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）：同种异体移植生存没有不良影响是移植的最终目标。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。但是，免疫抑制不能保证接受器官，组织和造血干细胞（HPSC）移植的患者的预防随着时间的流逝而预防。结果，患者屈服于移植物抗宿主病（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既不能避免预先存在的记忆细胞，也不能区分异种反应性和非异种反应性T细胞。因此，尽管可以通过免疫抑制在某些程度上控制GVHD，但它却是支付移植失败，白血病复发和对移植后感染的免疫力的成本增加，例如巨细胞病毒（CMV）。因此，一种防止GVHD的新型治疗策略，同时保留宿主对感染和移植物与白血病（GVL）的影响（GVL）的影响将为患者带来巨大好处。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）可以对不同的抗原特异性T细胞的质量和数量进行编程 方式。在已测试的LLR中，DC-亚种糖蛋白受体（DC-ASGPR）具有独特的功能来产生产生IL-10的抗原特异性Tregs。少数此类Treg足以抑制相同的抗原特异性效应T细胞增殖和炎症细胞因子的表达。通过抗DC-ASGPR抗体Express IL-10激活DCS，该抗原特异性Treg响应。此外，抗DC-ASGPR抗体可显着降低同种异体T细胞增殖。因此，DC-ASGPR可能是在患者中安装异抗原特异性Treg的新目标，而不会干扰病原体和GVL效应的宿主免疫。因此，在这项研究中，我们建议研究DC-ASGPR诱导的同种抗原特异性耐受性的分子（AIM 1）和细胞（AIM 2）机制，以及GVHD中新型抗DC-ASGPR抗体的有效性（AIM 3）和同种异体抑制（AIM 4）。在这项R01研究的结尾，我们将了解DC-ASGPR诱导的同种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接受移植的患者的新型免疫治疗药的合理设计和开发具有直接的影响。