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: 8258183
• 负责人: WILLIAM JOSEPH MURPHY
• 金额: $ 37.63万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 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 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258183
• 关键词: Adoptive Transfer; Affect; Allogenic; Animals; Antiviral Response; Behavior; Biological Process; Biology; Cancer Model; Cell Count; Cell Therapy; Cell physiology; Cells; Clinical; Complex; Cytomegalovirus Infections; Data; Development; Engraftment; Environment; Excision; Family; Future; Genes; Graft Rejection; Graft-Versus-Tumor Induction; Haplotypes; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Human; Immune; Immune response; Immunotherapeutic agent; Interleukin-15; Knowledge; Left; Licensing; Long-Term Effects; Lymphoid; Lymphoid Cell; Malignant Neoplasms; Mediating; Modeling; Mouse Strains; Murid herpesvirus 1; Mus; Myelogenous; Natural Killer Cells; Nature; Opportunistic Infections; Outcome; Patients; Pattern; Play; Population; Pre-Clinical Model; Process; Production; Recovery; Regulation; Relapse; Resistance; Rest; Role; T-Lymphocyte Subsets; Therapeutic; Therapeutic Effect; Time; Translations; Viral Cancer; Virus; Virus Diseases; arm; base; cancer cell; cancer stem cell; cancer therapy; cell killing; cell type; clinical application; congenic; critical period; cytokine; gene therapy; graft vs host disease; in vivo; insight; killings; neoplastic cell; novel; reconstitution; stem cell population; tumor; viral resistance

DESCRIPTION (provided by applicant): Hematopoietic stem cell transplantation (HSCT) is increasingly used in cancer therapy and has been shown to provide significant graft-versus-tumor effects for several cancers. However, significant issues limit the efficacy of HSCT including relapse for the tumor, graft rejection, graft-versus-host disease (GVHD) and a profound period of immune deficiency leaving the patient highly susceptible to opportunistic infections. Natural killer (NK) cells represent critical components of the innate immune response and are being increasingly used as a therapeutic arm in HSCT. However, the increasing complexity of NK cells and their regulation along with the relatively sparse knowledge on NK cell development/recovery after HSCT seriously hampers clinical application of NK cells as an immunotherapeutic approach. NK subsets exist and may differ markedly in their function due to differential licensing. We will build on exciting preliminary data demonstrating that mouse NK cell subsets have markedly opposing and differential effects on HSCT outcome using several preclinical models assessing effects on viral resistance, tumor relapse and donor engraftment/GVHD after congenic or allogeneic HSCT. To do this we propose 3 SPECIFIC AIMS: Specific Aim 1 will build on our data demonstrating that Ly49G2 represents a global activation/development marker of NK cells as it is predominant after HSCT or with general activation and is independent of MHC. This aim will examine the mechanisms underlying the expansion of this and other subsets and determine their functional roles using resistance to mouse cytomegalovirus (MCMV) following congenic HSCT. As preliminary data indicate that NK cell licensing with Ly49A+, Ly49G2+, and Ly49C/I+ subsets can indeed be observed post-HSCT and not in resting mice with regard to viral resistance, we hypothesize that the environment post-HSCT represents a unique means to understand NK cell subset interactions and that the Ly49 family is diverse with regard to function/licensing. Specific Aim 2 will build on our exciting preliminary data demonstrating that host NK cell subsets appear capable of regulating each other consistent with licensing and performing "helper" or "suppressor" functions with regard to donor hematopoietic engraftment after allogeneic HSCT. This will characterize these subsets which appear to behave as licensed or unlicensed and seek to expand on their beneficial effects in vivo in allogeneic HSCT. This aim will also determine long-term effects on outcome after HSCT including myeloid and lymphoid reconstitution and GVHD. Specific Aim 3 will build on the data from the previous aims and new data to determine the mechanisms underlying the effects of donor transferred NK cell "helper" or "suppressor/effector" subsets with regard to anti-tumor effects after congenic or allogeneic HSCT. This aim will seek to augment these effects with administration of immunomodulating agents (IL-15 and neutralization of TGF-2). Finally, we will determine the effects of the adoptive NK cell therapy using subsets against cancer stem cell (CSC) populations which may represent critical targets for NK cell therapy (using subsets). These aims will not only aid in the characterization of mouse NK cell subsets with regard to function but will also help in developing means to clinically exploit human NK cells or their subsets therapeutically, particularly in the context of HSCT and cancer as human subsets become better defined. PUBLIC HEALTH RELEVANCE: Natural Killer (NK) cells play important roles in the defense against viruses and cancer. This proposal seeks to develop and optimize means to use NK cells as a therapy in cancer by understanding their biology.

