Myeloablative conditioning and late complications in ARTEMIS-deficient SCID

ARTEMIS 缺陷 SCID 的清髓调理和晚期并发症

• 批准号: 9251366
• 负责人: JoAnn Sekiguchi
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-20 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251366
• 关键词: Adaptive Immune System; Alkylating Agents; Alleles; Antigen Receptors; Antigens; Area; Autoimmunity; B-Lymphocytes; Bone Marrow Transplantation; Busulfan; Cell physiology; Cells; Chemotherapy-Oncologic Procedure; Clinical; Code; Cyclophosphamide; DNA Double Strand Break; DNA Repair; DNA Repair Gene; DNA lesion; DNA-PKcs; Defect; Dental; Development; Disease; Double Strand Break Repair; Endocrine; Engraftment; Exhibits; Failure; Gene Mutation; Gene Rearrangement; Genes; Goals; Growth; Hematopoietic Stem Cell Transplantation; Human; Hypersensitivity; Immune; Immunologic Deficiency Syndromes; Immunologics; Impairment; Individual; Inherited; Investigation; Ionizing radiation; J segment gene; LIG4 gene; Late Effects; Lead; Lymphocyte; Lymphoid; Malignant Neoplasms; Mature B-Lymphocyte; Monoclonal Antibodies; Morbidity - disease rate; Mutate; Mutation; Myeloablative Chemotherapy; Natural Killer Cells; Nonhomologous DNA End Joining; Organ; Pathway interactions; Patients; Phenotype; Play; Predisposition; Process; Proteins; Proto-Oncogene Protein c-kit; Radiation; Radiation Tolerance; Receptor Gene; Regimen; Reporting; Research; Role; Severe Combined Immunodeficiency; Severities; T-Lymphocyte; Time; Tissues; Toxic effect; Transplantation Conditioning; V(D)J Recombination; artemis; cell type; chemotherapy; conditioning; congenital immunodeficiency; curative treatments; cytotoxic; cytotoxicity; effective therapy; endonuclease; hematopoietic cell transplantation; improved; insight; irradiation; mortality; mouse model; mutant; null mutation; prevent; radiosensitive; receptor; reconstitution; repaired; response; success; tumorigenesis

PROJECT ABSTRACT The vastly diverse antigen receptor genes are assembled from numerous V, D and J coding segments via the lymphoid specific DNA rearrangement, V(D)J recombination. Defective V(D)J recombination impairs lymphocyte development and thus, results in immunodeficiency. The non-homologous end joining (NHEJ) pathway is required during V(D)J recombination by virtue of its role as one of the major DNA double strand break (DSB) repair pathways. Mutations in nearly all of the NHEJ genes have been found in association with human primary immunodeficiency syndromes. ARTEMIS is the most frequently mutated NHEJ gene and was initially discovered in the radiation sensitive severe combined immunodeficiency syndrome, RS-SCID. NHEJ- deficient patients can undergo hematopoietic cell transplantation to reconstitute T and B cell functions. However, because NHEJ is critical for DSB repair in all cell types, conditioning regimens involving radiation cause excessive tissue damage and can lead to mortality. ARTEMIS-deficient patients have been successfully engrafted with T and B cells with myeloablative conditioning using alkylating agents. However, these patients exhibit late complications including growth failure, endocrine deficiencies and dental abnormalities. The goals of this proposal are to elucidate the mechanisms underlying the toxicities associated with myeloablative conditioning with alkylating agents using our previously developed and characterized mouse models of NHEJ- deficient SCID and to determine the efficacy of alternative conditioning regimens. The potential for late onset tumorigenesis associated will also be examined. Together, these studies will provide mechanistic insight into the causes of late toxicities in NHEJ-deficient primary immunodeficiencies and potentially lead to the development of more effective therapies.

项目摘要 各种各样的抗原受体基因由许多V、D和J编码片段组装而成 通过淋巴特异性DNA重排，V（D）J重组。缺陷性V（D）J重组损害 淋巴细胞发育，从而导致免疫缺陷。非同源末端连接（NHEJ） 由于其作为主要DNA双链之一的作用，在V（D）J重组过程中需要一条途径 破坏（DSB）修复途径。几乎所有NHEJ基因的突变都被发现与 人类原发性免疫缺陷综合征。ARTEMIS是最常见的突变NHEJ基因， 最初发现于放射敏感性严重联合免疫缺陷综合征，RS-SCID。NHEJ- 缺陷型患者可进行造血细胞移植以重建T和B细胞功能。 然而，由于NHEJ对于所有细胞类型中的DSB修复都是至关重要的，因此涉及辐射的预处理方案， 造成过度的组织损伤并可能导致死亡。ARTEMIS缺陷患者已成功地 移植T和B细胞，并使用烷化剂进行清髓性调节。但这些患者 出现晚期并发症，包括生长障碍、内分泌缺陷和牙齿畸形。的目标 这一建议的目的是阐明与清髓性化疗相关的毒性的潜在机制， 使用我们先前开发和表征的NHEJ小鼠模型， 缺陷的SCID，并确定替代预处理方案的疗效。迟发性的可能性 还将检查相关的肿瘤发生。总之，这些研究将提供机械洞察力， NHEJ缺陷型原发性免疫缺陷中晚期毒性的原因，并可能导致 开发更有效的治疗方法。