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，该领域的研究和不良表征。该项目的重点是宿主同种异体NK细胞与供体同种异体树突状细胞之间的相互相互作用，以及这种相互作用对移植模型中T效应细胞和Tregs激活的机制和结果。这是基于我们最近发现的，天生的NK细胞在通过共刺激性阻断治疗诱导同种异体移植生存中起关键的调节作用。我们发现，NK细胞似乎控制了移植受者中移植物源细胞的存活和传播，从而调节T细胞启动中的关键过程，最终是同种异体移植的命运。我们提供了令人信服的初步数据，表明NK细胞和DC都非常异质。此外，它们对细胞因子和炎症刺激的反应也很高，因此，宿主同种异体反应性NK细胞与供体同种异体DC之间的相互相互作用很可能很复杂，并且这种相互作用对同种异体移植反应的性质（拒绝VS.公差）的影响很大。该提议中提出的假设是，NK细胞在诱导效应子类型（排斥）或免疫反应的调节类型（公差）中起着至关重要的作用，通过调节移植受者中不同供体DC亚群的生命和死亡。该项目的新颖性是检查耐受性诱导的新机制，同种异体NK细胞在同种异体移植反应中的新作用以及在移植模型中NK细胞的新子集。这项研究的含义是，除T细胞外，还应在诱导移植耐受性的情况下进行治疗方法。拟议的研究可能导致在诊所耐受性诱导中开发新的治疗方案。这些研究还可能导致基于特定移植物在诊所耐受性诱导中DC的组成的DST方案或量身定制的免疫抑制方案的合理设计。我们在开发更好的动物模型和细胞选择/识别技术方面投入了大量时间和精力，这使得这些研究可行。我们相信，在完成该项目后，将在理解对同种异体的先天免疫反应方面的新进展。 公共卫生相关性：移植通常是终末期器官衰竭治疗的唯一选择，但是移植患者必须终身服用免疫抑制药物。当前的免疫抑制药物经常看到的不良副作用以及尽管最大的免疫抑制，我们无法控制慢性移植损失，这是发展出更好，更具体的耐受性诱导策略的令人信服的理由。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植物的反应以及这种反应性在移植排斥和耐受诱导中的影响。这项研究将为制定耐受性诱导策略的发展提供新的机会。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的影响，包括自身免疫性疾病，骨髓移植和癌症疗法。