描述（由申请人提供）：造血干细胞移植（HSCT）越来越多地用于癌症治疗，并且已被证明对多种癌症具有显着的移植物抗肿瘤作用。然而，一些重大问题限制了 HSCT 的疗效，包括肿瘤复发、移植物排斥、移植物抗宿主病 (GVHD) 以及长期的免疫缺陷，使患者极易受到机会性感染。自然杀伤 (NK) 细胞是先天免疫反应的关键组成部分，并且越来越多地用作 HSCT 的治疗手段。然而，NK 细胞及其调控的复杂性日益增加，以及 HSCT 后 NK 细胞发育/恢复的知识相对匮乏，严重阻碍了 NK 细胞作为免疫治疗方法的临床应用。 NK 子集是存在的，并且由于许可的差异，它们的功能可能显着不同。我们将基于令人兴奋的初步数据，证明小鼠 NK 细胞亚群对 HSCT 结果具有显着相反和差异性的影响，使用几种临床前模型评估同源或同种异体 HSCT 后对病毒耐药性、肿瘤复发和供体植入/GVHD 的影响。为此，我们提出 3 个具体目标： 具体目标 1 将建立在我们的数据之上，证明 Ly49G2 代表 NK 细胞的全局激活/发育标记，因为它在 HSCT 后或一般激活后占主导地位，并且独立于 MHC。这一目标将检查该亚群和其他亚群扩张的机制，并利用同源 HSCT 后对小鼠巨细胞病毒 (MCMV) 的抗性来确定其功能作用。由于初步数据表明 NK 细胞许可 Ly49A+、Ly49G2+ 和 Ly49C/I+ 子集确实可以在 HSCT 后观察到，而在静息小鼠中则观察不到病毒抵抗力，我们假设 HSCT 后的环境代表了一种独特的方式来理解NK 细胞亚群相互作用，并且 Ly49 家族在功能/许可方面具有多样性。具体目标 2 将建立在我们令人兴奋的初步数据的基础上，这些数据表明宿主 NK 细胞亚群似乎能够在许可的情况下相互调节，并在同种异体 HSCT 后的供体造血移植方面发挥“辅助”或“抑制”功能。这将表征这些似乎表现得许可或未许可的子集，并寻求扩大它们在同种异体 HSCT 中的体内有益作用。这一目标还将确定对 HSCT 后结果的长期影响，包括骨髓和淋巴重建以及 GVHD。具体目标 3 将建立在先前目标的数据和新数据的基础上，以确定供体转移的 NK 细胞“辅助细胞”或“抑制子/效应子”子集在同源或同种异体 HSCT 后抗肿瘤作用的潜在机制。这一目标将寻求通过施用免疫调节剂（IL-15 和中和 TGF-2）来增强这些效果。最后，我们将确定使用子集的过继 NK 细胞疗法对癌症干细胞 (CSC) 群体的影响，这些细胞可能代表 NK 细胞疗法的关键目标（使用子集）。这些目标不仅有助于表征小鼠 NK 细胞亚群的功能，还将有助于开发在临床上利用人类 NK 细胞或其亚群进行治疗的方法，特别是在 HSCT 和癌症的背景下，因为人类亚群得到了更好的定义。 公共卫生相关性：自然杀伤 (NK) 细胞在防御病毒和癌症方面发挥着重要作用。该提案旨在通过了解 NK 细胞的生物学特性来开发和优化使用 NK 细胞作为癌症疗法的方法。