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）仍然是改善造血干细胞移植结局的主要障碍。 细胞移植（HCT）受者。缺乏生物标志物，可以识别患者之前， 疾病的发展。通过全基因组关联研究确定cGVHD的遗传标记 （GWAS），其不询问GM（γ标记）等位基因，尚未被复制。有很好的理由 免疫球蛋白GM基因参与cGVHD的发病机制。GM等位基因调节 巨细胞病毒（CMV）是HCT后常见的病毒感染，尽管 抗病毒治疗的改进，可导致约10%的HCT接受者发生危及生命的CMV疾病。CMV 表达三种诱饵Fcg受体（FcgR），其干扰Fc介导的效应子功能，例如 抗体依赖性细胞毒性（ADCC），一种有效的宿主免疫监视机制。 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不同。转基因基因也有助于个体间差异的大小， 对CMV的体液免疫此外，转基因基因还与人类的免疫生物学有关。 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 观察结果和我们的初步研究结果显示，CMV UL 70抗体水平较高， 在非cGVHD受试者中的GM等位基因和抗体应答比在患有cGVHD的受试者中的GM等位基因和抗体应答更高， 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之间是否存在显著差异 患者来自发生cGVHD的HCT接受者和来自未发生cGVHD的HCT接受者的血清/血浆样品- 从BMT CTN 0201参与者中获得的基因将被分型为几个GM等位基因。我们将确定 高度多态性GM基因座的等位基因是否可作为cGVHD的预后遗传标记;（2） 确定抗CMV（UL 70）抗体应答的幅度是否在 cGVHD和非cGVHD患者，如果GM等位基因有助于这些个体间差异， 应答我们的初步研究结果表明，抗UL 70抗体可能发挥保护作用， 在cGVHD发展中的作用。重要的是在独立的研究人群中复制这一发现。 我们将测量BMT CTN 0201标本中抗UL 70抗体的水平，并确定 这些抗体受到GM等位基因的影响。这次调查的结果很有可能 确定急需的cGVHD预后标志物。此外，它们还可以提供以下目标： 免疫治疗这种疾病。最近对HCT小鼠模型的研究表明，CMV再激活可 可以通过输注株特异性抗CMV抗体来预防。可能输注单克隆抗UL 70 抗体可以类似地防止CMV再激活，这是一些HCT接受者中危及生命的并发症。