Radiation-sensitive severe combined immunodeficiency: The arguments for and against conditioning before hematopoietic cell transplantation-what to do?
Radiation-sensitive severe combined immunodeficiency: The arguments for and against conditioning before hematopoietic cell transplantation-what to do?
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DOI：
10.1016/j.jaci.2015.04.027
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发表时间：
2015-11-01
影响因子：
14.2
通讯作者：
Gennery, Andrew R.
中科院分区：
文献类型：
--
作者：
Cowan, Morton J.;Gennery, Andrew R.
涉及非同源末端连接（NHEJ）DNA修复途径的DNA交联修复1C（DCLRE1C）、蛋白激酶DNA活化催化多肽（PRKDC）、连接酶4（LIG4）、NHEJ1和NBS1的缺陷导致辐射敏感性严重联合免疫缺陷（SCID）。造血细胞移植治疗辐射敏感性SCID的结果表明，尽量减少暴露于烷化剂和电离辐射是重要的优化生存和尽量减少迟发效应。然而，与单独无预处理或免疫抑制相比，使用烷化剂预处理与完全T细胞和B细胞重建的可能性更大相关。使用氟达拉滨和低剂量环磷酰胺的低强度方案可能对LIG4，NHEJ1和NBS1缺陷患者有效，尽管需要更多的数据来证实这些发现并表征晚期效应。对于DCLRE1C（Artemis缺陷型SCID）突变的患者，没有使用标准剂量烷化剂而无显著晚期效应的最佳方法。在非化疗药物（如抗CD45或抗CD117）可用之前，选择包括尽量减少暴露于烷化剂，如单药低剂量靶向白消安，或实现T细胞重建，几年后采用调理方案恢复B细胞免疫力。这些疾病的基因治疗将最终消除排斥反应和移植物抗宿主病的问题。需要前瞻性多中心研究来评估这些方法在这种罕见但高度脆弱的患者人群中的应用。
Defects in DNA cross-link repair 1C (DCLRE1C), protein kinase DNA activated catalytic polypeptide (PRKDC), ligase 4 (LIG4), NHEJ1, and NBS1 involving the nonhomologous end-joining (NHEJ) DNA repair pathway result in radiation-sensitive severe combined immunodeficiency (SCID). Results of hematopoietic cell transplantation for radiation-sensitive SCID suggest that minimizing exposure to alkylating agents and ionizing radiation is important for optimizing survival and minimizing late effects. However, use of preconditioning with alkylating agents is associated with a greater likelihood of full T-and B-cell reconstitution compared with no conditioning or immunosuppression alone. A reduced-intensity regimen using fludarabine and low-dose cyclophosphamide might be effective for patients with LIG4, NHEJ1, and NBS1 defects, although more data are needed to confirm these findings and characterize late effects. For patients with mutations in DCLRE1C (Artemis-deficient SCID), there is no optimal approach that uses standard dose-alkylating agents without significant late effects. Until nonchemotherapy agents, such as anti-CD45 or anti-CD117, become available, options include minimizing exposure to alkylators, such as single-agent low-dose targeted busulfan, or achieving T-cell reconstitution, followed several years later with a conditioning regimen to restore B-cell immunity. Gene therapy for these disorders will eventually remove the issues of rejection and graft-versus-host disease. Prospective multicenter studies are needed to evaluate these approaches in this rare but highly vulnerable patient population.