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: 8823729
• 负责人: SangKon Oh
• 金额: $ 39.2万
• 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/8823729
• 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; Health; 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; functional plasticity; graft failure; graft vs host disease; in vivo; leukemia; microbial; mouse model; new therapeutic target; nonhuman primate; novel; novel therapeutics; pathogen; prevent; programs; receptor; response; success

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.

描述（由申请人提供）：同种异体移植物存活且无副作用是移植的最终目标。在过去的几十年里，大量的免疫抑制剂被开发出来并用于患者。然而，免疫抑制并不能保证在接受器官、组织和造血干细胞 (HPSC) 移植的患者中随着时间的推移防止同种反应。结果，患者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，用非特异性免疫抑制控制 GVHD 既不能保护预先存在的记忆细胞，也不能区分同种反应性和非同种反应性 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，但其代价是移植失败、白血病复发的发生率增加以及对移植后感染（例如巨细胞病毒（CMV））的免疫力受损。因此，一种预防GVHD、同时保留宿主对感染和移植物抗白血病（GVL）效应的免疫力的新治疗策略将为患者带来巨大益处。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）可以在不同的环境中编程抗原特异性T细胞的质量和数量。 方式。在测试的 LLR 中，DC-脱唾液酸糖蛋白受体 (DC-ASGPR) 具有独特的功能，可以生成产生 IL-10 的抗原特异性 Tregs。少量的此类 Tregs 足以抑制相同抗原特异性效应 T 细胞的增殖和炎症细胞因子的表达。通过 DC-ASGPR 和抗 DC-ASGPR 抗体激活的 DC 表达 IL-10，从而促进抗原特异性 Treg 反应。此外，抗 DC-ASGPR 抗体显着降低同种异体 T 细胞增殖。因此，DC-ASGPR 可能是在患者体内安装同种异体抗原特异性 Tregs 的新靶标，而不干扰宿主对病原体的免疫和 GVL 效应。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（目标 1）和细胞（目标 2）机制，以及我们的新型抗 DC-ASGPR 抗体在 GVHD（目标 3）和同种异体移植排斥（目标 4）中的有效性。在这项 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不久的将来接受移植的患者新型免疫疗法的合理设计和开发产生直接影响。