MARROW TRANSPLANT IN CANCER THERAPY--T-CELL RECOVERY

骨髓移植(BMT)现在是一种主要的治疗方法 癌症患者的治疗选择。尽管在使用上有所增加 骨髓移植在许多机构的成功、发病率和死亡率 移植后感染仍然是主要问题。重新建立了 正常的T细胞反应性是发育过程中必不可少的组成部分 骨髓移植后对传染病的抵抗力。这是特别的 对于处理潜伏病毒、巨细胞病毒(CMV)和 爱泼斯坦-巴尔病毒(EBV)。在缺乏足够的T细胞的情况下 反应性，这些病毒往往是致命的。在过去的实验中 小鼠骨髓移植模型系统已经证明了T细胞的模式 受体(TCR)基因重排在受者发育中的T细胞中的表达 动物是不正常的。人类骨髓移植中是否应该存在类似的情况 接受者，接受者对感染的异常易感性，甚至 可以解释为移植后的晚期。现在 提案将审查儿科TCR曲目的再生 接受骨髓移植的癌症患者。这项研究中的患者将成为接受者 自体、人类白细胞抗原相合或人类白细胞抗原不相合的骨髓，会有所不同 因此，他们对传染病的易感性也有所增加。RNA将会是 从患者和对照外周血白细胞(PBL)分离 CDNA的制备及聚合酶链式反应分析 (PCR)、DNA克隆和DNA测序方法。此外，TCR 从患者和患者建立的EBV特异性T细胞克隆的谱系 将确定控制PBL。这些衡量T细胞质量的指标将是 与一般T细胞功能的建立相关(将 通过对超抗原的增殖反应进行评估)，患者的 抗击疾病的能力，以及骨髓移植程序的最终成功。 这项建议中要检验的主要假设是，TCR BMT接收者可用的曲目被异常地限制， 导致定性和定量的T细胞免疫缺陷。 通过检验上述假设而获得的信息将是 不仅作为骨髓移植成功的预测指标， 但作为未来治疗方法发展的指南，旨在 根除骨髓移植患者的致命传染病。

Bone marrow transplantation (BMT) now constitutes a major therapeutic option in the treatment of cancer patients. Despite increases in the use and success of BMT in many institutions, morbidity and mortality from infection post-transplant remain major problems. The re-establishment of normal T-cell responsiveness is an essential component in the development of resistance to infectious disease following BMT. This is particularly important for dealing with the latent viruses, Cytomegalovirus (CMV) and Epstein Barr Virus (EBV). In the absence of adequate T-cell responsiveness, these viruses are often fatal. Past experiments with a mouse model system for BMT have demonstrated that the patterns of T-cell receptor (TCR) gene rearrangements among developing T-cells in recipient animals are abnormal. Should a similar situation exist among human BMT recipients, the unusual susceptibility of recipients to infection, even in late stages following transplantation, may be explained. The present proposal will examine the regeneration of the TCR repertoire in pediatric cancer patients following BMT. Patients in this study will be recipients of autologous, HLA-matched, or HLA-mismatched marrow, and will differ accordingly in their susceptibility to infectious disease. RNA will be isolated from patient and control peripheral blood leukocytes (PBL) for the preparation of cDNA and analysis by the polymerase chain reaction (PCR), DNA cloning, and DNA sequencing methods. In addition, the TCR repertoire among EBV-specific T-cell clones established from patient and control PBL will be determined. These measures of T-cell quality will be correlated with the establishment of general T-cell function (to be assessed by proliferative responses to superantigens), the patient's ability to combat disease, and the ultimate success of the BMT procedure. The main hypothesis to be tested in this proposal is that the TCR repertoire available to the BMT recipient is abnormally restricted, yielding a qualitative as well as quantitative T-cell immunodeficiency. Information to be gained by the testing of the above hypothesis will be of substantial value, not only as a prognostic measure of BMT success, but as a guide for the development of future treatments aimed at the eradication of fatal infectious disease in BMT patients.