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

DC-ASGPR 作为控制 GVHD 和同种异体移植排斥的新靶点

• 批准号: 8632179
• 负责人: SangKon Oh
• 金额: $ 33.06万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632179
• 关键词: Adverse effects; Alloantigen; Allogenic; Allografting; Antibodies; Antigen-Presenting Cells; Antigens; Asialoglycoprotein Receptor; CD34 gene; Cells; Cytomegalovirus; Data; Dendritic Cell Pathway; Dendritic Cells; Dendritic cell activation; Development; Effectiveness; Experimental Models; Future; Generations; Goals; Graft Rejection; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Immune; Immune Tolerance; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; In Vitro; Incidence; Infection; Inflammatory; Influenza; Interleukin-10; Lectin; Life; Memory; Modeling; Molecular; Monoclonal Antibodies; Organ; Organ Transplantation; Patients; Pattern recognition receptor; Phenotype; Prevention; Prostate-Specific Antigen; Regulatory T-Lymphocyte; Relapse; Signal Transduction; Skin; Skin graft; T cell response; T-Cell Depletion; T-Cell Proliferation; T-Lymphocyte; Testing; Time; Tissues; Transplantation; Work; allograft rejection; cost; cytokine; design; graft failure; graft vs host disease; in vivo; leukemia; microbial; mouse model; new therapeutic target; nonhuman primate; novel; novel therapeutics; pathogen; prevent; programs; public health relevance; receptor; response; success

Program Director/Principal Investigator (Last, First, Middle): Oh, SangKon PROJECT TITLE: DC-ASGPR AS A NOVEL TARGET FOR CONTROLLING GVHD AND ALLOGRAFT REJECTION 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.

项目总监/首席调查员(最后、第一、中间)：哦，SangKon 项目名称：DC-ASGPR作为控制移植物抗宿主病和同种异体移植排斥反应的新靶点 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， 免疫抑制不能保证随着时间的推移在接受免疫治疗的患者中预防同种反应 器官、组织和造血干细胞(HPSC)移植。因此，患者会屈从于 移植物抗宿主病(GVHD)以及终身免疫抑制的严重副作用。 此外，用非特异性免疫抑制来控制GVHD也不能幸免于先前存在的记忆细胞 也不区分同种异体反应和非同种异体反应的T细胞。因此，尽管GVHD是可以控制的 在某种程度上，免疫抑制是以移植失败、白血病发生率增加为代价的。 复发，对移植后感染的免疫力下降，如巨细胞病毒(CMV)。因此， 预防移植物抗宿主病的新治疗策略，同时保持宿主对感染和移植物抗宿主的免疫力 白血病(GVL)效应将给患者带来极大的好处。 我们最近发现，通过不同的凝集素样受体(LLR)激活的人树突状细胞(DC)可以 以不同的方式规划抗原特异性T细胞的质量和数量。在测试的LLR中，DC- 去唾液酸糖蛋白受体(DC-ASGPR)具有独特的功能，可以产生抗原特异性Treg，从而 产生IL-10。少量这样的Tregs足以抑制相同的抗原特异性效应器T 细胞增殖和炎性细胞因子表达。通过带有抗DC-ASGPR的DC-ASGPR激活的DC 抗体表达IL-10，促进抗原特异性Treg反应。此外，反DC-ASGPR 抗体显著降低同种异体T细胞的增殖。因此，DC-ASGPR可能是一个新的靶点 在不干扰宿主对病原体和GVL免疫的情况下在患者体内安装同种异体抗原特异性Treg 效果。因此，在这项研究中，我们建议研究分子(目标1)和细胞(目标2)。 DC-ASGPR诱导同种异体抗原特异性耐受的机制及新型抗DC-DNA抗体的作用 GVHD中的ASGPR抗体(AIM 3)和同种异体移植排斥反应(AIM 4)。 在R01研究结束时，我们将了解DC-ASGPR的分子和细胞机制。 诱导同种异体抗原特异性免疫耐受。这项研究的结果将直接影响到 肾移植患者新型免疫治疗药物的合理设计与开发 在不久的将来。