Middleton P G, Taylor P R, Jackson G, Proctor S J, Dickinson A M
Leukaemia Research Fund (LRF) Laboratory, Catherine Cookson Building, The Medical School, Framlington Place, Newcastle upon Tyne, UK.
Blood. 1998 Nov 15;92(10):3943-8.
It is now well known that the initial phase of graft-versus-host disease (GVHD) involves cytokine release during preconditioning of the recipient of an allogeneic bone marrow transplant (BMT). Tumor necrosis factor (TNF), in particular, has been implicated in pathological damage and is released pretransplant due to irradiation and cytotoxic preconditioning regimens. Interleukin-10 (IL-10), a natural immunosuppressant of TNF, may be involved in downregulation of these responses, which may be an individual patient-specific effect. In this study, we determined the genotype for polymorphisms associated with TNF and IL-10 in 80 potential allo-BMT recipients and correlated the genotype with the severity of GVHD in 49 patients for whom clinical data relating to GVHD was available. The widely studied TNF -308 polymorphism does not show any significant associations, but the d3 homozygous allele of the TNFd microsatellite is preferentially associated with grade III/IV GVHD (7 of 11 patients) compared with its occurrence in 8 of 38 patients with grade 0/II GVHD (P =.006). Alleles of the IL-10 (-)1064 promoter region microsatellite polymorphism that possess greater numbers of dinucleotide (CA) repeats also significantly associate with more severe GVHD. This region has been demonstrated to be important in the regulation of the IL-10 promoter. Eighteen of 38 patients with grade 0-II GVHD possessed alleles with greater numbers (12 or more) of dinucleotide repeats, compared with 9 of 11 cases with grade III-IV GVHD (P <.02). Of the 38 patients with grade 0-II GVHD, 3 of 38 had a both TNFd3/d3 and IL-10 (12-15) genotype, compared with 6 of 11 patients with grade III-IV GVHD (P <.001). There was no association of either the TNFd or IL-10 microsatellite polymorphisms with mortality (P =.43 and.51, respectively). Our results suggest that patient cytokine gene polymorphism genotypes may influence GVHD outcome by affecting cytokine activation during the pretransplant conditioning regimens, and these results are the first to suggest a genetic predisposition to this important transplant-related complication.
现在众所周知，移植物抗宿主病（GVHD）的初始阶段涉及同种异体骨髓移植（BMT）受者预处理期间的细胞因子释放。特别是肿瘤坏死因子（TNF），已被认为与病理损伤有关，并且由于放疗和细胞毒性预处理方案而在移植前释放。白细胞介素-10（IL-10）是TNF的天然免疫抑制剂，可能参与这些反应的下调，这可能是个体患者特异性效应。在本研究中，我们确定了80名潜在异基因BMT受者中与TNF和IL-10相关的多态性基因型，并将该基因型与49名有GVHD临床数据的患者的GVHD严重程度相关联。广泛研究的TNF -308多态性未显示任何显著关联，但与0/II级GVHD的38名患者中有8名出现相比，TNFd微卫星的d3纯合等位基因优先与III/IV级GVHD相关（11名患者中有7名）（P = 0.006）。IL-10（-）1064启动子区域微卫星多态性中具有更多二核苷酸（CA）重复的等位基因也与更严重的GVHD显著相关。该区域已被证明在IL-10启动子的调控中很重要。0-II级GVHD的38名患者中有18名拥有二核苷酸重复数更多（12个或更多）的等位基因，而III-IV级GVHD的11例患者中有9名（P < 0.02）。在0-II级GVHD的38名患者中，38名中有3名具有TNFd3/d3和IL-10（12-15）基因型，而III-IV级GVHD的11名患者中有6名（P < 0.001）。TNFd或IL-10微卫星多态性与死亡率均无关联（P分别为0.43和0.51）。我们的结果表明，患者细胞因子基因多态性基因型可能通过影响移植前预处理方案期间的细胞因子激活来影响GVHD结果，并且这些结果首次表明对这种重要的移植相关并发症存在遗传易感性。
