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

项目摘要 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。这是由于公认的移植物抗肿瘤反应，部分由供体天然免疫细胞介导。 杀伤（NK）细胞。NK细胞对恶性细胞的细胞毒性由一系列细胞表面蛋白控制， 包括杀伤性Ig样受体（KIR），其与靶点上的1类人类白细胞抗原（HLA）相互作用， 细胞以校准NK细胞效应子功能。KIR具有遗传多样性：显著的个体间差异 存在于KIR基因表达的数量和单个KIR基因内的等位基因多态性方面。 这种遗传变异决定了KIR蛋白具有激活或抑制NK细胞的多样化能力， 考虑到移植受体的HLA。因此，供体KIR/受体HLA的基因分型 是定义和选择具有更多同种异体反应性NK细胞的同种异体供体的潜在机制，从而 防止移植受者的复发。 异基因造血细胞移植（allo HCT）历史上只提供给高风险患者， 有HLA匹配的同胞或无关供体的恶性肿瘤患者。HLA-半相合供体部分 匹配的，家族性供体在>95%的患者中可用，但以前由于以下原因而避免作为供体 它们导致移植后移植物抗宿主病（GVHD）的高发病率。最新进展 在移植后使用环磷酰胺预防GVHD中， 半相合供体同种异体移植后相关死亡率<10-20%。尽管如此，复发发生在30-60%的 单倍移植受体，是这些患者中最常见的死亡原因。作为单倍相合的供体 代表广泛可用且具有成本效益的供体来源，优化其功效是 改善移植结果。这些结果特别适用于具有族裔和/或种族背景的人。 少数民族，他们更经常没有HLA匹配的供体选择。 建议拨款的目的是利用KIR基因和等位基因分型来识别具有以下特征的单倍型供体： 预测NK对受体恶性细胞的同种异体反应性更高。使用一组450对供体/受体， 这一提议将检验供体NK同种异体反应性越强，复发率越低的假设， 提高单倍移植受者的无复发生存率。在第二个目标中，该提案将解决 假设HLA可以从受体基质细胞传递到供体NK细胞，并将检查 移植后HLA交换对供体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.