Optimizing NK Education and Alloreactivity after HLA-Haploidentical Allogeneic Hematopoietic Cell Transplantation

项目总结 异基因造血细胞移植是治疗高危血液病的有效方法 恶性肿瘤。这是由于一种公认的移植物抗肿瘤反应，部分是由供者自然介导的。 杀伤(NK)细胞。NK细胞对恶性细胞的杀伤作用由一系列细胞表面蛋白控制， 包括杀伤Ig样受体(KIR)，它与靶点上的人类1类白细胞抗原(HLA)相互作用 用于校准NK细胞效应器功能的细胞。KIR具有遗传多样性：显著的个体间差异 根据KIR基因表达的数量和单个KIR基因内的等位基因多态而存在。 这种遗传变异决定了KIR蛋白在以下情况下具有激活或抑制NK细胞的各种能力 与移植受者的人类白细胞抗原一起考虑。因此，供体KIR/受体人类白细胞抗原的基因分型 是一种潜在的机制来定义和选择具有更多异基因反应的NK细胞的同种异体供者，从而 防止移植受者复发。 异基因造血细胞移植(Allo Hct)历来只适用于高危患者。 具有匹配兄弟姐妹或无血缘关系的供者的恶性肿瘤患者。人类白细胞抗原单倍体相合的捐献者部分 95%的患者有匹配的家族性捐赠者，但以前由于以下原因而避免作为捐赠者 它们导致移植后移植物抗宿主病(GVHD)的发生率很高。最新进展 在预防移植物抗宿主病中，移植后使用环磷酰胺可降低移植的发生率 单倍体相合的同种异体供者移植后的相关死亡率为10-20%。尽管如此，30%-60%的人会复发 单倍体移植受者，是这些患者最常见的死亡原因。作为半相合的捐赠者 是一种可广泛获得和具有成本效益的捐赠者来源，优化其效力是 改善移植结果。这些结果特别适用于种族和/或种族人士。 少数族裔，他们更经常没有匹配的捐赠者选择。 建议拨款的目的是使用KIR基因和等位基因分型来识别单倍体相合的捐赠者 预测NK对受体恶性细胞的同种异体反应性更强。使用450个施主/受主对的集合， 这一提议将检验这样一个假设，即更大的供者NK同种异体反应性将导致减少复发和 改善单倍体移植受者的无复发存活率。在第二个目标中，这项提案将解决 假设HLA可能从受者基质细胞传递到供者NK细胞，并将检查 人类白细胞抗原置换对供者移植后NK细胞活化状态的影响

PROJECT SUMMARY Allogeneic hematopoietic cell transplantation is an effective therapy for patients with high risk hematologic malignancies. This is due to a well recognized graft versus tumor reaction mediated in part by donor natural killer (NK) cells. NK cell cytotoxicity against malignant cells is controlled by an array of cell surface proteins, including the killer Ig-like receptors (KIR), which interact with class 1 human leukocyte antigens (HLA) on target cells to calibrate NK cell effector function. KIR are genetically diverse: Significant inter-individual variation exists in terms of the number of KIR genes expressed and allelic polymorphism within individual KIR genes. This genetic variation determines KIR proteins with variegated capacity to activate or inhibit the NK cell when taken into consideration with the transplant recipient’s HLA. Therefore, genotyping of donor KIR/recipient HLA is a potential mechanism to define and select allogeneic donors that have more alloreactive NK cells, thereby preventing relapse in the transplant recipient. Allogeneic hematopoietic cell transplantation (allo HCT) was historically offered only to patients with high risk malignancies who had HLA matched sibling or unrelated donors. HLA-haploidentical donors are partially matched, familial donors that are available in >95% of patients, but were previously avoided as donors due to their resulting in a high incidence of graft versus host disease (GVHD) after transplantation. Recent advances in GVHD prevention using post-transplant cyclophosphamide have decreased the incidence of transplant related mortality to <10-20% after haploidentical donor allografts. Despite this, relapse occurs in 30-60% of haplotransplant recipients and is the most frequent cause of death in these patients. As haploidentical donors represent a broadly available and cost effective donor source, optimizing their efficacy is an important step in improving transplant outcomes. These results are particularly applicable to persons of ethnic and/or racial minorities, who are more frequently without a HLA matched donor option. The purpose of the proposed grant is to use KIR gene and allele typing to identify haploidentical donors with greater predicted NK alloreactivity against recipient malignant cells. Using a set of 450 donor/recipient pairs, this proposal will test the hypothesis that greater donor NK alloreactivity will result in decreased relapse and improved relapse-free survival in haplotransplant recipients. In a second aim, this proposal will address the hypothesis that HLA may be passed from recipient stromal cells to donor NK cells and will examine the resulting effects of HLA exchange on donor NK cell activation state after transplantation.