Loughran T P, Raff R F, Graham T C, Appelbaum F R, Schuening F G, Sale G E, Storb R
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104.
Exp Hematol. 1990 Nov;18(10):1126-31.
Dogs conditioned with 9.2 Gy total body irradiation (TBI) and given histoincompatible marrow transplants have a high rate of graft failure. Engraftment can be achieved by using 18 Gy fractionated TBI as preparative regimen. In this study, we tested the effects of infusing, at the time of histoincompatible marrow transplantation, autologous cells that had been stored before beginning high-dose (18 Gy) TBI. Our aim was to identify the peripheral blood mononuclear cells (PBMC) that contribute to failure of marrow grafts. Marrow graft failure was observed in three of three dogs receiving a mean of 2.1 x 10(8) unfractionated autologous PBMC/kg body weight as well as in two of two dogs receiving a mean dose of 0.075 x 10(8) PBMC/kg. When the dose of PBMC was decreased to 0.01 x 10(8)/kg, engraftment was seen in two of two dogs. These experiments thus established a cell dose response for causing marrow graft failure; further studies evaluated which subset of cells mediated this effect. Infusion of 0.09 x 10(8) nylon wool-nonadherent, plastic-nonadherent PBMC/kg was effective in causing marrow graft failure in three of three dogs. In contrast, infusion of 0.03 x 10(8) autologous monocytes/kg, enriched threefold above the number contained in the lower dose of PBMC causing graft failure, was associated with engraftment in four of six dogs. Infusion of 0.13 x 10(8) PBMC/kg treated with L-leucyl-L-leucine methyl ester (Leu-Leu-OMe), a drug that depletes canine cytotoxic T-lymphocytes (CTL), natural killer (NK) cells, and monocytes, permitted engraftment in three of four dogs. These data suggest that cytotoxic lymphocytes mediate failure of histoincompatible marrow grafts.
接受9.2 Gy全身照射（TBI）并进行组织不相容骨髓移植的犬，移植物失败率很高。采用18 Gy分次TBI作为预处理方案可实现植入。在本研究中，我们测试了在组织不相容骨髓移植时输注在开始高剂量（18 Gy）TBI之前储存的自体细胞的效果。我们的目的是确定导致骨髓移植失败的外周血单个核细胞（PBMC）。接受平均2.1×10⁸个未分离的自体PBMC/kg体重的三只犬中有三只出现骨髓移植失败，接受平均剂量0.075×10⁸个PBMC/kg的两只犬中也有两只出现骨髓移植失败。当PBMC剂量降至0.01×10⁸/kg时，两只犬中有两只出现植入。这些实验因此确定了导致骨髓移植失败的细胞剂量反应；进一步的研究评估了哪些细胞亚群介导了这种效应。输注0.09×10⁸个尼龙毛非黏附、塑料非黏附PBMC/kg可有效导致三只犬中有三只出现骨髓移植失败。相比之下，输注0.03×10⁸个自体单核细胞/kg，其数量比导致移植失败的较低剂量PBMC中所含数量富集了三倍，六只犬中有四只出现植入。输注0.13×10⁸个经L-亮氨酰-L-亮氨酸甲酯（Leu-Leu-OMe）处理的PBMC/kg，Leu-Leu-OMe是一种可耗尽犬细胞毒性T淋巴细胞（CTL）、自然杀伤（NK）细胞和单核细胞的药物，四只犬中有三只出现植入。这些数据表明细胞毒性淋巴细胞介导了组织不相容骨髓移植的失败。
