Modulation of innate immune cells to create transplant tolerance

调节先天免疫细胞以产生移植耐受

• 批准号: 8232053
• 负责人: Xian Chang Li
• 金额: $ 36.47万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8232053
• 关键词: Address; Adverse effects; Affect; Alloantigen; Allogenic; Allograft Tolerance; Allografting; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Area; Autoimmune Diseases; Bone Marrow Transplantation; Cell Surface Receptors; Cells; Cessation of life; Chronic; Clinic; Complex; Data; Dendritic Cells; Development; Effector Cell; Environment; Equilibrium; Exhibits; Frequencies; Goals; Graft Rejection; Graft Tolerance; Immune; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; Inflammatory; Injury; Interleukin-10; Knowledge; Lead; Licensing; Life; Ligands; Malignant Neoplasms; Mediating; Memory; Modeling; Mus; Natural Killer Cells; Nature; Organ Transplantation; Pathway interactions; Pharmaceutical Preparations; Play; Predisposition; Procedures; Process; Production; Property; Protocols documentation; Research; Role; Solid; System; T-Lymphocyte; Techniques; Testing; Therapeutic Intervention; Time; Tissue Grafts; Transplant Recipients; Transplantation; allotransplant; base; cancer therapy; cell type; clinically relevant; cytokine; design; end-stage organ failure; killings; novel therapeutics; public health relevance; response

DESCRIPTION (provided by applicant): This proposal is designed to address the issue of innate immune responses to allografts following transplantation, an area that is poorly studied and ill characterized. The focus of this project is on reciprocal interactions between host alloreactive NK cells and donor allogeneic dendritic cells, and the mechanisms and consequence of such interactions on the activation of T effector cells and Tregs in transplant models. This is based on our recent discovery that the innate NK cells play a critical regulatory role in the induction of allograft survival by costimulatory blockade treatment. We found that NK cells appear to control survival and dissemination of graft-derived donor cells in transplant recipients, thereby regulating a critical process in T cell priming, and eventually the fate of an allograft. We have provided convincing preliminary data showing that both NK cells and DCs are extremely heterogeneous. In addition, they are also highly responsive to cytokines and inflammatory stimulations, and therefore, the reciprocal interactions between host alloreactive NK cells and donor allogeneic DCs are likely to be complex, and the impact of such interactions on the nature of the allograft response (rejection vs. tolerance) is likely to be significant. The hypothesis proposed in this proposal is that NK cells play a critical role in the induction of an effector type (rejection) or a regulatory type (tolerance) of immune responses by regulating life and death of different donor DC subsets in transplant recipients. The novelty of this project is the examination of new mechanisms of tolerance induction, new roles of alloreactive NK cells in the allograft response, and new subsets of NK cells in transplant models. The implication of this study is that, besides T cells, the alloreactive NK cells should also be therapeutically manipulated for the induction of transplant tolerance. The proposed studies may lead to the development of new therapeutic protocols in tolerance induction in the clinic. These studies may also lead to the rational design of DST protocols or tailored immunosuppressive protocols based on the composition of DCs in a particular graft in tolerance induction in the clinic. We have invested considerable time and efforts in the development of better animal models and cells selection/identification techniques, which makes execution of these studies feasible. We are confident that new advances in our understanding of innate immune responses to allografts will be made after accomplishment of this project. PUBLIC HEALTH RELEVANCE: Transplantation is often the only choice of treatment for end-stage organ failure, but transplant patients must take immunosuppressive drugs for life. The unwanted side effects frequently seen with current immunosuppressive drugs and our inability to control chronic graft loss despite maximal immunosuppression are the compelling reasons for the development of better and more specific tolerance- inducing strategies. Our project is designed to specifically study how innate immune cells react to allotransplants and the impact of such reactivity in graft rejection and tolerance induction. This line of research will open new opportunities for the development of tolerance-induction strategies. Moreover, knowledge gained from those studies will have a broad impact on therapeutic interventions of other conditions including autoimmune disorders, bone marrow transplantation, and cancer therapies.

描述（由申请人提供）：该提案旨在解决移植后对同种异体移植物的先天免疫反应问题，这是一个研究很少且特征不明确的领域。该项目的重点是宿主同种异体 NK 细胞和供体同种异体树突状细胞之间的相互作用，以及这种相互作用对移植模型中 T 效应细胞和 Tregs 激活的机制和后果。这是基于我们最近的发现，即先天 NK 细胞在共刺激阻断治疗诱导同种异体移植物存活中发挥着关键的调节作用。我们发现 NK 细胞似乎可以控制移植受者体内移植物来源的供体细胞的存活和传播，从而调节 T 细胞启动的关键过程，并最终调节同种异体移植物的命运。我们提供了令人信服的初步数据，表明 NK 细胞和 DC 都具有极大的异质性。此外，它们对细胞因子和炎症刺激也高度敏感，因此，宿主同种异体反应性 NK 细胞和供体同种异体 DC 之间的相互作用可能很复杂，并且这种相互作用对同种异体移植反应性质（排斥与耐受）的影响可能很大。该提案提出的假设是，NK 细胞通过调节移植受者中不同供体 DC 亚群的生死，在诱导效应型（排斥型）或调节型（耐受型）免疫反应中发挥关键作用。该项目的新颖之处在于检查耐受诱导的新机制、同种异体反应性 NK 细胞在同种异体移植反应中的新作用以及移植模型中 NK 细胞的新亚群。这项研究的意义在于，除了 T 细胞外，还应该对同种异体 NK 细胞进行治疗操作，以诱导移植耐受。拟议的研究可能会导致临床耐受诱导新治疗方案的开发。这些研究还可能导致合理设计 DST 方案或根据临床耐受诱导中特定移植物中 DC 的组成定制免疫抑制方案。我们投入了大量的时间和精力来开发更好的动物模型和细胞选择/识别技术，这使得这些研究的执行变得可行。我们相信，在该项目完成后，我们对同种异体移植物的先天免疫反应的理解将取得新的进展。 公共卫生相关性：移植通常是终末期器官衰竭的唯一治疗选择，但移植患者必须终生服用免疫抑制药物。目前的免疫抑制药物经常出现不良副作用，以及尽管最大限度地进行免疫抑制，但我们仍无法控制慢性移植物丢失，这是开发更好、更特异的耐受诱导策略的重要原因。我们的项目旨在专门研究先天免疫细胞如何对同种异体移植物做出反应，以及这种反应性对移植物排斥和耐受诱导的影响。这一系列研究将为耐受诱导策略的发展带来新的机遇。此外，从这些研究中获得的知识将对其他疾病的治疗干预产生广泛影响，包括自身免疫性疾病、骨髓移植和癌症治疗。