Correlating TCR diversity to immune reconstitution after cord blood transplant

描述（由申请人提供）：许多需要干细胞移植治疗恶性血液病的患者无法找到合适的HLA匹配的同胞或无关供体。使用脐带血干细胞的移植为这些患者提供了另一种选择，允许移植在不太严格的HLA匹配要求下进行。不幸的是，除了疾病复发的风险外，接受脐带血移植的患者由于免疫系统重建缓慢而有很高的感染死亡风险。 在这项临床观察性研究中，我们建议使用外周血T细胞受体（TCR）和免疫球蛋白重链（IgH）基因的高通量DNA测序来研究脐带血移植后适应性免疫系统的重建。我们将使用高通量测序来估计在移植后的规定时间点约240例患者中的T细胞和B细胞受体的多样性，并证明我们对适应性免疫受体多样性的测量与感染并发症的后续发病率和死亡率之间的相关性。 该技术的进一步发展将导致临床干预研究的III期应用，其中该测定将提供一种诊断方法，以识别移植后不久感染并发症的高风险患者。临床护理将管理一个增加强度的抗菌预防方案，以高风险患者。我们希望早期识别高危患者，并对这些患者进行更积极的预防，将降低脐带血移植中与治疗相关的高死亡率。

DESCRIPTION (provided by applicant): Many patients requiring stem cell transplantation for hematological malignancies are unable to find a suitable HLA-matched sibling or unrelated donor. Transplants using stem cells from umbilical cord blood provide an alternative for these patients, allowing transplantation to proceed with less stringent HLA-matching requirements. Unfortunately, in addition to the risk of relapsed disease, patients undergoing cord blood transplants have a high risk of death from infections due to slow reconstitution of their immune system. In this clinical observational study, we propose to use high-throughput DNA sequencing of T- Cell Receptor (TCR) and Immunoglobulin heavy chain (IgH) genes from peripheral blood to study the reconstitution of the adaptive immune system following cord blood transplant. We will use high-throughput sequencing to estimate the diversity of T- and B-cell receptors in each of approximately 240 patients at defined time-points following transplant, and demonstrate a correlation between our measure of adaptive immune receptor diversity and subsequent morbidity and mortality from infectious complications. Further development of this technique would lead to a Phase III application with a clinical intervention study in which this assay would provide a diagnostic method to identify patients at high risk for infectious complications soon after transplant. Clinical care would be administered for an increased-intensity regimen of antimicrobial prophylaxis to high-risk patients. We expect that early identification of high-risk patients, combined with more aggressive prophylaxis for these patients, will reduce the high treatment-related mortality present in cord blood transplants.