Li H, Kaufman C L, Boggs S S, Johnson P C, Patrene K D, Ildstad S T
Department of Surgery, University of Pittsburgh, PA 15261, USA.
J Immunol. 1996 Jan 1;156(1):380-8.
Evidence in experimental models suggests that many autoimmune diseases can be prevented by transplantation of bone marrow from disease-resistant donors. For potential clinical application, it would be important to avoid the morbidity and mortality associated with lethal conditioning and achieve mixed chimerism using less than complete recipient ablation. We report here for the first time that stable chimerism achieved in NOD mice using a sublethal radiation-based conditioning approach is sufficient to prevent beta-cell destruction and abrogate insulitis in prediabetic NOD mice. The percentage of NOD mouse recipients (8 wk of age) that engrafted with donor bone marrow correlated with the dose of irradiation and number of bone marrow cells transplanted. Engraftment of B10.BR bone marrow occurred in > or = 94% of animals receiving > or = 750 cGy of total body irradiation before bone marrow transplantation and > or = 30 x 10(6) bone marrow cells, while reproducible engraftment did not occur at radiation doses of less than 700 cGy and cellular doses of less than 30 x 10(6) bone marrow cells. All chimeric animals remained free of diabetes (n = 38) for 10 mo following bone marrow transplantation. Moreover, in all animals examined, no insulitis was present from 12 to 36 wk following reconstitution. In striking contrast, 61% (22 of 36) of NOD recipients that were conditioned but did not receive bone marrow developed acute diabetes by 12 mo. Insulitis was present in all remaining animals. These results suggest that allogeneic chimerism achieved using a sublethal conditioning approach can prevent the onset of diabetes and even reverse preexisting insulitis in NOD mice.
实验模型中的证据表明，许多自身免疫性疾病可通过移植抗病供体的骨髓来预防。对于潜在的临床应用而言，避免与致死性预处理相关的发病率和死亡率，并在不完全消融受体的情况下实现混合嵌合体，将具有重要意义。我们在此首次报告，使用基于亚致死性辐射的预处理方法在NOD小鼠中实现的稳定嵌合体足以预防糖尿病前期NOD小鼠的β细胞破坏并消除胰岛炎。移植了供体骨髓的NOD小鼠受体（8周龄）的比例与照射剂量和移植的骨髓细胞数量相关。在骨髓移植前接受全身照射≥750 cGy且骨髓细胞≥30×10⁶个的动物中，B10.BR骨髓的植入率≥94%，而在辐射剂量小于700 cGy且细胞剂量小于30×10⁶个骨髓细胞时，未出现可重复的植入。所有嵌合动物在骨髓移植后10个月内均未患糖尿病（n = 38）。此外，在所有检查的动物中，重建后12至36周均未出现胰岛炎。与之形成鲜明对比的是，经过预处理但未接受骨髓移植的NOD受体中，61%（36只中的22只）在12个月时发展为急性糖尿病。其余所有动物均出现胰岛炎。这些结果表明，使用亚致死性预处理方法实现的同种异体嵌合体可预防NOD小鼠糖尿病的发生，甚至逆转已存在的胰岛炎。
