Analysis of molecular mechanism of antibody deficiencies and development of their therapeutics

抗体缺陷的分子机制分析及其治疗方法的开发

• 批准号: 08670872
• 负责人: TSUGE Ikuya
• 金额: $ 1.41万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08670872/
• 关键词: antibody deficiency; severe combined immunodeficiency; bone marrow transplantation; 抗体産生不全症

Since 1981, a total of ten HLA-matched or -partially matched bone marrow transplantations (BMT) were performed on patients with severe combined immunodeficiency (SCID) at the Department of Pediatrics of the Nagoya University Hospital. Nine of these patients survived, but two X-linked SCID (X-SCID) patients showed a persistent deficiency of antibody production, despite their normal T cell functions and the existence of a normal number of B cells. Bone marrow condioning was not performed in the BMT for SCID and normal to elevated number of B cells exists before BMT in case of X-SCID patients. Therefore, it can be speculated that a chimeric state of donor-derived T cells and recipient-derived B cells persists for a long period. As antibody production were consistently recovered after HLA-matched BMT in this situation, persistent deficiency of antibody production seems not to be due to intrinsically defective B cells from patients, but to be due to defects of T cell- B cell cooperation. To evaluate this hypothesis and to get a clue to clarify the pathogenesis of primary antibody deficiency diseases, we analyzed the chimeric states and the in vitro antibody production of these patients. The results demonstrated that patient-derived B cells persists for a long period after BMT for X-SCID,that the degree of defective gc did not affect the persistent defects of antibody production, and that B cells ; seemed to be in a state similar to an antigen-unresponsiveness. Further study in necessary to clarify the mechanism of the unresponsiveness. I will continue to study the pathogenesis of antibody deficiencies to develop better methods for diagnosis and treatments.

自1981年以来，在名古屋大学附属医院儿科共对10例严重联合免疫缺陷（SCID）患者进行了HLA匹配或部分匹配的骨髓移植（BMT）。这些患者中有9人存活，但2名X连锁SCID（X-SCID）患者显示抗体产生持续缺乏，尽管他们的T细胞功能正常，B细胞数量正常。在用于SCID的BMT中未进行骨髓调理，并且在X-SCID患者的情况下，在BMT之前存在正常至升高数量的B细胞。因此，可以推测来源于供体的T细胞和来源于宿主的B细胞的嵌合状态长期持续。由于在这种情况下，HLA匹配的BMT后抗体产生持续恢复，抗体产生的持续缺乏似乎不是由于患者的固有缺陷B细胞，而是由于T细胞- B细胞合作的缺陷。为了评估这一假设，并得到一个线索，以澄清原发性抗体缺乏性疾病的发病机制，我们分析了嵌合状态和体外抗体产生的这些患者。结果表明，患者来源的B细胞在针对X-SCID的BMT后持续很长时间，缺陷gc的程度不影响抗体产生的持续缺陷，并且B细胞似乎处于类似于抗原无反应性的状态。需要进一步研究以阐明无反应性的机制。我将继续研究抗体缺乏的发病机制，以开发更好的诊断和治疗方法。

项目成果

Tsuge I,et al.: "Interleukin-2 receptor γ-chain mutations in severe combined immunodeficiency with Blymphocytes." Eur J Pediatr. 155. 1018-1024 (1996)

Tsuge I 等人：“白细胞介素 2 受体 γ 链突变导致 B 淋巴细胞严重联合免疫缺陷。”Eur J Pediatr。155. 1018-1024 (1996)

Hashimoto, S., et al: "Identification of Bruton's tyrosine kinase(BtK)gene mutations and characterization of the derived proteins in 35X-linked agammaglobulinemia families:a nationwide study of BtK deficiency in Japan." Bloodl. 88. 561-573 (1996)

Hashimoto, S. 等人：“布鲁顿酪氨酸激酶 (BtK) 基因突变的鉴定和 35X 连锁无丙种球蛋白血症家族中衍生蛋白的表征：日本 BtK 缺乏症的全国性研究。”

Tsuge, I., et al: "Scuccessful PCR-based diagnosis of fungal meningitis in a patient with chronic granulomatous disease." Acta Ped Jpn. (in press).

Tsuge, I. 等人：“基于 PCR 的成功诊断慢性肉芽肿病患者的真菌性脑膜炎。”

Kuzushima, K., et al: "Establishment of anti-Epstein-Barr virus(EBV)cellular immunity by adoptive transfer of virus-specific cytotoxic T lymphocytes from an HLA-matched sibling to a patient with severe chronic active EBV infection." Clin Exp Immunol. 103.

Kuzushima, K. 等人：“通过将病毒特异性细胞毒性 T 淋巴细胞从 HLA 匹配的兄弟姐妹过继转移至严重慢性活动性 EBV 感染患者，建立抗 Epstein-Barr 病毒 (EBV) 细胞免疫。”

Hashimoto S,et al.: "Identification of Bruton's tyrosine kinase (Btk) gene mutations and characterization of the derived proteins in 35 X-linked agammaglobulinemia families." Blood. 88. 561-573 (1996)

Hashimoto S 等人：“布鲁顿酪氨酸激酶 (Btk) 基因突变的鉴定以及 35 个 X 连锁无丙种球蛋白血症家族中衍生蛋白的表征。”