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

IGHG 基因（GM 同种型）和抗 CMV (UL70) 抗体反应作为慢性移植物抗宿主病的预后标志物

• 批准号: 10624498
• 负责人: JANARDAN P PANDEY
• 金额: $ 11.33万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624498
• 关键词: Alleles; Antibodies; Antibody Response; Antigen-Antibody Complex; Antigens; Antiviral Therapy; Autoimmune Diseases; Binding; Biological Markers; Candidate Disease Gene; Clinical; Complex; Complication; Cystic Fibrosis; Cytomegalovirus; Development; Disease; Genes; Genetic Markers; Genetic study; Genome; Genotype; Heavy-Chain Immunoglobulins; Herpesviridae; Humoral Immunities; Immune response; Immune system; Immunity; Immunobiology; Immunoglobulin G; Immunoglobulins; Immunologic Surveillance; Immunotherapy; Individual Differences; Infusion procedures; International; Investigation; Life; Measures; Mediating; Meta-Analysis; Participant; Patients; Plasma; Play; Prognostic Marker; Proteins; RL13; Risk; Role; Sampling; Scleroderma; Serum; Severities; Single Nucleotide Polymorphism; Specimen; Testing; Transplant Recipients; Variant; Viral; Virus; Virus Diseases; antibody-dependent cell cytotoxicity; chronic graft versus host disease; genome wide association study; genome-wide analysis; genotyping technology; hematopoietic cell transplantation; improved; improved outcome; mouse model; prevent; prognostic; receptor; response; study population

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.

慢性移植物抗宿主病（cGVHD）仍然是改善造血结果的主要障碍 细胞移植（HCT）接受者缺乏可以在移植前识别患者的生物标志物。 通过全基因组关联研究鉴定出 cGVHD 的遗传标记。 （GWAS），不询问 GM（γ 标记）等位基因，尚未被复制，这是有很好的理由的。 免疫球蛋白 GM 基因参与 cGVHD 的发病机制，并调节 GM 等位基因。 巨细胞病毒（CMV）的免疫逃避策略，这是 HCT 后常见的病毒感染，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 CMV 疾病。 表达三种诱饵 Fcg 受体 (FcgR)，这些受体会干扰 Fc 介导的效应功能，例如 抗体依赖性细胞毒性（ADCC），一种针对病毒的有效宿主免疫监视机制。 暗示，GM 等位基因调节这种病毒策略：表达不同 GM 等位基因的 IgG 抗体结合 诱饵 GM 基因的差异也导致了个体间的差异。 此外，GM 基因与 CMV 的免疫生物学有关。 硬皮病，一种自身免疫性疾病，其临床特征与 cGVHD 相似。 观察结果以及我们的初步研究结果显示 CMV UL70 抗体水平较高 在非 cGVHD 受试者中比在患有 cGVHD 受试者中——我们追求 GM 等位基因和抗体对 CMV 蛋白是 cGVHD 的预后标志物 以下具体目标将检验我们的假设：(1) 确定 GM 等位基因的分布在 cGVHD 和非 cGVHD 之间是否存在显着差异 来自发生 cGVHD 的 HCT 接受者和未发生 cGVHD 的患者的血清/血浆样本—— 从 BMT CTN 0201 参与者获得的数据 - 我们将确定几个 GM 等位基因的基因型。 (2)高度多态性GM位点的等位基因是否可以作为cGVHD的预后遗传标记； 确定抗 CMV (UL70) 抗体反应的幅度是否存在显着差异 cGVHD 和非 cGVHD 患者，以及 GM 等位基因是否导致这些个体间差异 我们的初步研究结果表明，抗 UL70 抗体可能起到保护作用。 在 cGVHD 发展中的作用在独立研究人群中复制这一发现非常重要。 我们将测量 BMT CTN 0201 样本中的抗 UL70 抗体水平，并确定 这些抗体受到 GM 等位基因的影响，这项研究的结果很可能会受到影响。 确定急需的 cGVHD 预后标志物。 最近对 HCT 小鼠模型的研究表明，CMV 重新激活可以治疗这种疾病。 可以通过输注毒株特异性抗 CMV 抗体来预防。也许输注单克隆抗 UL70。 抗体同样可以防止 CMV 重新激活，这是一些 HCT 接受者中危及生命的并发症。