Positive and Negative Regulation of Natural Killer Cells After BMT

描述（由申请人提供）：同种异体骨髓移植（BMT）目前用于治疗多种癌症，但移植物抗宿主病（GVHD）、移植后免疫缺陷和复发仍然是限制疗效的重要障碍。开发一种提高BMT抗肿瘤作用的方法是相当重要的。自然杀伤（NK）细胞已被证明在体内和体外介导许多抗肿瘤作用。我们以前已经证明，供体型NK细胞可以防止GVHD和促进小鼠异基因BMT后的抗肿瘤作用。NK细胞可以通过多种介质以正向和负向方式进行调节。该提案将开发优化异基因BMT后NK细胞恢复和活性的方法，从而产生更大的抗肿瘤效果。为此，提出了三个具体目标：具体目标1将建立在我们最近的数据表明，调节性T细胞（T细胞）可以抑制NK活性。我们建议确定这种抑制的机制，并确定同种异体BMT后Treg耗竭对NK重建和活性的影响。然后，特定目标2将寻求通过使用IL 15的流体动力学基因递送来加速BMT后的供体NK细胞恢复。将确定对GVHD、供体重建以及抗肿瘤作用的影响。具体目标3将确定NK细胞亚群对供体恢复，GVHD保护和抗肿瘤作用的作用，通过建立我们的数据，这些亚群之间的相互作用对体内活性产生显著影响。从该提案中获得的数据应该产生对NK细胞生物学的重要见解，并允许开发导致上级抗肿瘤效果的方法。

DESCRIPTION (provided by applicant): Allogeneic bone marrow transplantation (BMT) is currently used for the treatment of a variety of cancers but graft-versus host disease (GVHD), immune deficiency following the transplant, and relapse remain significant obstacles limiting efficacy. Development of a means to improve the anti-tumor effects of BMT is of considerable importance. Natural killer (NK) cells have been shown to mediate numerous anti-tumor effects both in vivo and in vitro. We have previously demonstrated that donor-type NK cells can prevent GVHD and promote anti-tumor effects following allogeneic BMT in mice. NK cells can be regulated, both in positive and negative manners by a variety of mediators. This proposal will develop means to optimize NK cell recovery and activity following allogeneic BMT resulting in greater anti-tumor effects. To do this three specific aims are proposed: Specific Aim 1 will build on our recent data demonstrating that regulatory T (Tregs) cells can suppress NK activity. We propose to determine the mechanism(s) underlying this suppression and to ascertain the effects of Treg depletion on NK reconstitution and activity following allogeneic BMT. Specific Aim 2 will then seek to accelerate donor NK cell recovery post-BMT through the use of hydrodynamic gene delivery of IL15. Effects on GVHD, donor reconstitution as well as anti-tumor effects will be determined. Specific Aim 3 will determine the role of NK cell subpopulations on donor recovery, GVHD protection, and anti-tumor effects by building on our data that the interactions between these subsets result in significant effects on activity in vivo. The data obtained from this proposal should yield significant insights into NK cell biology as well as allowing the development of approaches that result in superior anti-tumor effects.