NK Receptors and Bone Marrow Transplant Outcome

描述(由申请人提供)： Katherine C.Hsu博士是纪念西安-凯特琳癌症中心的初级教员，她的研究兴趣是杀伤免疫球蛋白样受体(KIR)在异基因造血干细胞移植中的影响。异基因造血干细胞移植(AHSCT)是治疗急性白血病和慢性粒细胞白血病的有效方法。自然杀伤(NK)细胞可能影响移植后早期和晚期并发症，如移植物抗宿主病(GVHD)、疾病复发和病毒感染。本研究的总体目标是深入了解NK杀伤细胞Ig样受体(KIR)对AHSCT结局的影响。对14个编码激活和抑制KIR的已知基因进行分型，这些基因将用于来自HLA-A、-B和-DR相合异基因移植的移植供者和受者。许博士假设，KIR基因分型可以预测NK介导的AHSCT预后影响：对于某些白血病，缺乏激活KIR基因的供者会使移植后病毒感染和疾病复发，但对于其他白血病，则不会；供者和受者抑制性KIR基因差异会影响接受HLA-C基因差异异基因移植的患者的疾病复发/存活率(KIR表位不匹配)；供者和受者之间的KIR基因差异可能影响非清髓移植的植入和GVHD。许博士旨在通过以下途径解决这些假设：1)确定供体KIR对接受T细胞耗尽的CML和AML同胞AHSCT患者的总存活率和移植后并发症的影响；2)在多中心分析中确定供体KIR基因型和供体-受者KIR差异对接受无关AHSCT的患者的影响；以及3)前瞻性评估NK受体(包括供体和宿主KIR)对接受非清髓调节的移植患者的植入、GVHD和总存活率的影响。徐博士有两位导师，博·杜邦博士和理查德·奥赖利博士，他们之前曾担任过临床研究和基础研究科学家的导师。格伦·海勒博士是这项拟议研究的生物统计学家。作为她的近期目标，许博士希望最终证明激活的KIR对移植结果的影响，并确定抑制KIR在哪些临床环境中可能在影响移植结果方面发挥作用。此外，她试图了解供者和受者NK细胞在非清髓性移植中的相互作用，并确定KIR是否可以指导它们的相互作用和对移植结果的影响。最终，她希望利用这些信息来开发使用NK细胞的采用细胞疗法。许博士打算在NK细胞免疫遗传学和异基因造血干细胞移植领域发展成为一名独立研究员。

DESCRIPTION (provided by applicant): Dr. Katherine C. Hsu is a junior faculty member at Memorial SIoan-Kettering Cancer Center, whose research interest is in the impact of killer immunoglobulin-like receptors (KIR) on allogeneic hematopoietic stem cell transplantation. AIIogeneic hematopoietic stem cell transplantation (AHSCT) is a valuable therapy for acute leukemias and chronic myelogenous leukemia. Natural killer (NK) cells may influence early and late post-transplant complications, such as graft-versus-host disease (GVHD), disease relapse, and viral infection. The overall objective of this study is to gain insight into the influence of NK killer Ig-like receptors (KIR) on AHSCT outcome. Typing for the 14 known genes encoding activating and inhibitory KIR will be performed for transplant donors and recipients from HLA-A, -B, and -DR-matched allogeneic transplants. Dr. Hsu hypothesizes that KIR genotypes can predict NK-mediated influence on AHSCT outcome: lack of donor activating KIR genes will predispose to post-transplant viral infection and to disease relapse for certain leukemias but not others; donor-recipient inhibitory KIR gene disparity will influence disease relapse/survival in patients receiving transplants from HLA-C disparate donors (KIR epitope mismatched); and donor-recipient KIR gene disparity may influence engraftment and GVHD in nonmyeloablative transplants. Dr. Hsu aims to address these hypotheses through: 1) determining the influence of donor KIR on overall survival and post-transplant complications in patients receiving T-cell depleted HLA-identical sibling AHSCT for CML and AML; 2) determining in a multi-center analysis, the influence of donor KIR genotype and donor-recipient KIR disparity in patients undergoing unrelated AHSCT; and 3) evaluating prospectively the influence of NK receptors, including both donor and host KIR, on engraftment, GVHD and overall survival in patients undergoing transplants with non-myeloablative conditioning. Dr. Hsu has two mentors, Dr. Bo Dupont and Dr. Richard O'Reilly who have previously served as mentors for both clinical research and basic research scientists. Dr. Glenn Heller is the biostatistician for the proposed studies. As her immediate goals, Dr. Hsu hopes to demonstrate conclusively the influence of the activating KIR on transplant outcome and to identify in which clinical setting the inhibitory KIR may play a role in affecting transplant outcome. In addition, she seeks to understand the interplay between donor and recipient NK cells in non-myeloablative transplants and to determine if KIR may direct their interaction and influence on transplant outcome. Eventually, she hopes to utilize this information to develop adoptive cell therapy using NK cells. Dr. Hsu intends to develop a career as an independent investigator in the field of NK cell immunogenetics and allogeneic hematopoietic stem cell transplantation.