DC-ASGPR AS A 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: 8663535
• 负责人: SangKon Oh
• 金额: $ 36.85万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8663535
• 关键词: Adverse effects; Alloantigen; Allogenic; Allografting; Antibodies; Antigen-Presenting Cells; Antigens; Asialoglycoprotein Receptor; Cells; Cytomegalovirus; Data; Dendritic Cells; Dendritic cell activation; Development; Effectiveness; Experimental Models; Future; Generations; Goals; Graft Rejection; Hematopoietic Stem Cell Transplantation; 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; Mus; Organ; Organ Transplantation; Pathway interactions; Patients; Pattern recognition receptor; Play; Prevention; Regulatory T-Lymphocyte; Relapse; Role; 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; 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 study (R01), we will understand the molecular and cellular mechanisms of DC-ASGPR- induced alloantigen-specific immune tolerance. More importantly, data generated from this study will support humanization of our novel antibody 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）：无不良反应的同种异体移植物存活是移植的最终目标。在过去的几十年中，已经开发了大量的免疫抑制剂并用于患者。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预防同种异体反应。因此，患者死于移植物抗宿主病（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控制GVHD既不保留预先存在的记忆细胞，也不区分同种异体反应性和非同种异体反应性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、白血病复发和对移植后感染（如巨细胞病毒（CMV））的免疫力受损的发生率增加。因此，一种新的治疗策略，防止GVHD，同时保留宿主免疫感染和移植物抗白血病（GVL）的影响将带来巨大的好处，患者。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）可以在不同的免疫应答中编程抗原特异性T细胞的质量和数量。 的方式在所测试的LLR中，DC-脱唾液酸糖蛋白受体（DC-ASGPR）具有产生产生IL-10的抗原特异性T细胞的独特功能。少量的这种TclA足以抑制相同的抗原特异性效应T细胞增殖和炎性细胞因子表达。用抗DC-ASGPR抗体通过DC-ASGPR活化的DC表达IL-10，其促进抗原特异性Treg应答。此外，抗DC-ASGPR抗体显著降低同种异体T细胞增殖。因此，DC-ASGPR可能是一种新的靶点，可以在患者体内安装同种异体抗原特异性T细胞，而不会干扰宿主对病原体的免疫和GVL效应。因此，在本研究中，我们提出研究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反应（目标4）中的有效性。在本研究结束时（R 01），我们将了解DC-ASGPR诱导同种抗原特异性免疫耐受的分子和细胞机制。更重要的是，从这项研究中产生的数据将支持我们的新型抗体的人源化，用于在不久的将来为接受移植的患者合理设计和开发新型免疫治疗药物。