Curative haploidentical BMT in a murine model of X-linked chronic granulomatous disease.
Curative haploidentical BMT in a murine model of X-linked chronic granulomatous disease.
复制标题
X连锁慢性肉芽肿病小鼠模型中的治愈性单倍相合 BMT。
DOI：
10.1007/s12185-015-1799-8
复制
发表时间：
2015
期刊：
影响因子：
2.1
通讯作者：
Ohtsu M.
中科院分区：
文献类型：
--
作者：
Takeuchi Y;Takeuchi E;Ishida T;Onodera M;Nakauchi H;Ohtsu M.
慢性肉芽肿病（CGD）是一种原发性免疫缺陷疾病，其特征是吞噬细胞中微生物杀灭缺陷。CGD患者的长期预后通常较差，这突出了开发毒性最小的治愈性治疗方法的必要性。我们在这里描述了一种小鼠模型的建立，其中X连锁CGD可以通过异基因骨髓移植治愈。使用非清髓性剂量全身照射和单次注射抗CD40配体单克隆抗体的组合，在单倍相合移植环境中，全骨髓细胞移植在X连锁CGD小鼠中实现了持久的混合嵌合体。即使在低范围（<20%供体细胞），稳定的混合嵌合体也维持长达1年，表明诱导了供体特异性耐受。该方案诱导轻度骨髓抑制，无严重急性并发症。稳定的嵌合体是治疗性的，因为它抑制皮肤肉芽肿形成在体内试验适合于评价治疗效果的小鼠CGD模型。这些结果保证了未来开发一种简化的异基因造血细胞移植方案，该方案通过允许使用单倍体相合供体移植物而使CGD患者受益，而无需严重关注严重的治疗相关毒性。
Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder characterized by defective microbial killing in phagocytes. Long-term prognosis for CGD patients is generally poor, highlighting the need to develop minimally toxic, curative therapeutic approaches. We here describe the establishment of a mouse model in which X-linked CGD can be cured by allogeneic bone marrow transplantation. Using a combination of non-myeloablative-dose total body irradiation and a single injection of anti-CD40 ligand monoclonal antibody, transplantation of whole bone marrow cells achieved long-lasting mixed chimerism in X-linked CGD mice in a haploidentical transplantation setting. Stable mixed chimerism was maintained for up to 1 year even at a low range (<20 % donor cells), indicating induction of donor-specific tolerance. The regimen induced mild myelosuppression without severe acute complications. Stable chimerism was therapeutic, as it suppressed cutaneous granuloma formation in an in vivo test suited for evaluation of treatment efficacy in murine CGD models. These results warrant future development of a simplified allogeneic hematopoietic cell transplantation regimen that would benefit CGD patients by allowing the use of haploidentical donor grafts without serious concerns of severe treatment-related toxicity.