Clinical Transplantation Exploiting NK Cell Activity

项目总结（见说明）： 在前一个资助期，我们确定了一个无关供体（URD）KIR B 单倍型在防止AML患者复发和无复发生存方面产生统计学显著和有意义的改善。新的分析已经将有利的KIR B基因座细化为编码与改善的临床结果相关的供体KIR活化受体的基因座。我们将通过前瞻性评估KIR基因分型对AML患者URD造血细胞移植（HCT）供体选择的逻辑和临床影响，进一步探索这些遗传基因座的临床重要性。我们假设在具有最佳HLA配型的URD中，供体KIR基因分型可以识别出更好的供体，从而可能改善临床结局。结合项目1，我们将探讨这些KIR B基因座的功能意义，它们与HLA I类的相互作用和KIR区域的等位基因多态性，以进一步完善我们的理解和前瞻性供体选择的方法。在项目2中，我们将分析URD HCT后NK细胞功能随时间的发展以及这种NK发展与HCT后并发症（包括植入、GVHD、感染、复发和生存）的相关性。这些独特的分析伴随着BMT CTN前瞻性试验，试验血液与骨髓作为URD HCT的移植物来源 并提供了一个独特的平台，了解NK细胞的发展，KIR基因分型和功能性免疫重建如何改变移植后的并发症和结果。此外，NK细胞治疗的基本原理，以减少复发的耐药白血病和改善太阳/ival移植后will.be直接测试。在一项降低强度的单倍体相合HCT加供体NK输注治疗耐药AML的多中心试验中，我们将评估NK细胞治疗对高耐药白血病的直接影响。前瞻性临床试验将确定这种治疗更安全应用的基本要素。总的来说，这些研究可以改善AML异基因HCT后的生存和复发保护。我们的研究概述了新的和令人兴奋的机会，以改善供体选择和最大限度地提高同种异体移植的安全性和有效性。

PROJECT SUMMARY (See instructions): In the previous funding period we identified immunogenetic loci that an unrelated donor (URD) KIR B haplotype yields statistically significant and meaningful improvement in protection against relapse and relapse free-survival fpr patients with AML. New analyses have refined the favprable KIR B loci to those which encode donor KIR activating receptors associated with improved clinical outcome. We will further explore the clinical importance of these genetic loci by prospectively evaluating the logistics and clinical impact of donor selection by KIR genotyping for URD hematopoietic cell transplantation (HCT) in AML. We hypothesize that amongst URD with optimal HLA matching, donor KIR genotyping can identify better donors likely to yield improved clinical outcome. In conjunction Project 1, we will explore the functional significance of these KIR B loci, their interaction with HLA Class I and allelic polymorphism in the KIR regions to further refine our understanding and methods for prospective donor selection. With Project 2 we will analyze NK cell functional development over time after URD HCT and correlation of this NK development with the complications following HCT including engraftment, GVHD, infections, relapse and survival. These unique analyses accompany a BMT CTN prospective trial testing blood vs. marrow as a graft source for URD HCT and offer a unique platform for understanding how NK cell development, KIR genotyping and functional immune reconstitution can modify post-transplant complications and outcomes. Additionally, the fundamentals of NK cell therapy to reduce recurrence of resistant leukemia and improve sun/ival after transplantation will.be directly tested. In a multicenter trial of reduced intensity haploidentical HCT plus donor NK infusions for resistant AML we will evaluate the direct impact of NK cell therapy on highly resistant leukemia. Prospective clinical trials will define elements essential for safer application of this treatment. Overall, these studies can improve the survival and relapse protection following allogeneic HCT for AML. Our studies outline new and exciting opportunities to improve donor selection and maximize the safety and effectiveness of allotransplantation.