Role of CCR2+ monocytes and Mo-DCs in defense against IA and GVHD development

CCR2 单核细胞和 Mo-DC 在防御 IA 和 GVHD 发展中的作用

• 批准号: 8701013
• 负责人: Amariliz Rivera
• 金额: $ 18.23万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701013
• 关键词: Adverse effects; Affect; African American; Allogeneic Bone Marrow Transplantation; Allogenic; Antifungal Agents; Aspergillosis; Bacteria; Biological; Biology; Blood; Blood Cells; Bone Marrow; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; Caucasians; Caucasoid Race; Cells; Dendritic Cells; Development; Disease; Hematologic Neoplasms; Hereditary Disease; Hispanics; Histocompatibility; Immune; Immunity; Impairment; Infection; Infection prevention; Innovative Therapy; Kinetics; Knowledge; Life; Link; Marrow; Minority; Modeling; Monitor; Mouse Strains; Mus; Mycoses; Outcome; Patients; Play; Predisposition; Prevention; Procedures; Process; Registries; Regulation; Risk; Role; Shapes; Staging; Stem cell transplant; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Transgenic Mice; Transplantation; United States; Virus; antimicrobial; design; fungus; graft vs host disease; improved; in vivo; insight; monocyte; novel; novel therapeutic intervention; pathogen; prevent; programs; reconstitution; response; success

DESCRIPTION (provided by applicant): Allogeneic bone marrow transplantation (ABMT) can be a life-saving procedure as therapy against a variety of hematologic malignancies. The broad application of ABMT has been hampered by serious complications including life-threatening fungal infections (especially invasive aspergillosis, IA) and graft versus host disease (GVHD) development. The curative effects of ABMT could be more broadly exploited by ameliorating infection and GVHD side effects through novel therapeutic interventions. A detailed understanding of basic biological aspects of ABMT would facilitate the identification of relevant targets for the development of innovative therapies. In this application we seek to further our current knowledge of ABMT by examining the specific contributions of CCR2+ monocytes and monocyte-derived dendritic cells (Mo-DCs) in defense against fungal infection and in the development of GVHD. In the proposed studies we will test two main hypothesis: 1) monocytes prevent the development of IA after ABMT through direct antifungal effects and by playing non- redundant roles in maintaining T cell responses after ABMT, 2) Mo-DC influence the development of GVHD as donor and/or host derived DCs. The proposed studies will be made possible by employing novel mouse strains that facilitate the selective tracking and depletion of CCR2+ monocytes and Mo-DCs. We will also exploit our previously developed model for tracking the in vivo development of fungus-specific CD4 T cell responses to specifically examine the impact of ABMT and GVHD on the development of antifungal immunity. Altogether, the successful completion of the proposed studies would significantly advance our understanding of immune reconstitution after ABMT and illuminate previously unknown aspects of GVHD development. Moreover, we believe that our studies have the potential to uncover novel contributions of CCR2+ monocytes and derivate cells that could be exploited to prevent life-threatening fungal infections and GVHD development after ABMT.

描述（由申请人提供）：同种异体骨髓移植（ABMT）可以是一种挽救生命的程序，作为针对各种血液学恶性肿瘤的治疗。严重的并发症（包括威胁生命的真菌感染（尤其是侵袭性曲霉菌病，IA），IA）和移植物与宿主疾病（GVHD）发育（GVHD）发育，阻碍了ABMT的广泛应用。通过新颖的治疗干预措施改善感染和GVHD副作用，可以更广泛地利用ABMT的治愈作用。对ABMT的基本生物学方面的详细理解将有助于识别相关的创新疗法的靶标。在此应用中，我们试图通过研究CCR2+单核细胞和单核细胞衍生的树突状细胞（MO-DC）在防御真菌感染和GVHD发展中的特定贡献，以进一步进一步了解ABMT的知识。在拟议的研究中，我们将检验两个主要假设：1）单核细胞通过直接抗真菌效应和通过在ABMT后保持T细胞反应中发挥非冗余作用来阻止ABMT后IA的发展，2）MO-DC影响GVHD作为供体和/或宿主的DCS的发展。提出的研究将通过采用新型的小鼠菌株来促进CCR2+单核细胞和MO-DC的选择性跟踪和耗竭。我们还将利用我们先前开发的模型，用于跟踪真菌特异性CD4 T细胞反应的体内开发，以专门检查ABMT和GVHD对抗真菌免疫发展的影响。总而言之，拟议研究的成功完成将大大提高我们对ABMT和阐明GVHD开发方面未知方面的免疫重建的理解。此外，我们认为我们的研究有可能发现CCR2+单核细胞的新贡献，并衍生出可以利用的细胞，以防止ABMT后威胁生命的真菌感染和GVHD发育。