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: 7627952
• 负责人: WILLIAM JOSEPH MURPHY
• 金额: $ 11.24万
• 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 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7627952
• 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）：当前使用同种异体骨髓移植（BMT）来治疗各种癌症，但移植宿主疾病（GVHD），移植后的免疫缺乏，并且复发仍然是限制效力的重大障碍。开发一种改善BMT抗肿瘤作用的方法至关重要。天然杀伤（NK）细胞已显示可介导体内和体外的许多抗肿瘤作用。我们以前已经证明，在小鼠同种异体BMT后，供体型NK细胞可以防止GVHD并促进抗肿瘤作用。 NK细胞可以通过各种介体以正极和负的方式调节NK细胞。该建议将开发出在同种异体BMT后优化NK细胞恢复和活性的方法，从而产生更大的抗肿瘤作用。提出了这三个特定目的：具体目标1将基于我们最近的数据，表明调节性t（Tregs）细胞可以抑制NK活性。我们建议确定这种抑制的基础机制，并确定Treg耗竭对同种异体BMT后NK重建和活动的影响。然后，特定的目标2将寻求通过使用IL15的流体动力基因递送来加速BMT后BMT的供体NK细胞恢复。将确定对GVHD，捐助者重建以及抗肿瘤效应的影响。特定的目标3将通过建立我们的数据来确定NK细胞亚群对供体回收，GVHD保护和抗肿瘤效应的作用，即这些子集之间的相互作用会对体内的活性产生重大影响。从该提案中获得的数据应对NK细胞生物学产生重大见解，并允许开发导致抗肿瘤效应的方法。