DC-ASGPR as Novel Target for Controlling GVHD and Allograft Rejection

描述(申请人提供)：无不良反应的同种异体移植物存活是移植的最终目标。在过去的几十年里，大量的免疫抑制剂已经被开发出来并用于患者。然而，在接受器官、组织和造血干细胞(HPSC)移植的患者中，免疫抑制并不能保证随着时间的推移防止同种反应的发生。因此，患者会死于移植物抗宿主病(GVHD)以及终身免疫抑制带来的严重副作用。此外，使用非特异性免疫抑制来控制GVHD既不能保留原有的记忆细胞，也不能区分同种异体反应的T细胞和非同种反应的T细胞。因此，尽管GVHD可以通过免疫抑制在一定程度上得到控制，但它的代价是移植物失败、白血病复发和对移植后感染(如巨细胞病毒)的免疫力下降。因此，一种既能预防移植物抗宿主病，又能保护宿主对感染的免疫力和移植物抗白血病(GVL)作用的新的治疗策略将给患者带来极大的好处。我们最近发现，由不同的凝集素样受体(LLR)激活的人树突状细胞(DC)可以在不同的时间内编程抗原特异性T细胞的质量和数量 方式。在所测试的LLR中，DC-去唾液酸糖蛋白受体(DC-ASGPR)具有独特的功能，能够产生产生IL-10的抗原特异性Tregs。少量这样的Tregs足以抑制同一抗原特异性效应T细胞的增殖和炎性细胞因子的表达。DC-ASGPR与抗DC-ASGPR抗体共同激活的DC表达IL-10，促进抗原特异性Treg反应。此外，抗DC-ASGPR抗体显著降低同种异体T细胞的增殖。因此，DC-ASGPR可能成为一种新的靶点，在不干扰宿主对病原体的免疫和GVL效应的情况下，在患者体内安装同种异体抗原特异性Tregs。因此，在这项研究中，我们建议研究DC-ASGPR诱导的同种异体抗原特异性耐受的分子(AIM 1)和细胞(AIM 2)机制，以及我们的新型抗DC-ASGPR抗体在GVHD(AIM 3)和同种异体移植排斥反应(AIM 4)中的有效性。在R01研究结束时，我们将了解DC-ASGPR诱导同种异体抗原特异性免疫耐受的分子和细胞机制。这项研究的结果将对在不久的将来为接受移植的患者合理设计和开发新的免疫疗法具有直接的意义。

DESCRIPTION (provided by applicant): Allograft survival with no adverse effects is an ultimate goal in transplantation. Over the past several decades, a large array of immunosuppressive agents has been developed and used for patients. However, immunosuppression does not guarantee the prevention of alloreaction over time in patients who receive organs, tissues, and hematopoietic stem cell (HPSC) transplantation. As a consequence, patients succumb to graft-versus-host disease (GVHD) as well as serious side effects from life-long immunosuppression. Furthermore, controlling GVHD with nonspecific immunosuppression neither spares pre-existing memory cells nor discriminates between alloreactive and non-alloreactive T cells. Thus, although GVHD could be controlled in some degrees by immunosuppression, it is at the cost of increased incidence of graft failure, leukemia relapse, and compromised immunity to post-transplant infections, such as cytomegalovirus (CMV). Therefore, a novel therapeutic strategy that prevents GVHD, while preserving host immunity to infections and graft versus leukemia (GVL) effects will bring great benefit to patients. We have recently found that human dendritic cells (DCs) activated via different lectin-like receptors (LLRs) can program the quality and quantity of antigen-specific T cells in different ways. Of the LLRs tested, DC-asialoglycoprotein receptor (DC-ASGPR) has a unique function to generate antigen-specific Tregs that produce IL-10. Small numbers of such Tregs were sufficient to suppress the same antigen-specific effector T cell proliferation and inflammatory cytokine expression. DCs activated via DC-ASGPR with anti-DC-ASGPR antibody express IL-10, which promotes antigen-specific Treg responses. In addition, anti-DC-ASGPR antibody significantly reduces allogeneic T cell proliferation. Thus, DC-ASGPR could be a novel target to mount alloantigen-specific Tregs in patients without interfering with host immunity to pathogens and GVL effects. In this study, therefore, we propose to investigate the molecular (Aim 1) and cellular (Aim 2) mechanisms of DC-ASGPR-induced alloantigen-specific tolerance and the effectiveness of our novel anti-DC-ASGPR antibody in GVHD (Aim 3) and allograft rejection (Aim 4). At the end of this R01 study, we will understand the molecular and cellular mechanisms of DC-ASGPR-induced alloantigen-specific immune tolerance. The results of this study will have immediate implications for the rational design and development of novel immunotherapeutics for patients who undergo transplantation in the near future.