Tsujimoto T, Lisukov I A, Huang N, Mahmoud M S, Kawano M M
Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Japan.
Blood. 1996 Apr 15;87(8):3375-83.
By using two-color phenotypic analysis with fluorescein isothiocyanate-anti-CD38 and phycoerythrin-anti-CD19 antibodies, we found that pre-B cells (CD38+CD19+) signifcantly decreased depending on the number of plasma cells (CD38++CD19+) in the bone marrow (BM) in the cases with BM plasmacytosis, such as myelomas and even polyclonal gammopathy. To clarify how plasma cells suppress survival of pre-B cells, we examined the effect of plasma cells on the survival of pre-B cells with or without BM-derived stromal cells in vitro. Pre-B cells alone rapidly entered apoptosis, but interleukin-7 (IL-7), a BM stromal cell line (KM-102), or culture supernatants of KM-102 cells could support pre-B cell survival. On the other hand, inhibitory factors such as transforming growth factor-beta1 (TGF-beta1) and macrophage inflammatory protein-1beta (MIP-1beta) could suppress survival of pre-B cells even in the presence of IL-7. Plasma cells alone could not suppress survival of pre-B cells in the presence of IL-7, but coculture of plasma cells with KM-102 cells or primary BM stromal cells induced apoptosis of pre-B cells. Supernatants of coculture with KM-102 and myeloma cell lines (KMS-5) also could suppress survival of pre-B cells. Furthermore, we examined the expression of IL-7, TGF-beta1, and MIP-1beta mRNA in KM-102 cells and primary stromal cells cocultured with myeloma cell lines (KMS-5). In these cells, IL-7 mRNA was downregulated, but the expression of TGF-beta1 and MIP-1beta mRNA was augmented. Therefore, these results suggest that BM-derived stromal cells attached to plasma (myeloma) cells were modulated to secrete lesser levels of supporting factor (IL-7) and higher levels of inhibitory factors (TGF-beta1 and MIP-1beta) for pre-B cell survival, which could explain why the increased number of plasma (myeloma) cells induced suppression of pre-B cells in the BM. This phenomenon may represent a feedback loop between pre-B cells and plasma cells via BM stromal cells in the BM.
通过使用异硫氰酸荧光素标记的抗CD38抗体和藻红蛋白标记的抗CD19抗体进行双色表型分析，我们发现，在骨髓浆细胞增多症的病例中，如骨髓瘤甚至多克隆丙种球蛋白病，骨髓（BM）中前B细胞（CD38+CD19+）的数量会根据浆细胞（CD38++CD19+）的数量显著减少。为了阐明浆细胞如何抑制前B细胞的存活，我们在体外研究了浆细胞对有无骨髓来源基质细胞情况下前B细胞存活的影响。单独的前B细胞会迅速进入凋亡状态，但白细胞介素-7（IL-7）、一种骨髓基质细胞系（KM-102）或KM-102细胞的培养上清液可以支持前B细胞的存活。另一方面，诸如转化生长因子-β1（TGF-β1）和巨噬细胞炎性蛋白-1β（MIP-1β）等抑制因子即使在有IL-7存在的情况下也能抑制前B细胞的存活。单独的浆细胞在有IL-7存在时不能抑制前B细胞的存活，但浆细胞与KM-102细胞或原代骨髓基质细胞共培养会诱导前B细胞凋亡。与KM-102和骨髓瘤细胞系（KMS-5）共培养的上清液也能抑制前B细胞的存活。此外，我们检测了与骨髓瘤细胞系（KMS-5）共培养的KM-102细胞和原代基质细胞中IL-7、TGF-β1和MIP-1β mRNA的表达。在这些细胞中，IL-7 mRNA表达下调，但TGF-β1和MIP-1β mRNA的表达增加。因此，这些结果表明，附着于浆细胞（骨髓瘤细胞）的骨髓来源基质细胞被调节为分泌较低水平的支持因子（IL-7）和较高水平的抑制因子（TGF-β1和MIP-1β）以影响前B细胞的存活，这可以解释为什么浆细胞（骨髓瘤细胞）数量增加会导致骨髓中前B细胞受到抑制。这种现象可能代表了骨髓中前B细胞和浆细胞通过骨髓基质细胞形成的反馈回路。
