Costimulation blockade, busulfan, and bone marrow promote titratable macrochimerism, induce transplantation tolerance, and correct genetic hemoglobinopathies with minimal myelosuppression
Costimulation blockade, busulfan, and bone marrow promote titratable macrochimerism, induce transplantation tolerance, and correct genetic hemoglobinopathies with minimal myelosuppression
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DOI：
10.4049/jimmunol.167.2.1103
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发表时间：
2001-07-15
影响因子：
4.4
通讯作者：
Larsen, CP
中科院分区：
文献类型：
--
作者：
Adams, AB;Durham, MM;Larsen, CP
混合造血嵌合有可能纠正遗传性血液病（镰状细胞性贫血、地中海贫血）并消除器官移植后的慢性免疫抑制治疗。迄今为止，大多数策略需要接受受体调节（伽马射线照射，外周免疫系统的耗竭）或施用“大”剂量的骨髓以促进可靠的植入。尽管令人鼓舞，但仍然存在许多问题可能限制或阻止此类策略的临床应用。我们描述了一种基于非辐射的替代策略，使用单剂量的白消安、共刺激阻断和 T 细胞耗尽的供体骨髓，该策略促进可滴定的大嵌合和 T 细胞库的重塑。嵌合体表现出强大的供体特异性耐受性，这通过接受完全同种异体皮肤移植物和在体内移植物抗宿主疾病同种反应性模型中未能产生供体特异性增殖反应来证明。在该模型中，供体细胞输注和不含白消安的共刺激阻断不足以诱导耐受，因为供体特异性产生 IFN-γ 的 T 细胞重新出现，并且皮肤移植物在大约 100 天时被排斥。当应用于小鼠β-地中海贫血模型时，该方法可以使血液学参数正常化并替换患病的红细胞区室。这样的方案可能允许在患有终末期器官疾病或血红蛋白病的患者中临床应用混合嵌合策略。
Mixed hemopoietic chimerism has the potential to correct genetic hemological diseases (sickle cell anemia, thalassemia) and eliminate chronic immunosuppressive therapy following organ transplantation. To date, most strategies require either recipient conditioning (gamma -irradiation, depletion of the peripheral immune system) or administration of "mega" doses of bone marrow to facilitate reliable engraftment. Although encouraging, many issues remain that may restrict or prevent clinical application of such strategies. We describe an alternative, nonirradiation based strategy using a single dose of busulfan, costimulation blockade, and T cell-depleted donor bone marrow, which promotes titratable macrochimerism and a reshaping of the T cell repertoire. Chimeras exhibit robust donor-specific tolerance, evidenced by acceptance of fully allogeneic skin grafts and failure to generate donor-specific proliferative responses in an in vivo graft-versus-host disease model of alloreactivity. In this model, donor cell infusion and costimulation blockade without busulfan were insufficient for tolerance induction as donor-specific IFN-gamma -producing T cells re-emerged and skin grafts were rejected at similar to 100 days. When applied to a murine beta -thalassemia model, this approach allows for the normalization of hemologic parameters and replacement of the diseased red cell compartment. Such a protocol may allow for clinical application of mixed chimerism strategies in patients with end-stage organ disease or hemoglobinopathies.