NK CELL ACTIVATING RECEPTORS ON EFFECTOR CELLS IN MYELOMA PATIENTS RECEIVING TRA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 骨髓瘤的自体移植可提高存活率，但这种改善的免疫学机制尚不清楚。我们的数据表明，NKG2D+CD8+T细胞可能是这种好处的一个原因。NKG2D是四种NK激活受体之一，存在于一些CD8+T细胞上，介导TCR非依赖性和非MHC限制性的肿瘤细胞杀伤。由于NKG2D受体识别骨髓瘤细胞上表达的配体，这些NKG2D+CD8+T细胞积极杀伤骨髓瘤细胞，提供了独特的免疫治疗机会。免疫动员，使用IL-2和生长因子(即刺激造血细胞进入血液，可用于移植)扩大CD8+T细胞毒细胞，获得NKG2D受体，并使用NKG2D执行其杀伤。我们发现移植后早期体内NKG2D+CD8+T细胞的数量和功能都有所增加。当用嵌合NKG2D受体转导小鼠CD8+T细胞并注射到骨髓瘤荷瘤小鼠体内时，小鼠的存活率为100%。我们推测，将免疫动员细胞作为移植细胞的一部分注入骨髓瘤患者体内，通过增加NKG2D+CD8+T细胞的数量和功能，将显著增强免疫重建。这些研究将明确NK细胞激活受体在体内恢复移植后CD8+T细胞的存在、功能和机制。我们的长期假设是，该方案将通过促进移植后早期免疫恢复来提高存活率。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Autolgous transplantation for myeloma improves survival, but the immunologic mechanisms accounting for this improvement are unknown. Our data indicate that NKG2D+CD8+T cells may be one reason for this benefit. NKG2D, one of four NK activating receptors, has been identified on some CD8+T cells that mediate TCR-independent and non-MHC restricted tumor cell killing. Since the NKG2D receptor recognizes ligands expressed on myeloma cells, these NKG2D+CD8+T cells aggressively kill myeloma cells and provide a unique immunotherapy opportunity. Immune mobilization, using IL-2 and growth factors (i.e. stimulation of hematopoietic cells into the blood that can be used for transplant) expands CD8+T cytotoxic cells that acquire the NKG2D receptor and perform their killing using NKG2D. We have identified an increase number and function of NKG2D+CD8+T cells in vivo early post-transplant. When murine CD8+T cells are transduced with a chimeric NKG2D receptor and injected into myeloma-bearing mice, 100% of the mice survive. We hypothesize that the infusion of immune mobilized cells into myeloma patients as part of the transplanted cells will markedly enhance immune reconstitution, by increasing the number and function of NKG2D+CD8+T cells. These proposed studies will define the presence, function and mechanisms of NK cell activating receptors on recovering CD8+T cells in vivo following transplant. Our long-term hypothesis is that this regimen will improve survival by enhancing early immune recovery following transplantation.