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对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佳的领域。本项目的重点是宿主同种异体反应性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T细胞活化的机制和后果。这是基于我们最近的发现，即先天性NK细胞在通过共刺激阻断治疗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细胞似乎控制移植物来源的供体细胞在移植受体中的存活和传播，从而调节T细胞引发的关键过程，并最终影响同种异体移植物的命运。我们已经提供了令人信服的初步数据，表明NK细胞和DC都是非常异质的。此外，它们还对细胞因子和炎性刺激具有高度反应性，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是复杂的，并且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。该提案中提出的假设是NK细胞通过调节移植受体中不同供体DC亚群的生死，在诱导效应型（排斥）或调节型（耐受）免疫应答中发挥关键作用。该项目的新奇在于研究了诱导耐受的新机制、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。这项研究的意义是，除了T细胞，同种异体反应性NK细胞也应该在治疗上被操纵用于诱导移植耐受。拟议的研究可能会导致在临床上的耐受诱导新的治疗方案的发展。这些研究也可能导致DST方案的合理设计或基于特定移植物中DC的组成的定制免疫抑制方案在临床上诱导耐受。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变得可行。我们有信心，在我们对同种异体移植物的先天免疫反应的理解方面，在这个项目完成后将取得新的进展。 公共卫生相关性：移植通常是治疗终末期器官衰竭的唯一选择，但移植患者必须终身服用免疫抑制药物。当前免疫抑制药物经常出现的不希望的副作用以及我们在最大免疫抑制下无法控制慢性移植物丢失是开发更好和更特异性的耐受诱导策略的令人信服的原因。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反应以及这种反应在移植排斥和耐受诱导中的影响。这一系列的研究将为耐受诱导策略的发展开辟新的机会。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影响，包括自身免疫性疾病，骨髓移植和癌症治疗。

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.