Positive and Negative Regulation of Natural Killer Cells After BMT

BMT后自然杀伤细胞的正向和负向调节

• 批准号: 7472572
• 负责人: WILLIAM JOSEPH MURPHY
• 金额: $ 35万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-18 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7472572
• 关键词: Address; Adoptive Transfer; Advanced Malignant Neoplasm; Affect; Allogeneic Bone Marrow Transplantation; Allogenic; Bone Marrow Transplantation; Cell Differentiation process; Cell physiology; Cells; Cellular biology; Clinical Research; Data; Development; Disease; Disease susceptibility; Engraftment; Excision; Gene Delivery; Goals; Homing; IL15 gene; Immune; Immune system; In Vitro; Interleukin-15; KLRA1 gene; Licensing; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Mus; Natural Killer Cells; Opportunistic Infections; Outcome; Recovery; Recovery of Function; Regulation; Relapse; Research Personnel; Role; Stimulus; Transplantation; Tumor Burden; Viral; base; cancer therapy; cell type; congenic; cytokine; gene therapy; graft vs host disease; improved; in vivo; insight; prevent; programs; receptor; reconstitution; tool; trafficking; tumor

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.

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）、移植后的免疫缺陷和复发仍然是限制疗效的重大障碍。开发一种提高BMT抗肿瘤效果的方法具有相当重要的意义。自然杀伤 (NK) 细胞已被证明可以在体内和体外介导多种抗肿瘤作用。我们之前已经证明，供体型 NK 细胞可以预防 GVHD，并在小鼠同种异体 BMT 后促进抗肿瘤作用。 NK 细胞可以受到多种介质的正向和负向调节。该提案将开发优化同种异体 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 将基于我们最近的数据，证明调节性 T (Treg) 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 Treg 耗竭对同种异体 BMT 后 NK 重建和活性的影响。具体目标 2 将寻求通过使用 IL15 的流体动力学基因传递来加速 BMT 后供体 NK 细胞的恢复。将确定对 GVHD、供体重建以及抗肿瘤作用的影响。具体目标 3 将根据我们的数据确定 NK 细胞亚群对供体恢复、GVHD 保护和抗肿瘤作用的作用，这些数据表明这些亚群之间的相互作用会对体内活性产生显着影响。从该提案中获得的数据应该会对 NK 细胞生物学产生重要的见解，并允许开发产生卓越抗肿瘤效果的方法。