Lorenz E, Schwartz D A, Martin P J, Gooley T, Lin M T, Chien J W, Hansen J A, Clark J G
Department of Medicine, Duke University, Durham, North Carolina, USA.
Biol Blood Marrow Transplant. 2001;7(7):384-7. doi: 10.1053/bbmt.2001.v7.pm11529488.
Lipopolysaccharide (LPS) has been implicated in the pathogenesis of graft-versus-host disease (GVHD). The toll-like receptor (TLR)-4 has been recently identified as a major receptor for LPS. Mutations of TLR4 have been associated with LPS hyporesponsiveness. We hypothesized that TLR4 mutations reduce the risk of acute GVHD in allogeneic marrow transplant recipients. In a preliminary study to determine the frequency of TLR4 mutations and their possible association with GVHD, we tested 237 patients and their HLA-identical sibling donors for 2 TLR4 polymorphisms. All patients received methotrexate and cyclosporine for GVHD prophylaxis. One or more mutants were detected in 10.8% of patients and 10.6% of donors. Multivariable logistic regression models were used to analyze the association between TLR4 mutations and probability (1-sided) of GVHD. The odds ratio (adjusted for advanced disease, total body irradiation dose, and patient age) for development of grades II to IV GVHD when a mutation was present in the recipient was 0.63 (95% confidence interval [CI], 0.25-1.60; P = .16). When a mutation was present in the donor, the adjusted odds ratio was 0.88 (95% CI, 0.36-2.17; P = .40). When a mutation was present in both recipient and donor, the odds ratio was 0.72 (95% CI, 0.22-2.32; P = .29). Among 24 patients with TLR4 mutations in either donor or recipient, 4 (16.7%) developed gram-negative bacteremia. Among 213 patients without mutations, 14 (6.6%) developed gram-negative bacteremia (P = .09). The data indicate that a reduced risk of acute GVHD is associated with TLR4 mutations and that TLR4 mutations may increase the risk for gram-negative bacteremia. However, these associations are not statistically significant in recipients of HLA-matched sibling marrow transplants who are prophylactically treated for infections and GVHD. A much larger study population would be needed to confirm the role of LPS in the pathogenesis of GVHD in humans.
脂多糖（LPS）与移植物抗宿主病（GVHD）的发病机制有关。Toll样受体（TLR）-4最近被确定为LPS的主要受体。TLR4突变与LPS低反应性相关。我们假设TLR4突变可降低异基因骨髓移植受者发生急性GVHD的风险。在一项初步研究中，为确定TLR4突变的频率及其与GVHD的可能关联，我们检测了237例患者及其HLA匹配的同胞供者的2种TLR4多态性。所有患者均接受甲氨蝶呤和环孢素预防GVHD。10.8%的患者和10.6%的供者检测到一种或多种突变体。使用多变量逻辑回归模型分析TLR4突变与GVHD概率（单侧）之间的关联。当受者存在突变时，发生II至IV级GVHD的比值比（校正了晚期疾病、全身照射剂量和患者年龄）为0.63（95%置信区间[CI]，0.25 - 1.60；P = 0.16）。当供者存在突变时，校正后的比值比为0.88（95%CI，0.36 - 2.17；P = 0.40）。当受者和供者均存在突变时，比值比为0.72（95%CI，0.22 - 2.32；P = 0.29）。在供者或受者中有TLR4突变的24例患者中，4例（占16.7%）发生了革兰阴性菌血症。在无突变的213例患者中，14例（占6.6%）发生了革兰阴性菌血症（P = 0.09）。数据表明，急性GVHD风险降低与TLR4突变相关，且TLR4突变可能增加革兰阴性菌血症的风险。然而，在接受感染和GVHD预防性治疗的HLA匹配同胞骨髓移植受者中，这些关联无统计学意义。需要更大的研究群体来证实LPS在人类GVHD发病机制中的作用。
