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.

慢性移植抗宿主病（CGVHD）仍然是改善造血预后的主要障碍 细胞移植（HCT）受体。生物标志物很少，可以识别患者 疾病的发展。 CGVHD的遗传标记通过基因组关联研究确定 （GWAS）不审问GM（γ标记）等位基因，但尚未复制。有很好的理由 为了使免疫球蛋白GM基因参与CGVHD的疗法发生。 GM等位基因调节 巨细胞病毒（CMV）的免疫避免策略，这是HCT后经常病毒感染的一种，该策略要求 抗病毒疗法的改善会导致约10％的HCT接受者威胁生命的CMV疾病。 CMV 表达三个诱饵FCG受体（FCGRS），干扰FC介导的效应器功能，例如 抗体依赖性细胞毒性（ADCC）是针对病毒的潜在宿主免疫监视机制。 有趣的是，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 与诱饵FCGR有区别。 GM基因也有助于个人间差异 对CMV的体液免疫学。此外，GM基因在免疫生物学中也隐含 硬皮病，一种自身免疫性疾病，其临床特征类似于CGVHD。基于这些 观察结果以及我们的初步研究的结果，该研究表明CMV UL70的抗体水平较高 在非CGVHD受试者中，与患有CGVHD的受试者相比，我们假设GM等位基因和抗体反应 CMV蛋白是CGVHD的预后标记。以下具体目的将检验我们的假设：（1） 确定GM等位基因的分布是否显着区分CGVHD和非CGVHD 患者。来自HCT接受者的血清/血浆样本，他们开发了CGVHD，以及没有的人 - 从BMT CTN 0201参与者获得的，将对几个GM等位基因进行基因分型。我们将确定 高度多态GM基因座的等位基因是否充当CGVHD的预后遗传标记； （2） 确定抗CMV（UL70）抗体反应的大小是否有明显的不同 CGVHD和非CGVHD患者，以及GM等位基因是否有助于这些差异 回答。我们的初步研究的结果表明，抗UL70抗体可能会受到保护 在CGVHD发展中的作用。在独立研究人群中复制这一发现很重要。 我们将测量BMT CTN 0201标本中抗IL70抗体的水平，并确定是否水平。 这些抗体受到转基因等位基因的影响。这项调查的结果很有可能 确定CGVHD急需的预后标记。此外，它们可能为 这种疾病的免疫疗法。 HCT鼠模型的最新研究表明，CMV重新激活可以 通过输注菌株特异性抗CMV抗体可以预防。也许会输注单克隆抗UL70 抗体类似地可以防止CMV重新激活，这是某些HCT受体的生命并发症。