OBJECTIVE:In the absence of immunodeficiency, only microchimerism (<0.1%) has been achieved in human fetal recipients or nonhuman primates following in utero hematopoietic cell transplantation (IUHCT). We hypothesized that enhanced long-term engraftment might be more reliably achieved in microchimeric systems if higher levels of chimerism existed during development of adaptive immunity. To evaluate this hypothesis, we stimulated the donor cells with vascular endothelial growth factor (VEGF) and stem cell factor (SCF) prior to IUHCT in a chimerism-resistant murine strain combination. METHODS:Donor Balb/c marrow was cultured in media with or without VEGF and SCF supplementation for 12 hours prior to IUHCT into B6 fetuses at 14 days postcoitum (dpc). Donor cell phenotype, homing, and chimerism were assessed at short and long-term time points and transplanted animals received skin allografts at 8 weeks. RESULTS:In pretreated allogeneic recipients, early chimerism rates were more than double that of controls (71% vs 33%, p = 0.01). These differences were associated with higher numbers of pretransplant donor cell colony-forming cells without change in donor cell homing. Despite prolonged skin allograft survival for pretreated recipients compared with controls (mean survival = 20.8 vs 8.2 days, p < 0.001), long-term engraftment was unchanged. CONCLUSIONS:These findings demonstrate that higher levels of early chimerism in recipients of cytokine-stimulated marrow result in improved short-term chimerism and tolerance. Future studies are needed to confirm the existence of a "threshold" level of chimerism necessary to sustain long-term engraftment.

译文

目的:在缺乏免疫缺陷的情况下,子宫内造血细胞移植(IUHCT)后,人类胎儿接受者或非人类灵长类仅获得微嵌合体(<0.1%)。我们假设,如果在适应性免疫发展过程中存在较高水平的嵌合体,则在微嵌合系统中可以更可靠地实现增强的长期植入。为了评估该假设,我们在抗嵌合体的鼠类菌株组合中,在IUHCT之前用血管内皮生长因子(VEGF)和干细胞因子(SCF)刺激了供体细胞。
方法:在IUHCT植入后的第14天(dpc)将IUBCT注入B6胎儿之前,在添加或不添加VEGF和SCF的培养基中培养供体Balb / c骨髓12小时。在短期和长期的时间点评估供体细胞的表型,归巢和嵌合,移植的动物在第8周接受皮肤同种异体移植。
结果:在经过预处理的同种异体受体中,早期嵌合率是对照的两倍以上(71%vs 33%,p = 0.01)。这些差异与更高数量的移植前供体细胞集落形成细胞相关,而未改变供体细胞归巢。尽管与对照组相比,经过预处理的接受者的皮肤同种异体移植存活时间延长(平均存活率= 20.8 vs 8.2天,p <0.001),但长期移植并未改变。
结论:这些发现表明,受细胞因子刺激的骨髓受体的早期嵌合水平较高,可改善短期嵌合和耐受性。需要进行进一步的研究,以确认是否存在维持长期植入所必需的“阈值”水平的嵌合体。

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