Successful allogeneic neonatal bone marrow transplantation devoid of myeloablation requires costimulatory blockade
Successful allogeneic neonatal bone marrow transplantation devoid of myeloablation requires costimulatory blockade
复制标题
DOI：
10.4049/jimmunol.171.6.3270
复制
发表时间：
2003-09-15
影响因子：
4.4
通讯作者：
Barker, JE
中科院分区：
文献类型：
--
作者：
Soper, BW;Lessard, MD;Barker, JE
大量非恶性、进行性儿童疾病对骨髓移植（BMT）有反应。毒性清髓性预处理方案、移植物衰竭和移植物抗宿主病使BMT在新生儿治疗中的应用复杂化。我们最近在新生动物中证明了高剂量BMT能够在没有毒性骨髓消融的情况下实现嵌合体植入。阻断T细胞共刺激的试剂（抗CD 40 L mAb和/或CTLA-4 Ig）在成人受者中建立耐受性同种异体植入。供体淋巴细胞输注（DLI）通过移植物抗白血病反应重建失败的移植物并治疗恶性复发。在这项研究中，我们测试了这样一个假设，即结合这些方法将允许在患有溶酶体贮积病的新生正常和突变小鼠中进行耐受性同种异体移植，而不进行骨髓消融。在DLI之前，仅在抗CD 40 L mAb和CTLA-4 Ig存在下实现耐受性嵌合同种异体植入。DLI扩增同种异体移植物至完全供体长期植入。DLI治疗的小鼠要么保持长期耐受性，要么发展为迟发性慢性移植物抗宿主病。这种组合方法提供了一种无毒的方法，以建立耐受性同种异体移植治疗进行性儿童疾病。
A significant number of nonmalignant, progressive childhood disorders respond to bone marrow transplantation (BMT). Toxic myeloablative pretreatment regimens, graft failure, and graft-vs-host disease complicate the utility of BMT for neonatal treatment. We recently demonstrated high-dose BMT in neonatal animals enables chimeric engraftment without toxic myeloablation. Reagents that block T cell costimulation (anti-CD40L mAb and/or CTLA-4Ig) establish tolerant allogeneic engraftment in adult recipients. Donor lymphocyte infusion (DLI) re-establishes failing grafts and treats malignant relapse via a graft-vs-leukemia response. In this study, we tested the hypothesis that combining these approaches would allow tolerant allogeneic engraftment devoid of myeloablation in neonatal normal and mutant mice with lysosomal storage disease. Tolerant chimeric allogeneic engraftment was achieved before DLI only in the presence of both anti-CD40L mAb and CTLA-4Ig. DLI amplified allografts to full donor engraftment long-term. DLI-treated mice either maintained long-term tolerance or developed late-onset chronic graft-vs-host disease. This combinatorial approach provides a nontoxic method to establish tolerant allogeneic engraftment for treatment of progressive childhood diseases.