Maris Michael, Storb Rainer
Fred Hutchinson Cancer Research Center, and University of Washington, Seattle, WA, USA.
Immunol Res. 2003;28(1):13-24. doi: 10.1385/IR:28:1:13.
Originally, allogeneic hematopoietic stem cell transplantation (HSCT) was viewed as a form of rescue from the marrow lethal effects of high doses of chemo-radiotherapy used to both eradicate malignancy and to provide sufficient immunosuppression to ensure allogeneic engraftment. Clear evidence of a therapeutic graft-versus-tumor (GVT) effect mediated by allogeneic effector cells (T cells) has prompted the exploration of HSCT regimens that rely solely upon host immunosuppression (non-myeloablative) to facilitate allogeneic donor engraftment. The engrafted donor effector cells are then used to accomplish the task of eradicating host malignant cells. The non-myeloblative regimen developed in Seattle uses 2 Gy total body irradiation (TBI) before transplant followed by postgrafting cyclosporine (CSP) and mycophenolate mofetil (MMF). This regimen resulted in initial mixed donor-host chimerism in all patients with hematologic malignancies and genetic disorders who received HLA-matched sibling allografts. The 17% incidence of graft rejection was reduced to 3% with the addition of fludarabine, 30 mg/m2/day on d -4, -3, and -2. The non-myeloablative combination of fludarabine/TBI has also been successful at achieving high engraftment rates in recipients of 10 of 10 HLA antigen matched unrelated donor HSCTs in patients with hematologic malignancies. By reducing acute toxicities relative to conventional HSCT, most patients have received their pre- and post-HSCT therapy almost exclusively as outpatients. Acute and chronic GVHD occur after non-myeloablative HSCT, but the incidence and severity appear less compared to conventional HSCT. As in conventional transplants, immune dysregulation from GVHD and its treatment and delayed reconstitution of immune function continue to present risks to patients who have otherwise undergone successful non-myeloablative HSCT. Cellular therapeutic effects have been observed after non-myeloablative HSCT such as correction of inherited genetic disorders, and eradication of hematologic malignant diseases and renal cell carcinoma via GVT responses.
最初，异基因造血干细胞移植（HSCT）被视为一种从高剂量化疗放疗的骨髓致死效应中挽救患者的方法，高剂量化疗放疗用于根除恶性肿瘤并提供足够的免疫抑制以确保异基因植入。由异基因效应细胞（T细胞）介导的治疗性移植物抗肿瘤（GVT）效应的明确证据促使人们探索仅依赖宿主免疫抑制（非清髓性）来促进异基因供体植入的HSCT方案。然后，植入的供体效应细胞用于完成根除宿主恶性细胞的任务。西雅图开发的非清髓性方案在移植前使用2 Gy全身照射（TBI），随后在移植后使用环孢素（CSP）和霉酚酸酯（MMF）。该方案在所有接受HLA匹配同胞异基因移植的血液系统恶性肿瘤和遗传性疾病患者中均导致最初的混合供体-宿主嵌合现象。添加氟达拉滨（在第-4、-3和-2天，30 mg/m²/天）后，移植物排斥发生率从17%降至3%。氟达拉滨/TBI的非清髓性联合方案在10例接受10/10 HLA抗原匹配无关供体HSCT的血液系统恶性肿瘤患者中也成功实现了高植入率。通过相对于传统HSCT降低急性毒性，大多数患者几乎完全作为门诊患者接受HSCT前后的治疗。非清髓性HSCT后会发生急性和慢性移植物抗宿主病（GVHD），但其发生率和严重程度与传统HSCT相比似乎较低。与传统移植一样，GVHD及其治疗引起的免疫失调和免疫功能的延迟重建仍然给那些成功接受非清髓性HSCT的患者带来风险。在非清髓性HSCT后已观察到细胞治疗效果，如遗传性疾病的纠正，以及通过GVT反应根除血液系统恶性疾病和肾细胞癌。
