The role of tolerogenic dendritic cells in islet-cell allograft transplantation

耐受性树突状细胞在胰岛细胞同种异体移植中的作用

• 批准号: 7659533
• 负责人: Sherrie Jill Divito
• 金额: $ 4.62万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659533
• 关键词: Address; Adoptive Transfer; Adverse effects; Alloantigen; Allogenic; Allograft Tolerance; Allografting; Antigen-Presenting Cells; Apoptosis; Apoptotic; Area; Attention; Autoimmune Process; Autoimmunity; Biological Assay; Blood Glucose; Bone Marrow; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Culture Techniques; Cell Maturation; Cell Therapy; Cell membrane; Cells; Cholecalciferol; Chronic; Chronic Disease; Clinical; Data; Dendritic Cell Therapy; Dendritic Cells; Dependence; Diabetes Mellitus; Dioxygenases; Enzyme-Linked Immunosorbent Assay; Evaluation; Flow Cytometry; Graft Rejection; Hepatic; Immune; Immune response; Immunologics; Immunosuppression; Immunosuppressive Agents; In Vitro; Infection; Injection of therapeutic agent; Insulin; Insulin Resistance; Islet Cell; Islets of Langerhans; Islets of Langerhans Transplantation; Life; Ligands; Link; MHC Class I Genes; Malignant Neoplasms; Mediating; Mediator of activation protein; Memory; Microscopy; Modeling; Morbidity - disease rate; Mus; Outcome; Pancreatectomy; Pathway interactions; Patients; Phagocytosis; Phenotype; Play; Population; Predisposition; Production; Protocols documentation; Reporting; Research; Resistance; Risk; Role; Side; Staining method; Stains; T memory cell; T-Lymphocyte; Techniques; Testing; Therapeutic; Therapeutic immunosuppression; Time; Toxic effect; Transplantation; Transplantation Tolerance; Tryptophan 2,3 Dioxygenase; base; cellular development; cost; cytokine; glucose monitor; in vivo; indoleamine; mortality; prevent; public health relevance; response; success; therapy design; trafficking

DESCRIPTION (provided by applicant): Approximately 7% of the US population suffers from diabetes, a chronic disease with significant morbidity and mortality. Pancreatic islet-cell transplantation poses an ideal therapy that would relinquish dependence on daily insulin injection and blood glucose monitoring, and would prevent the devastating consequences of diabetes. The discovery that dendritic cells (DC) can tolerize an immune response heralded the potential therapeutic value of DC rendered maturation resistant (MR) in islet-cell allograft transplantation. This proposal aims to use adoptively transferred vitamin D3 generated MRDC to indefinitely prolong islet-cell allograft survival, and to determine the effect of MRDC therapy on naive and memory CD4 and CD8 T cell alloresponses through the direct (T cells recognize donor MHC) and indirect (T cells recognize self-MHC presenting donor allopeptide) pathways of allorecognition. Further, this proposal aims to investigate the fate of adoptively transferred donor DC, elucidate the mechanism(s) by which donor DC are reprocessed by recipient APC into alloantigen (Ag), and determine the duration of alloAg presentation that results. Finally, it aims to study the role that the inhibitory mediators programmed cell death ligand 1 and indoleamine 2,3- dioxygenase play in inducing allograft tolerance. This study utilizes numerous types of genetically modified mice to definitively investigate the above stated aims, including TCRtg mice whose CD4 or CD8 T cells are specific for alloAg. Techniques to be used include but are not limited to flow cytometry, immunofluorescent staining and fluorescent microscopy, cell culture, ELISA, in vivo proliferation assay and islet-cell transplantation. The proposed study will allow for evaluation of DC therapy clinical utility over other cellular therapies, and for design of protocols using DC therapy in conjunction with sub-therapeutic immunosuppressive agents to indefinitely prolong islet-cell allograft survival. Further, it will elucidate the mechanism(s) of in vivo tolerance induction, an important area of research in the setting of transplantation and autoimmunity. PUBLIC HEALTH RELEVANCE: Diabetes is a devastating chronic disease for which the only currently available cure is islet-cell transplantation. The lack of success of islet-cell transplantation is largely attributable to the toxicity of immunosuppressive agents used to prevent allograft rejection. Therefore, the development of cellular based therapies that prolong islet-cell transplant survival by inducing donor-specific tolerance without side effects is clearly advantageous.

描述（由申请人提供）：大约7%的美国人口患有糖尿病，这是一种具有显著发病率和死亡率的慢性疾病。胰岛细胞移植提供了一种理想的治疗方法，它将放弃对每日胰岛素注射和血糖监测的依赖，并将防止糖尿病的破坏性后果。树突状细胞（DC）能够耐受免疫应答的发现预示着DC成熟抵抗（MR）在胰岛细胞同种异体移植中的潜在治疗价值。本研究旨在利用过继性转移的维生素D3生成的MRDC无限期延长胰岛细胞异体移植存活时间，并通过直接（T细胞识别供体MHC）和间接（T细胞识别自身MHC呈递供体异体肽）途径确定MRDC治疗对初始和记忆CD4和CD8 T细胞异体反应的影响。此外，本研究旨在研究供体DC的命运，阐明供体DC被受体APC再加工成同种异体抗原（Ag）的机制，并确定同种异体抗原呈递的持续时间。最后，研究抑制介质程序性细胞死亡配体1和吲哚胺2,3-双加氧酶在诱导同种异体移植物耐受中的作用。本研究利用多种类型的转基因小鼠来明确地研究上述目标，包括CD4或CD8 T细胞对同种异体抗原特异性的TCRtg小鼠。使用的技术包括但不限于流式细胞术、免疫荧光染色和荧光显微镜、细胞培养、ELISA、体内增殖试验和胰岛细胞移植。拟议的研究将允许评估DC治疗与其他细胞治疗的临床效用，并设计使用DC治疗与亚治疗性免疫抑制剂联合使用的方案，以无限期延长胰岛细胞移植存活。此外，它将阐明体内耐受诱导的机制，这是移植和自身免疫环境下的一个重要研究领域。