Modulation of innate immune cells to create transplant tolerance

描述（由申请人提供）：本提案旨在解决移植后同种异体移植物的先天免疫反应问题，这是一个研究不足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treg活化的机制和后果。这是基于我们最近的发现，先天NK细胞通过共刺激阻断治疗在诱导同种异体移植物存活中起关键的调节作用。我们发现NK细胞似乎控制移植受体中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细胞都是非常异质的。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NK细胞和供体同种异体dc之间的相互作用可能是复杂的，这种相互作用对同种异体移植反应的性质（排斥与耐受）的影响可能是显著的。该提案提出的假设是，NK细胞通过调节移植受者不同供体DC亚群的生与死，在诱导效应型（排斥）或调节性（耐受）免疫反应中起关键作用。该项目的新颖之处在于研究耐受性诱导的新机制，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。这项研究的含义是，除了T细胞外，同种异体反应性NK细胞也应该通过治疗操作来诱导移植耐受。所提出的研究可能会导致临床耐受诱导的新治疗方案的发展。这些研究也可能导致合理设计DST方案或定制免疫抑制方案，基于特定移植物中dc的组成在临床耐受诱导。我们已经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/鉴定技术，这使得这些研究的执行是可行的。我们相信，在完成这个项目后，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。

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.