Neipp M, Exner B G, Ildstad S T
The Institute for Cellular Therapeutics, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania 19102, USA.
Transplantation. 1998 Oct 27;66(8):969-75. doi: 10.1097/00007890-199810270-00001.
The supply of solid organs for transplantation will never meet the growing demand. Xenotransplantation is considered to be a potential solution for the critical shortage of allografts. However, xenograft rejection is currently not controlled by conventional immunosuppressive agents. Bone marrow chimerism induces donor-specific tolerance without the requirement for chronic immunosuppressive therapy. The aim of this study was to develop a nonlethal recipient-conditioning approach to achieve mixed bone marrow chimerism and donor-specific tolerance.
C57BL/10SnJ mice were conditioned with total body irradiation followed by a single injection of cyclophosphamide on day +2. On day 0, mice were reconstituted with untreated bone marrow cells from Fischer 344 rats. Recipients were analyzed by flow cytometry for donor bone marrow engraftment and multilineage chimerism. Donor-specific tolerance was tested by skin grafting.
One hundred percent of recipients engrafted after irradiation with 600 cGy total body irradiation, transplantation with 80 x 10(6) Fischer 344 bone marrow cells, and injection with 50 mg/kg cyclophosphamide intraperitoneally. Donor chimerism was detectable in all engrafted animals for up to 11 months. This conditioning was nonlethal, because conditioned untransplanted animals survived indefinitely. Mixed xenogeneic chimeras were tolerant to donor-specific skin grafts but rejected third-party (Wistar Furth) grafts as rapidly as naive C57BL/10SnJ mice. In contrast, animals that received less efficacious conditioning regimens and did not exhibit detectable chimerism showed prolonged graft survival, but delayed graft rejection occurred in all animals within 10 weeks.
The induction of bone marrow chimerism and donor-specific tolerance after nonlethal conditioning might be useful to prevent the vigorous cellular and humoral rejection response to xenografts.
用于移植的实体器官供应永远无法满足不断增长的需求。异种移植被认为是同种异体移植物严重短缺的一种潜在解决方案。然而，目前传统免疫抑制剂无法控制异种移植排斥反应。骨髓嵌合体可诱导供体特异性耐受，而无需长期免疫抑制治疗。本研究的目的是开发一种非致死性的受体预处理方法，以实现混合骨髓嵌合体和供体特异性耐受。
对C57BL/10SnJ小鼠进行全身照射，随后在第+2天单次注射环磷酰胺。在第0天，用来自Fischer 344大鼠的未处理骨髓细胞对小鼠进行重建。通过流式细胞术分析受体的供体骨髓植入和多谱系嵌合体情况。通过皮肤移植测试供体特异性耐受。
在接受600 cGy全身照射、移植80×10(6)个Fischer 344骨髓细胞并腹腔注射50 mg/kg环磷酰胺后，100%的受体实现了植入。在所有植入的动物中，长达11个月均可检测到供体嵌合体。这种预处理是非致死性的，因为经过预处理但未进行移植的动物可无限期存活。混合异种嵌合体对供体特异性皮肤移植耐受，但排斥第三方（Wistar Furth）移植，排斥速度与未处理的C57BL/10SnJ小鼠一样快。相比之下，接受效果较差的预处理方案且未表现出可检测到的嵌合体的动物，移植存活时间延长，但所有动物在10周内均出现延迟移植排斥。
非致死性预处理后诱导骨髓嵌合体和供体特异性耐受可能有助于预防对异种移植物的强烈细胞和体液排斥反应。
