Clinical Transplantation Exploiting NK Cell Activity

项目总结(见说明)： 在之前的资助期间，我们确定了一个非血缘关系供者(URD)KIR B的免疫遗传基因座 单倍型在预防AML复发和无复发生存的FPR患者方面产生了统计上显着和有意义的改善。新的分析已经将可能的KIR B基因座提炼为编码供体KIR激活受体的基因，这些受体与改善临床结果相关。我们将通过前瞻性地评估KIR基因分型在急性髓细胞白血病URD造血细胞移植(HCT)供者选择中的物流和临床影响，进一步探讨这些基因座的临床重要性。我们推测，在具有最佳配型的URD中，供者KIR基因分型可以确定更好的供者，有可能产生改善的临床结果。结合项目一，我们将探索这些KIR B基因座的功能意义、它们与人类白细胞抗原I类的相互作用以及KIR区域的等位基因多态性，以进一步完善我们对未来供者选择的认识和方法。在项目2中，我们将分析URD HCT后随着时间的推移NK细胞功能的发展，以及这种NK细胞发展与HCT并发症(包括植入、GVHD、感染、复发和存活)的相关性。这些独特的分析伴随着一项BMT CTN前瞻性试验，测试血液和骨髓作为URD HCT移植物来源的情况 并为了解NK细胞发育、KIR基因分型和功能免疫重建如何改善移植后并发症和结果提供了一个独特的平台。此外，NK细胞治疗减少耐药白血病复发和改善移植后SUN/IVAL的基本原理将得到直接检验。在一项降低强度的半相合HCT加供者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更安全地应用这种治疗所必需的要素。总体而言，这些研究可以改善急性髓系白血病异基因红细胞移植后的存活率和复发保护。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.