权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Pathogenesis of lung injury mediated by lung-restricted antibodies

肺限制性抗体介导的肺损伤的发病机制

基本信息

批准号：
10673371
负责人：
Ankit Bharat
金额：
$ 71.16万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673371
关键词：
Acute Respiratory Distress Syndrome Affect Allografting Alveolar Alveolar Macrophages Antibodies Antigen-Antibody Complex Antigens Autoantibodies Autoantigens Award Binding Biological Assay COVID-19 CXCL2 gene Cells Chronic Chronic lung disease Clinical Clinical Research Collagen Type V Complement Complement Activation Complication Data Development Endothelium Epitopes Extracellular Matrix Proteins Extravasation Fc Receptor Flow Cytometry Functional disorder Funding High Prevalence Hour Human Image Immune Incidence Industry Collaboration Knockout Mice Life Ligation Link Lung Lung Transplantation Matrix Metalloproteinases Mediating Molecular Mus Mutate Neutrophil Collagenase Neutrophil Infiltration Organ Organ Transplantation Outcome PIK3CG gene Pathogenesis Pathway interactions Patient Care Patients Pattern Perfusion Permeability Postoperative Period Production Publishing Reaction Reperfusion Injury Risk Role Severities Signal Pathway Signal Transduction Solid Spleen TLR2 gene Testing Translating Transplant Recipients Transplantation Tubulin Variant Vascularization Work allograft rejection clinical application clinically actionable conditional knockout cytokine end stage disease graft dysfunction immunogenic improved insight lung allograft lung injury migration monocyte mortality mouse model neutrophil novel prospective reconstitution recruit response single-cell RNA sequencing two-photon

项目摘要

Primary graft dysfunction (PGD) affects over 50% of recipients within the first 24-72 hours after lung transplantation. PGD is the dominant risk for post-lung transplant mortality, transplant-associated multi-organ dysfunction, and chronic lung allograft rejection. Since lung transplantation is increasingly utilized as a life-saving treatment for both chronic lung diseases as well as acute respiratory distress syndrome, mitigation of PGD represents a critical component of a multi-pronged strategy to improve transplant outcomes. In a prospective clinical study, we found that over 30% of patients undergoing lung transplantation have lung- restricted autoantibodies (LRA) against self-antigens, collagen type V and k-alpha 1 tubulin, which was strongly associated with the development of PGD. Pre-existing LRA is associated with complement activation, neutrophil recruitment, a lower PaO2/FIO2 and worsened lung injury, all clinical hallmarks of PGD. In parallel work, we identified an important role for donor derived non-classical monocytes (NCM) that are retained in the lung grafts after perfusion in the development of PGD. Donor derived NCM sense damage associated molecular patterns (DAMPs) via redundant signaling through TLR2/4 to release CXCL2 and other cytokines that directly recruit neutrophils to the allograft and activate donor alveolar macrophages to recruit recipient classical monocytes stored in the spleen. Upon migration to the lung graft, the recipient classical monocytes (CM) permeabilize the pulmonary endothelium and amplify the extravasation of neutrophils to the alveolar space. Our published and preliminary data suggest important interactions between LRA, donor derived NCM and recipient derived CM in determining the severity of lung injury after lung transplantation. Specifically, we found that LRA bind Fc receptors on donor derived NCM to promote their retention in the allograft and activation. This enhances the recruitment of CM to the allograft which release IL-1. Permeabilization of the endothelium in response to IL-1 allows LRA access to the lung interstitium and promotes neutrophil migration into the alveolar space. In addition, CM release matrix metalloproteinase-8 (MMP8), which cleaves extracellular matrix proteins to release sequestered self-antigens and expose their immunogenic epitopes, enabling the extravasated LRA to form immune complexes. The resulting immune complexes activate complement to exacerbate lung injury in the first 24 hours after lung transplantation. Further preliminary data suggest LRA immune complexes activate donor derived NCM to release CXCL2 and promote neutrophil recruitment via a pathway that requires Src, PI3K and BTK but is independent of the TLR2/4/MyD88 pathway activated by DAMPs, resulting in delayed lung injury in the 48 to 72 hours after transplant. We will test the hypothesis that LRA interact with donor derived NCM and recipient CM to worsen PGD via complement dependent and independent pathways. Aim 1. To determine the mechanisms through which LRA activate NCM. Aim 2. To determine the role of IL-1 and MMP-8 released from recipient CM in the cleavage of sequestered self-antigens and their binding to LRA.

原发性移植物功能障碍（PGD）在术后24-72小时内影响超过50%的受者