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中，并已证明可以为多种癌症提供显着的移植物肿瘤效应。然而，重大问题限制了HSCT的疗效，包括肿瘤的复发，移植物排斥，移植物抗宿主病（GVHD）和严重的免疫缺陷时期，使患者非常容易受到机会性感染。天然杀伤（NK）细胞代表了先天免疫反应的关键成分，并越来越多地用作HSCT的治疗臂。但是，NK细胞及其调节的复杂性的增加，以及HSCT后NK细胞发育/恢复的相对稀疏知识严重阻碍了NK细胞作为免疫治疗方法的临床应用。 NK子集存在，并且由于差异许可，其功能可能明显不同。我们将基于令人兴奋的初步数据，表明小鼠NK细胞子集使用多种临床前模型对HSCT结果显着相反和差异影响，从而评估了对病毒抗性，肿瘤复发和供体植入/GVHD的影响，并在先行或同种异体HSCT之后。为此，我们提出了3个特定目标：特定目标1将基于我们的数据，表明LY49G2代表NK细胞的全局激活/开发标记，因为它在HSCT或一般激活后主要是主导，并且与MHC无关。该目标将检查该和其他子集扩展的基础机制，并在先天性HSCT后使用对小鼠巨细胞病毒（MCMV）的耐药性来确定其功能作用。如前数据表明，使用LY49A+，LY49G2+和LY49C/I+子集的NK细胞许可确实可以观察到HSCT后HSCT后观察到，而不是在病毒耐药性方面静止的小鼠，我们假设HSCT在HSCT后HSCT表示在NK细胞子集相互作用的独特手段，可以理解NK细胞子集的互动，以了解Ly49家族和Ly49家族的功能/多样。特定的目标2将基于我们令人兴奋的初步数据，表明宿主NK细胞子集似乎能够相互调节，这与同种异体HSCT后的供体造血造血植入有关的供体造血植入方面的许可和执行“助手”或“抑制”功能。这将表征这些子集的表现，这些子集似乎以许可或无牌的方式行事，并试图扩大其在同种异体HSCT中体内的有益效果。该目标还将确定HSCT后对结果的长期影响，包括髓样和淋巴样重建和GVHD。具体目标3将基于先前的目标和新数据的数据，以确定供体转移的NK细胞“助手”或“抑制器/效应子”子集对抗肿瘤效应后的抗肿瘤或同种异体HSCT后的效应的机制。该目标将旨在通过给予免疫调节剂（IL-15和TGF-2中和）来增强这些影响。最后，我们将使用亚基对癌症干细胞（CSC）群体（可能代表NK细胞疗法的关键靶标）（使用亚群）确定收养NK细胞治疗的影响。这些目标不仅将有助于表征小鼠NK细胞亚群在功能方面的表征，而且还有助于开发临床利用人类NK细胞或其亚群治疗的方法，尤其是在HSCT和癌症的背景下，随着人类子集的定义更好。 公共卫生相关性：自然杀手（NK）细胞在防御病毒和癌症中起重要作用。该提案旨在通过了解其生物学来开发和优化使用NK细胞作为癌症治疗的方法。