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（由申请人提供）：同种异体骨髓移植（ABMT）可以作为治疗多种血液恶性肿瘤的疗法来挽救生命。 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（特别是侵袭性曲霉病，IA）和移植物抗宿主病（GVHD）的发展。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 的疗效。详细了解 ABMT 的基本生物学方面将有助于确定开发创新疗法的相关靶点。在此应用中，我们试图通过检查 CCR2+ 炎症单核细胞和 CCR2+ 单核细胞衍生的树突状细胞 (Mo-DC) 在没有 GVHD 的 ABMT 背景下防御真菌感染的具体贡献，进一步加深我们对 ABMT 的了解。在初步研究中，我们采用了一种新型小鼠品系，该品系可以选择性去除 CCR2+ 单核细胞，以揭示 CCR2+ 炎症性单核细胞在防御 IA 中先前未识别的重要作用。根据我们已发表和未发表的观察结果，拟议的研究将检验两个主要假设： 1) ABMT 由于 CCR2+ 单核细胞重建和/或功能受损而导致 IA 易感性增强 2) ABMT 和 GVHD 由于保护性真菌特异性 CD4 T 细胞激活受损而导致 IA 易感性增强 回应。拟议的研究将通过使用有助于选择性追踪和消除 CCR2+ 炎症单核细胞和 Mo-DC 的新型小鼠品系来实现。我们还将利用我们之前开发的模型来跟踪真菌特异性 CD4 T 细胞反应的体内发育，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显着增进我们对 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，我们相信 我们的研究将揭示 ABMT 背景下新的易感性机制，并为未来利用炎症单核细胞预防 ABMT 患者危及生命的真菌感染的转化研究奠定基础。