Kaminitz Ayelet, Mizrahi Keren, Yaniv Isaac, Farkas Daniel L, Stein Jerry, Askenasy Nadir
Frankel Laboratory, Center for Stem Cell Research, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
J Autoimmun. 2009 Sep;33(2):83-91. doi: 10.1016/j.jaut.2009.07.001. Epub 2009 Jul 24.
The relative efficiencies of allogeneic and syngeneic bone marrow transplantation and the threshold levels of donor chimerism required to control autoimmune insulitis were evaluated in prediabetic NOD mice. Male and female NOD mice were conditioned by radiation and grafted with bone marrow cells from allogeneic and syngeneic sex-mismatched donors. Establishment of full allogeneic chimerism in peripheral blood reversed insulitis and restored glucose tolerance despite persistence of residual host immune cells. By contrast, sublethal total body irradiation (with or without syngeneic transplant) reduced the incidence and delayed the onset of diabetes. The latter pattern was also seen in mice that rejected the bone marrow allografts. Low levels of stable allogeneic hematopoietic chimerism (>1%) were sufficient to prevent the evolution of diabetes following allogeneic transplantation. The data indicate that immunomodulation attained at low levels of allogeneic, but not syngeneic, hematopoietic chimerism is effective in resolution of islet inflammation at even relatively late stages in the evolution of the prediabetic state in a preclinical model. However, our data question the efficacy and rationale behind syngeneic (autologous-like) immuno-hematopoietic reconstitution in type 1 diabetes.
在糖尿病前期的非肥胖糖尿病（NOD）小鼠中，评估了同种异体和同基因骨髓移植的相对效率以及控制自身免疫性胰岛炎所需的供体嵌合阈值水平。对雄性和雌性NOD小鼠进行辐射预处理，并移植来自性别不匹配的同种异体和同基因供体的骨髓细胞。尽管残留宿主免疫细胞持续存在，但外周血中完全同种异体嵌合的建立逆转了胰岛炎并恢复了糖耐量。相比之下，亚致死剂量的全身照射（无论是否进行同基因移植）均可降低糖尿病的发病率并延迟其发病。在排斥骨髓同种异体移植物的小鼠中也观察到了后一种模式。低水平的稳定同种异体造血嵌合（>1%）足以防止同种异体移植后糖尿病的进展。数据表明，在临床前模型中，在糖尿病前期状态演变的相对晚期阶段，低水平的同种异体而非同基因造血嵌合所实现的免疫调节对胰岛炎症的消退有效。然而，我们的数据质疑了1型糖尿病中同基因（类似自体）免疫造血重建的疗效和理论依据。
