Mechanisms of alloantibody production following renal transplantation

肾移植后同种抗体产生的机制

• 批准号: 10357956
• 负责人: Anna Valujskikh
• 金额: $ 62.1万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-22 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10357956
• 关键词: Acute; Address; Affect; Affinity; Alloantigen; Allografting; Anatomy; Animals; Antigen-Presenting Cells; Antigens; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Blood; Blood Vessels; CD80 Antigens; Cadaver; Cardiovascular Diseases; Cell Adhesion Molecules; Cell Maturation; Cell physiology; Cells; Cellular biology; Chronic; Chronic Kidney Failure; Clinical; Clinical Data; Clinical Research; Data; Endothelial Cells; Endothelium; Epithelial Cells; Generations; Histocompatibility Antigens Class II; Human; Immune; Immunoglobulin Class Switching; Impairment; Inflammation; Inflammatory; Injury; Investigation; Ischemia; Isoantibodies; Kidney; Kidney Transplantation; Knowledge; Ligands; Location; Lymphocyte Activation; MHC Class II Genes; Mediating; Mus; Natural Immunity; Organ Donor; Organ Transplantation; Outcome; Pathogenicity; Patients; Prevention; Production; Reperfusion Injury; Risk; Risk Factors; Role; Series; Signal Transduction; Source; Spleen; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Therapeutic Intervention; Time; Transplant Recipients; Transplantation; adaptive immune response; adaptive immunity; antibody-mediated rejection; assault; base; chemokine; cytokine; exosome; extracellular vesicles; graft failure; high risk; improved outcome; inhibiting antibody; isoimmunity; kidney allograft; mortality; mouse model; pathogen; post-transplant; receptor; response; targeted treatment; tissue injury; trafficking

ABSTRACT Acute and chronic antibody-mediated rejection (AMR) is a serious threat to the survival and function of transplanted organs. The current options for AMR prevention and treatment are limited by the incomplete understanding of the mechanisms underlying donor specific alloantibody (DSA) generation and pathogenic functions. Whereas the production of high affinity isotype-switched DSA is typically associated with germinal center formation by follicular B cells, the contribution of marginal zone (MZ) B cells to anti-donor responses following transplantation has not been previously addressed. Our preliminary studies identify MZ B cells as important players in orchestrating DSA responses and warrant detailed investigation of this B cell subset with an ultimate objective of reducing humoral alloimmunity in transplant recipients. Prolonged cold ischemia storage (CIS) of donor allografts and ensuing ischemia/reperfusion injury (IRI) remain among leading risk factors for poor transplant outcome. Using a mouse model of kidney transplantation in which allografts are subjected to 6 h CIS, we found that posttransplant inflammation specifically augments generation of class II-reactive DSA that mediate allograft glomerular injury. These findings are highly relevant to clinical studies revealing correlations between longer cold ischemia time, anti-class II DSA and late AMR in renal transplant patients. However, the mechanisms by which posttransplant inflammation affects generation of pathogenic class II DSA and the very source of donor class II antigens for B cell activation are poorly defined. Based on our preliminary data, we hypothesize that IRI amplifies class II DSA production through the following steps: 1) IRI up-regulates MHC class II expression on donor endothelial cells (EC) and EC release of class II containing extracellular vesicles (EEVs); 2) spleen MZ B cells rapidly acquire circulating EEVs, produce early DSA and facilitate further DSA production by FO B cells; and, 3) in addition to donor alloantigens, MZ B cell activation is initiated and enhanced by DAMPs carried by graft-derived EVs as well as by systemic effects of IRI. Therefore, targeting MZ B cell trafficking, activation and functions will inhibit generation of pathogenic class II DSA and improve outcome of renal allografts subjected to prolonged CIS. We will test this hypothesis in three Specific Aims: Aim 1. To test whether ischemia/reperfusion injury (IRI) augments class II DSA by enhancing endothelial extracellular vesicles (EEV) generation. Aim 2. To test the role of MZ B cells in DSA production following renal transplantation. Aim 3. To investigate the contribution of MZ B cells in the generation of pathogenic class II DSA after prolonged cold ischemia storage of renal allografts. The proposed studies will fill several gaps in current knowledge of humoral alloimmune responses to vascularized organ transplants and identify potential targets of therapeutic intervention to inhibit antibody- mediated rejection.

摘要