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: 8637016
• 负责人: Amariliz Rivera
• 金额: $ 16.77万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637016
• 关键词: Adverse effects; Affect; African American; Allogeneic Bone Marrow Transplantation; Allogenic; Antifungal Agents; Aspergillosis; Aspergillus; Aspergillus fumigatus; Biological; Biology; Blood; Blood Cells; Bone Marrow; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; Caucasians; Caucasoid Race; Defect; Dendritic Cells; Development; Disease; Figs - dietary; Foundations; Future; Hematologic Neoplasms; Hereditary Disease; Hispanics; Histocompatibility; ITGAM gene; ITGAX gene; Immune; Immunity; Impairment; Infection; Infection prevention; Inflammatory; Innovative Therapy; Kinetics; Knowledge; Lead; Life; Link; Lung; Maintenance; Marrow; Minority; Modeling; Monitor; Mouse Strains; Mus; Mycoses; Neutrophil Infiltration; Outcome; Patients; Play; Predisposition; Prevention; Procedures; Process; Publishing; Registries; Risk; Risk Factors; Role; Shapes; Stem cell transplant; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Th1 Cells; Transgenic Mice; Transplantation; United States; antimicrobial; base; design; fungus; graft vs host disease; improved; in vivo; insight; monocyte; neutrophil; novel; novel therapeutic intervention; pathogen; programs; public health relevance; reconstitution; response; success; translational study

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+ inflammatory monocytes and CCR2+ monocyte-derived dendritic cells (Mo-DCs) in defense against fungal infection in the context of ABMT with our without GVHD. In preliminary studies we have employed a novel mouse strain that allows for the selective depletion of CCR2+monocytes to uncover a previously unidentified essential role for CCR2+inflmmatory monocytes in defense against IA. Based on our published and unpublished observations the proposed studies will test two main hypothesis: 1) ABMT leads to enhanced susceptibility to IA due to impairments in CCR2+monocyte reconstitution and/or function 2) ABMT and GVHD lead to enhanced susceptibility to IA due to impairments in the activation of protective fungus- specific CD4 T cell responses. The proposed studies will be made possible by employing novel mouse strains that facilitate the selective tracking and depletion of CCR2+ inflammatory 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 identify crucial factors that control susceptibility to fungal infection. Moreover, we believe that our studies will uncover novel mechanisms of susceptibility in the context of ABMT and lay the foundation for future translational studies to exploit inflammatory monocytes in the prevention of life-threatening fungal infections in ABMT patients.

描述(申请人提供)：异基因骨髓移植(ABMT)可以是一种挽救生命的程序，作为治疗各种血液系统恶性肿瘤的方法。ABMT的广泛应用受到严重并发症的阻碍，包括危及生命的真菌感染(尤其是侵袭性曲霉病)和移植物抗宿主病(GVHD)的发展。通过新的治疗干预措施改善感染和GVHD副作用，可以更广泛地发挥ABMT的疗效。对ABMT的基本生物学方面的详细了解将有助于确定开发创新疗法的相关目标。在这一应用中，我们试图通过检测CCR2+炎性单核细胞和CCR2+单核细胞来源的树突状细胞(Mo-DC)在无GVHD的ABMT的背景下在抵御真菌感染中的特定贡献来进一步加深我们对ABMT的现有认识。在初步研究中，我们采用了一种新的小鼠品系，该品系允许选择性地耗尽CCR2+单核细胞，以揭示CCR2+炎性单核细胞在防御IA中的先前未知的重要作用。基于我们已发表和未发表的观察，拟议的研究将检验两个主要假设：1)由于CCR2+单核细胞重构和/或功能受损，ABMT和GVHD导致IA易感性增加；2)ABMT和GVHD由于保护性真菌特异性CD4T细胞激活受损，导致IA易感性增加 回应。拟议的研究将通过使用新的小鼠品系来实现，这些品系有助于选择性跟踪和耗尽CCR2+炎性单核细胞和Mo-DC。我们还将利用我们先前开发的模型来跟踪真菌特异性CD4T细胞反应的体内发展，以专门研究ABMT和GVHD对抗真菌免疫发展的影响。总之，拟议研究的成功完成将大大促进我们对ABMT后免疫重建的理解，并确定控制真菌感染易感性的关键因素。此外，我们认为， 我们的研究将揭示ABMT患者易感性的新机制，并为未来利用炎性单核细胞预防ABMT患者威胁生命的真菌感染奠定基础。