骨髓移植后采用异质性祖细胞和粒细胞巨噬细胞集落刺激因子治疗实现快速免疫重建和树突状细胞植入。

Rapid immune reconstitution and dendritic cell engraftment post-bone marrow transplantation with heterogeneous progenitors and GM-CSF treatment.

作者信息

Zhao Peilin, Liu Wei, Cui Yan

机构信息

Gene Therapy Program, Departments of Medicine and Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.

出版信息

Exp Hematol. 2006 Jul;34(7):951-64. doi: 10.1016/j.exphem.2006.04.015.

DOI:10.1016/j.exphem.2006.04.015

PMID:16797423

Abstract

OBJECTIVE

Bone marrow/hematopoietic stem cell transplantation (BMT) has been the treatment of choice for severe hematological diseases and cancers. Rapid host immune recovery following BMT is critical for reducing complications and improving therapeutic outcome. Here we report manipulations that facilitate rapid immune and dendritic cell (DC) reconstitution post-BMT for improvement in therapeutic outcome of BMT-based disease treatment.

METHODS

Using lentiviral vector-modified or unmodified murine hematopoietic stem cells, we examined the engraftment efficiency and kinetics in immune reconstitution of unfractionated bone marrow cells (BM), lineage marker-negative (Lin-) hematopoietic progenitor cells (HPC), or purified Lin-Sca-1+ hematopoietic stem cells (HSC) at an equal hematopoietic progenitor number.

RESULTS

Our study revealed that BM reconstituted host primary and secondary lymphoid tissues more efficiently and rapidly. Moreover, in a competitive BMT setting using lentiviral vector-engineered BM and HSC expressing GFP or DsRed respectively, we showed that GM-CSF treatment further enhanced DC reconstitution to therapeutic relevant level as early as 2 weeks post-BMT. On the other hand, Flt3 ligand was less effective in enhancing DC reconstitution till 3 weeks post-BMT. This accelerated DC engraftment by GM-CSF treatment correlated well with improved overall immune reconstitution and enhanced activation of antigen-specific T cells post-BMT.

CONCLUSION

This study suggests that use of heterogeneous BM for transplantation facilitates more rapid immune reconstitution, especially in the presence of DC-stimulating cytokines. This improved immune reconstitution would provide additional therapeutic benefits for BMT-based immunotherapy and gene therapy of genetic disorders and cancers.

摘要

目的

骨髓/造血干细胞移植（BMT）一直是严重血液疾病和癌症的首选治疗方法。BMT后宿主免疫的快速恢复对于减少并发症和改善治疗效果至关重要。在此，我们报告了一些操作方法，这些方法有助于BMT后免疫和树突状细胞（DC）的快速重建，以改善基于BMT的疾病治疗的疗效。

方法

我们使用慢病毒载体修饰或未修饰的小鼠造血干细胞，在造血祖细胞数量相等的情况下，检测了未分级骨髓细胞（BM）、谱系标记阴性（Lin-）造血祖细胞（HPC）或纯化的Lin-Sca-1+造血干细胞（HSC）在免疫重建中的植入效率和动力学。

结果

我们的研究表明，BM能更有效、快速地重建宿主的初级和次级淋巴组织。此外，在分别使用表达绿色荧光蛋白（GFP）或红色荧光蛋白（DsRed）的慢病毒载体工程化BM和HSC进行的竞争性BMT实验中，我们发现粒细胞-巨噬细胞集落刺激因子（GM-CSF）治疗可在BMT后2周就将DC重建进一步增强至治疗相关水平。另一方面，Flt3配体在BMT后3周之前增强DC重建的效果较差。GM-CSF治疗加速DC植入与BMT后整体免疫重建的改善以及抗原特异性T细胞的激活增强密切相关。