Guo Zhiguang, Wu Tao, Sozen Hakan, Pan Yisheng, Heuss Neal, Kalscheuer Hannes, Sutherland David E R, Blazar Bruce R, Hering Bernhard J
Diabetes Institute for Immunology and Transplantation, and Department of Surgery, MMC 195, University of Minnesota, 420 Delaware Street S.E., Minneapolis, MN 55455.
Transplantation. 2003 Apr 15;75(7):909-15. doi: 10.1097/01.TP.0000057832.92231.F5.
Mixed chimerism can induce tolerance to alloantigens and restore self-tolerance to autoantigens, thereby permitting islet transplantation. However, the minimal level of donor chimerism that is required to prevent islet allograft rejection and recurrence of autoimmune diabetes has not been established.
We investigated whether allogeneic Balb/c donor chimerism can be induced in C57BL/6 mice, in prediabetic NOD mice, and in diabetic NOD mice after transplantation of a modest dose of bone marrow by using purine nucleoside analogue, fludarabine phosphate and cyclophosphamide conditioning therapy, followed by short-term anti-CD40 ligand monoclonal antibody and rapamycin posttransplant treatment. We also investigated whether the induced donor chimerism is sufficient to prevent the onset of diabetes in prediabetic NOD mice and protect donor islet grafts in diabetic NOD mice.
Allogeneic donor chimerism could be induced under the authors' approach that is nonmyeloablative and radiation-free. Diabetes onset was prevented in chimeric prediabetic NOD mice. The induction of mixed chimerism protected donor-specific islet grafts in diabetic NOD mice. At 60 days after islet transplantation, all donor Balb/c islet grafts survived in diabetic NOD mice whose level of donor-derived lymphocytes was higher than 30% at the time of islet transplantation (n=8). In contrast, Balb/c islet grafts were rejected in five of seven diabetic NOD mice whose level was lower than 30%.
Our data demonstrate that a donor lymphocyte chimerism (>30%) at the time of islet transplantation is required to protect donor-specific islet grafts, and indicate that a strictly non-irradiation-based protocol can be used to achieve this goal.
混合嵌合体可诱导对同种异体抗原的耐受，并恢复对自身抗原的自身耐受，从而使胰岛移植成为可能。然而，预防胰岛同种异体移植排斥和自身免疫性糖尿病复发所需的供体嵌合体的最低水平尚未确定。
我们研究了在给予适量剂量骨髓移植后，使用嘌呤核苷类似物、磷酸氟达拉滨和环磷酰胺预处理方案，随后进行短期抗CD40配体单克隆抗体和雷帕霉素移植后治疗，能否在C57BL/6小鼠、糖尿病前期非肥胖糖尿病（NOD）小鼠以及糖尿病NOD小鼠中诱导出同种异体Balb/c供体嵌合体。我们还研究了诱导的供体嵌合体是否足以预防糖尿病前期NOD小鼠糖尿病的发生，并保护糖尿病NOD小鼠中的供体胰岛移植物。
在作者采用的非清髓性且无辐射的方法下，可以诱导出同种异体供体嵌合体。嵌合的糖尿病前期NOD小鼠的糖尿病发病得到了预防。混合嵌合体的诱导保护了糖尿病NOD小鼠中供体特异性胰岛移植物。在胰岛移植后60天，所有供体Balb/c胰岛移植物在胰岛移植时供体来源淋巴细胞水平高于30%的糖尿病NOD小鼠中存活（n = 8）。相比之下，在七只供体来源淋巴细胞水平低于30%的糖尿病NOD小鼠中，有五只的Balb/c胰岛移植物被排斥。
我们的数据表明，胰岛移植时需要供体淋巴细胞嵌合体（>30%）来保护供体特异性胰岛移植物，并表明可以使用严格的非辐射方案来实现这一目标。
