Parathyroid and Thymus Transplants in DiGeorge Syndrome

迪乔治综合征的甲状旁腺和胸腺移植

• 批准号: 6808686
• 负责人: M. Louise MARKERT
• 金额: $ 21.24万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6808686
• 关键词: 1,25 dihydroxycholecalciferol; DiGeorge' s syndrome; antiserum; biopsy; calcium; clinical research; endocrine pharmacology; endocrine transplantation; endocrinology; enzyme linked immunosorbent assay; homologous transplantation; human subject; human therapy evaluation; immune response; infant human (0-1 year); longitudinal human study; lymphocyte; muscle; parathyroid gland; parathyroid hormones; patient oriented research; thymus transplantation; transplantation immunology

DESCRIPTION (provided by applicant): DiGeorge syndrome is a congenital anomaly characterized by defects of the 3rd and 4th pharyngeal pouches and intervening 4th pharyngeal arch. Infants are born with defects of the heart, parathyroid and thymus. Experimental thymus transplantation has led to the development of normal immunity and also leaves the recipient tolerant of the thymus donor. Despite this advance in treatment of the immune deficiency of complete DiGeorge syndrome, the lack of parathyroid function remains problematic in approximately thirty percent of patients resulting in tetany, seizures, ectopic calcifications, hospitalizations, and infections of central lines (needed for intravenous calcium administration). Under this protocol, four children with complete DiGeorge syndrome and hypoparathyroidism will be treated with allogeneic postnatal thymus transplantation in conjunction with parental parathyroid transplantation. The recipient will be pretreated with rabbit anti human thymocyte globulin. Both tissues will be placed in the quadriceps muscle at sites separate from each other. This grant proposal will test the hypotheses that infants with complete DiGeorge syndrome will be tolerant of the parental parathyroid transplant and that the transplanted parathyroid tissue will function. For the first two patients, a parental parathyroid gland will be transplanted at the same time into a separate site in one quadriceps of the recipient. If the first two parathyroid transplants are unsuccessful, the parathyroid transplants in the third and fourth research subjects will be placed immediately adjacent to the thymus tissue in the quadriceps in one leg. The first aim will assess parathyroid function. Parathyroid function will be considered a success if the patient can be removed from all calcium and calcitriol supplementation. If the Parathyroid ceases functioning between 3 months and 1 year, a follow up biopsy of the parathyroid tissue will be done. The second aim focuses on immune development and tolerance to the parathyroid donor. To assess thymopoiesis, each research subject will undergo biopsy of the thymus allograft at three months (a time point that is usually before appearance of T cells in the periphery). Tolerance to the parathyroid donor will be assessed by mixed lymphocyte reactions. Indirect allorecognition as a mechanism of graft rejection will be assessed by ELISpot. The third aim will assess safety and tolerability.

描述（由申请人提供）：Digeorge综合征是一种先天性异常，其特征是第三和第4个咽袋的缺陷和中间的第4个咽弓。婴儿天生患有心脏缺陷，甲状旁腺和胸腺。实验性胸腺移植导致了正常免疫力的发展，并且还使受体耐受供体的受体供体耐受。尽管在治疗完全Digeorge综合征的免疫缺陷方面有了这一进步，但在大约30％的患者中，缺乏甲状旁腺功能仍然存在问题，导致四分之一的患者，癫痫发作，异位钙化，住院和中枢系感染（静脉钙给药所需）。根据该方案，将使用同种异体产后胸腺移植与亲本性远离甲状旁腺移植的同种异体胸腺移植治疗四个患有完全Digeorge综合征和甲状旁腺功能减退症的儿童。接受者将通过兔抗人胸腺细胞球蛋白预处理。两种组织都将在彼此分开的位置放置在股四头肌肌肉中。该赠款提案将检验以下假设，即患有完全Digeorge综合征的婴儿将耐受性甲状旁腺移植，并且移植后的甲状旁腺组织将起作用。对于前两名患者，父母的甲状旁腺将同时移植到一个受体的股四头肌中的单独部位中。如果前两个甲状旁腺移植不成功，则将立即将第三和第四个研究对象中的甲状旁腺移植物放置在一条腿的股四头肌中的胸腺组织。第一个目标将评估甲状旁腺功能。如果可以将患者从所有钙和骨化三醇补充中取出，则甲状旁腺功能将被认为是成功的。如果甲状旁腺在3个月至1年之间停止起作用，则将对甲状旁腺组织进行后续活检。第二个目标集中于免疫发育和对甲状旁腺供体的耐受性。为了评估胸腺波西斯，每个研究受试者将在三个月（通常是在外围T细胞出现之前）对胸腺同种异体移植进行活检。对甲状旁腺供体的耐受性将通过混合淋巴细胞反应评估。间接的同种异体识别作为移植物排斥的机制将由ELISPOT评估。第三个目标将评估安全性和耐受性。