Tolerogenic DC as Therapeutic Agents in GVHD

耐受性 DC 作为 GVHD 的治疗剂

基本信息

批准号：
7876846
负责人：
EUGENE C BUTCHER
金额：
$ 35.8万
依托单位：
PALO ALTO VETERANS INSTIT FOR RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-19 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7876846
关键词：
Abbreviations Allergic Allogenic Antibodies Antigen-Presenting Cells Antigens Autoimmune Process Award Biotin Bone Marrow CCL25 gene CCR9 gene CD4 Positive T Lymphocytes Cell Transplantation Cells Cessation of life Chlorophyll Clonal Deletion Comparative Study Cutaneous Cytotoxic T-Lymphocytes DNA Nucleotidylexotransferase Dendritic Cells Deoxyguanosine Dermal Development Disease model Effectiveness Enzyme-Linked Immunosorbent Assay Esters Fluorescein Fluorescein-5-isothiocyanate Fluoresceins Freund&apos s Adjuvant Generations Genes Goals Granulocyte-Macrophage Colony-Stimulating Factor High Endothelial Venule Histocytochemistry Home environment Homeostasis Homing Human Immigration Immune Immune System Diseases Immune Tolerance Immune response Immune system Immunity Immunoglobulins Immunosuppression Immunosuppressive Agents Immunotherapy In Situ Nick-End Labeling In Vitro Insulin Integrins Interferons Interleukins Isothiocyanates Knock-out Label Lamina Propria Lead Ligands Lipopolysaccharides Lymphoid Tissue Maintenance Major Histocompatibility Complex Mediation Mesentery Modeling Molecular Monoclonal Antibodies Mus Myelogenous Nose Ovalbumin Pathology Patients Peripheral Peritoneal Phenotype Phycoerythrin Population Principal Investigator Production Property Propidium Diiodide Proteins Rattus Regimen Regulation Regulatory T-Lymphocyte Role Serum Serum Albumin Signal Transduction Small Intestines Solutions Structure of aggregated lymphoid follicle of small intestine T-Cell Receptor T-Lymphocyte TNF gene TSLP gene Testing Tetradecanoylphorbol Acetate Therapeutic Therapeutic Agents Thrombospondin 1 Thymus Gland Tissue Transplantation Tissues Toll-like receptors Transforming Growth Factors Transplantation Tumor Necrosis Factor-alpha Tumor Necrosis Factors Vascular Endothelial Growth Factor Receptor-1 Venous allophycocyanin carboxyfluorescein central tolerance chemokine receptor conditioning cytokine experience fetal graft vs host disease human TSLP protein in vivo indoleamine insight leukemia lymph nodes novel strategies programs promoter receptor recombinase reconstitution research study response salt balance thymocyte tumor

项目摘要

Program Director/Principal Investigator (Last, First, Middle): Butcher, Eugene C. 1R01 AI082318-01 Our goal for this 2 year award is to define in detail the therapeutic potential of recently identified tolerogenic DC populations in graft versus host disease (GVHD). We have recently identified CCR9- expressing plasmacytoid DCs as an extremely potent tolerogenic subset of DCs. Our initial studies indicate that viable allogeneic CCR9+ pDCs inhibit GVHD in irradiated recipients reconstituted with allogeneic bone marrow and effector CD4+ T cells. Here, tolerogenic pDC requirements for effectiveness and durability of induced allo-specific tolerance in the GVHD model will be characterized in studies examining a) the role of pDC numbers in the context of optimal myeloablative recipient conditioning regimens, b) the ability of fixed or non-proliferative tolerogenic pDCs to suppress GVHD, and c) the role of CCR9 itself in tolerance induction. To test the hypothesis that pDCs are uniquely suited to GVHD treatment, the GVHD-suppressing potential of these highly tolerogenic pDCs will be compared to that of a putative tolerogenic myeloid DC population. Graft vs host responses are deleterious when directed at normal host tissues, but can be beneficial in therapeutic anti-tumor (graft vs tumor or GVT) regimens. Regulatory T cells (Tregs) can control systemic GVHD while allowing GVT activity. To test the hypothesis that CCR9+ pDCs can suppress GVHD without abrogating GVT, experiments will be carried out in a mouse leukemia model. Together, these studies will define in detail the potential of CCR9+ pDCs to suppress deleterious effects of GVHD in settings modeling situations in which human patients encounter pathogenic GVHD responses.

项目总监/首席研究员（最后，第一，中间）：Butcher，Eugene C. 1R01 AI082318-01 我们这2年奖的目标是详细定义最近确定的GRAFT与宿主疾病（GVHD）的耐受性DC种群的治疗潜力。我们最近确定了表达浆细胞类动物DC的CCR9是DC的极有效的耐受性子集。我们的初步研究表明，可行的同种异体CCR9+ PDC抑制了与同种异体骨髓和效应子CD4+ T细胞重构的受照射受体中的GVHD。在此，将在研究中对GVHD模型中诱导的异型特异性公差的有效性和耐用性的耐受性PDC要求进行表征a）a）PDC数量在最佳的骨髓性受体调节方案中的作用，b）固定耐受性PDC的能力，以抑制固定耐受性PDC的能力，以抑制gvhd and ccr ccr ccr ccr ccr ccr cccr cccr cccr cccr cccr ccccr cccr cccr cccr cc）ca）。为了检验PDC非常适合GVHD处理的假设，将将这些高耐受性PDC的GVHD抑制潜力与推定的耐受性髓样DC种群进行比较。当针对正常宿主组织时，移植物与宿主反应是有害的，但可能对治疗性抗肿瘤（移植物与肿瘤或GVT）方案有益。调节性T细胞（Tregs）可以在允许GVT活性的同时控制全身GVHD。为了测试CCR9+ PDC可以抑制GVHD而不会废除GVT的假设，将在小鼠白血病模型中进行实验。总之，这些研究将详细定义CCR9+ PDC抑制GVHD在设置建模情况下的有害影响的潜力，在这种情况下，人类患者遇到致病性GVHD反应。