新理解，并基于嵌合状态方案（包括多克隆调节性 T 细胞的细胞治疗）获得的机制见解，就如何实现广泛的临床转化提供了展望。
