Positive and Negative Regulation of Natural Killer Cells After BMT

描述(申请人提供)：异基因骨髓移植(BMT)目前用于治疗多种癌症，但移植物抗宿主病(GVHD)、移植后的免疫缺陷和复发仍是限制疗效的重大障碍。开发一种方法来提高骨髓移植的抗肿瘤效果是相当重要的。自然杀伤细胞(NK细胞)在体内和体外均可介导多种抗肿瘤作用。我们之前已经证明供者类型的NK细胞可以预防GVHD并促进同种异体骨髓移植后的抗肿瘤作用。NK细胞可以被多种介质以积极和消极的方式进行调节。这项建议将开发方法来优化异基因骨髓移植后NK细胞的恢复和活性，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基础上，证明调节性T(Tregs)细胞可以抑制NK活性。我们建议确定这种抑制的机制(S)，并确定Treg缺失对异基因骨髓移植后NK重建和活性的影响。然后，特殊目标2将寻求通过使用IL15的流体动力基因传递来加速骨髓移植后供者NK细胞的恢复。将确定对移植物抗宿主病、供体重建以及抗肿瘤作用的影响。具体目标3将根据我们的数据确定NK细胞亚群在供者恢复、GVHD保护和抗肿瘤效应中的作用，这些亚群之间的相互作用导致体内活性的显著影响。从这项建议中获得的数据应该会对NK细胞生物学产生重要的见解，并允许开发出产生优异抗肿瘤效果的方法。

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.