NK Receptors and Bone Marrow Transplant Outcome

点击翻译按钮获取中文摘要

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.