IGHG Genes (GM Allotypes) and Anti-CMV (UL70) Antibody Responses as Prognostic Markers for Chronic Graft-Versus-Host-Disease

慢性移植物抗宿主病(CGVHD)仍然是改善造血预后的主要障碍。 细胞移植(HCT)接受者。很少有生物标志物可以在患者死前识别患者 疾病的发展。全基因组关联研究确定慢性移植物抗宿主病的遗传标记 不询问GM(γ标记)等位基因的(GWAs)没有被复制。这有很好的理由 免疫球蛋白GM基因在慢性移植物抗宿主病发病机制中的作用。GM等位基因调节 巨细胞病毒(CMV)是HCT后一种常见的病毒感染，其免疫逃避策略，尽管 抗病毒治疗的改进可能导致约10%的HCT接受者患上危及生命的巨细胞病毒病。巨细胞病毒 表达三种诱骗FCG受体(FcgRs)，它们干扰Fc介导的效应功能，如 抗体依赖性细胞毒性(ADCC)，一种针对病毒的有效宿主免疫监控机制。 有趣的是，GM等位基因调节这一病毒策略：表达不同GM等位基因的抗体结合 与诱饵FcgRs不同。Gm基因也是造成个体间大小差异的原因。 对CMV的体液免疫。此外，GM基因已被认为与糖尿病免疫生物学有关。 硬皮病是一种自身免疫性疾病，其临床特征类似于cGVHD。基于这些 观察-和我们初步研究的结果显示，CMV UL70的抗体水平更高 在非cGVHD患者中，我们假设GM等位基因和抗体对cGVHD的反应 CMV蛋白是cGVHD的预后标志物。以下具体目标将验证我们的假设：(1) 确定GM等位基因在慢性移植物抗宿主病和非移植物抗宿主病之间的分布是否有显著差异 病人。患有cGVHD的HCT受者和未患cGVHD的患者的血清/血浆样本- 从BMT CTN 0201参与者那里获得的-将进行几个GM等位基因的基因分型。我们将决定 高度多态GM基因座的等位基因是否可作为慢性移植物抗宿主病预后的遗传标记； 确定抗CMV(UL70)抗体反应的大小是否存在显著差异 CGVHD和非cGVHD患者，以及GM等位基因是否导致这些患者的个体间差异 回应。我们的初步研究结果表明，抗UL70抗体可能起到保护作用 在慢性移植物抗宿主病发展中的作用。在独立研究人群中重复这一发现是很重要的。 我们将检测骨髓移植CTN 0201标本中抗UL70抗体的水平，并确定 这些抗体受GM等位基因的影响。这项调查的结果很有可能会 确定cGVHD急需的预后标记物。此外，它们可能为以下目标提供目标 免疫疗法这种疾病的免疫疗法最近对小鼠红细胞压积模型的研究表明，CMV的重新激活可以 可通过注射毒株特异性的抗CMV抗体来预防。或许可以输注抗UL70的单抗 抗体同样可以防止CMV重新激活，这是一些HCT接受者的一种危及生命的并发症。

Chronic graft-versus-host disease (cGVHD) remains a major obstacle to improving outcomes in hematopoietic cell transplant (HCT) recipients. There is a paucity of biomarkers that could identify patients before the development of the disease. Genetic markers of cGVHD identified by the genome-wide association studies (GWAS), which do not interrogate GM (γ marker) alleles, have not been replicated. There is excellent rationale for the involvement of immunoglobulin GM genes in the etiopathogenesis of cGVHD. GM alleles modulate an immunoevasion strategy of cytomegalovirus (CMV), a frequent viral infection after HCT, which, despite improvements in antiviral therapies, can lead to life-threatening CMV disease in ~10 % of HCT recipients. CMV expresses three decoy Fcg receptors (FcgRs), which interfere with Fc-mediated effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), a potent host immunosurveillance mechanism against viruses. Interestingly, GM alleles modulate this viral strategy: IgG antibodies expressing different GM alleles bind differentially to the decoy FcgRs. GM genes also contribute to the interindividual differences in the magnitude of humoral immunity to CMV. Furthermore, GM genes have been implicated in the immunobiology of scleroderma, an autoimmune disease whose clinical features resemble that of cGVHD. Based on these observations—and the results of our preliminary studies that showed higher levels of antibodies to CMV UL70 in non-cGVHD subjects than in those with cGVHD—we hypothesize that GM alleles and antibody responses to CMV proteins are prognostic markers for cGVHD. The following specific aims will test our hypothesis: (1) Determine if the distribution of GM alleles differs significantly between cGVHD and non-cGVHD patients. Serum/plasma samples from HCT recipients who developed cGVHD and from those who did not— obtained from the BMT CTN 0201 participants—will be genotyped for several GM alleles. We will determine whether the alleles of the highly polymorphic GM loci serve as prognostic genetic markers of cGVHD; (2) Determine if the magnitude of anti-CMV (UL70) antibody responses differs significantly between cGVHD and non-cGVHD patients, and if GM alleles contribute to the interindividual differences in these responses. The results of our preliminary studies suggest that anti-UL70 antibodies might play a protective role in the development of cGVHD. It is important to replicate this finding in an independent study population. We will measure the level of anti-UL70 antibodies in BMT CTN 0201 specimens and determine if the level of these antibodies is influenced by GM alleles. There is high likelihood that the results of this investigation will identify much-needed prognostic markers for cGVHD. Furthermore, they may provide targets for immunotherapy of this disease. Recent studies from a murine model of HCT show that CMV reactivation can be prevented by the infusion of strain-specific anti-CMV antibodies. Perhaps infusion of monoclonal anti-UL70 antibodies could similarly prevent CMV reactivation, a life-threatening complication in some HCT recipients.