Graft extracellular vesicles as promoters of anti-donor immunity in cardiac and skin transplantation

移植细胞外囊泡作为心脏和皮肤移植中抗供体免疫的促进剂

• 批准号: 10560271
• 负责人: Adrian E. Morelli
• 金额: $ 65.59万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560271
• 关键词: Adult; Affect; Allogenic; Allografting; Antigen-Presenting Cells; Antigens; Apoptotic; B-Lymphocytes; Biogenesis; Biological Markers; Biology; Blood group antigen S; Cardiac; Cardiovascular system; Caring; Cells; Childhood; Chronic; Clinical; Communication; Development; Disease; Disease Marker; Distant; Electron Microscopy; Experimental Models; Family; Future; Generations; Genetically Engineered Mouse; Goals; Graft Rejection; Heart; Heart Transplantation; Heart failure; Human; Immune; Immune response; Immune system; Immunity; Immunosuppression; Immunosuppressive Agents; In Situ; Intervention; Investigation; Knowledge; Lead; Leukocytes; Lipids; Lung; Lymphoid Tissue; MHC antigen; Malignant Neoplasms; Mediating; Mediator of activation protein; Medical; Messenger RNA; Methodology; Mus; Organ; Patients; Peptides; Proteins; Regimen; Resolution; Risk; Role; Secondary to; Signal Transduction; Skin; Skin Transplantation; Structure of germinal center of lymph node; T memory cell; T-Lymphocyte; Testing; Therapeutic immunosuppression; Tissue Grafts; Tissue Transplantation; Transplantation; Travel; Untranslated RNA; Vesicle; adaptive immune response; allograft rejection; base; bioimaging; clinically relevant; conditioning; exosome; extracellular vesicles; heart allograft; horizontal cell; humanized mouse; immunoreaction; immunoregulation; improved; in vivo; infection risk; isoimmunity; microvesicles; mouse model; novel; novel therapeutic intervention; prevent; promoter; response; side effect; skin allograft; translational model; transplant model; two photon microscopy; vesicular release

SUMMARY The innate and adaptive immune response against allografts is the main impediment to successful transplantation. Heart transplantation is the best option for selected pediatric and adult patients with end-stage heart failure, however, the threat of rejection remains high, despite improvements in immunosuppressive therapies, conditioning regimens and medical care. Importantly, currently used interventions are not donor-specific and therefore may cause increased risk of infections and cancer. A deeper understanding of the basis of allo-recognition is needed for the development of novel donor-specific therapies to treat graft rejection minimizing the harmful side effects. Recent studies have challenged the dogma that initiation or re-activation of anti-donor immunity in graft- draining secondary lymphoid tissues (SLTs) depends mainly on donor Ag-presenting cells (APCs) mobilized from the grafts. Increasing evidence and our preliminary studies indicate that heart and non-vascularized skin allografts release extracellular vesicles (EVs) carrying donor-Ag that traffic to the SLTs where the graft EVs stimulate donor- reactive B cells and T cells. Despite increasing information during the past 5 years on the role of graft EVs on elicitation of anti-donor immunity and their potential use as biomarkers in transplantation, the mechanisms in vivo by which graft EVs interact with recipient’s immune cells in graft-draining SLTs and promote anti-donor immunity remain largely unknown. The family of EVs encompasses vesicles with different biogenesis, size and composition that includes exosomes and microvesicles. Although growing evidence indicates that EVs represent a mechanism by which cells horizontally transfer proteins, mRNAs, non-coding RNAs and lipids, the function of EVs in vivo remains an enigma. Therefore, we propose to investigate the mechanisms in vivo by which graft EVs initiate or re-activate in graft-draining SLTs, the innate and adaptive immune responses that lead to rejection of allografts. We will analyze these mechanisms in mouse experimental models of cardiac and non-vascularized skin allografts. We hypothesize that “graft EVs constitute a cell-free platform that by multiple mechanisms initiates or re-activates the anti-donor immune response in the recipient’s SLTs”. This application will investigate these mechanisms in situ and in vivo using transplant models in mice and a translational model in humanized mice. We will test our hypothesis in the following aims: Aim 1 will investigate the origin of graft EVs and their effects on recipient APCs in graft-draining SLTs, Aim 2 will analyze the mechanisms by which graft EVs generate anti-donor B cell immunity in SLTs and Aim 3 will analyze how graft EVs elicit anti-donor T cell immunity in SLTs and its relevance to transplantation in humans. Our long-term goal is to understand how graft EVs function in vivo to provide new grounds for development of EV-based therapies and disease markers of clinical relevance to transplantation and immune-mediated disorders.

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