Document text
Principal Investigator: Anna Valujskikh
Organization: CLEVELAND CLINIC LERNER COM-CWRU
Fiscal Year: 2024
Award: $596,809
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <Acute><Address><Adhesion Molecule><Affect><Affinity><Alloantibodies><Alloantigen><Allografting><Anatomic Sites><Anatomic structures><Anatomy><Animals><Antigen-Presenting Cells><Antigens><B blood cells><B cell><B cells><B-Cell Activation><B-Cell Activation Antigen><B-Cell Subsets><B-Cells><B-Lymphocyte Subsets><B-Lymphocytes><B-cell><B-lymphocyte Activation Antigen B7-1><B7 Antigen><B7-1 Costimulatory Molecule><B7-1 Protein><B71 Antigen><BB-1><Blast Transformation><Blastogenesis><Blood><Blood Reticuloendothelial System><CD28 Antigen Ligand 1><CD80 Antigens><Cadaver><Cardiovascular Diseases><Cell Adhesion Molecule Gene><Cell Adhesion Molecules><Cell Body><Cell Communication and Signaling><Cell Function><Cell Maturation><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular biology><Chemotactic Cytokines><Chronic><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Class II Antigens><Class II Genes><Class II Major Histocompatibility Antigens><Class Switching><Class Switchings><Clinical><Clinical Data><Clinical Research><Clinical Study><Data><Endothelial Cells><Endothelium><Epithelial Cells><Generations><Germinal Center><Grafting Procedure><HLA Class II Genes><Histocompatibility Antigens Class II><Homologous Chemotactic Cytokines><Human><I-A Antigen><Ia Antigens><Ia-Like Antigens><Immune><Immune Response Antigens><Immune-Response-Associated Antigens><Immunes><Immunoglobulin Class Switching><Immunoglobulin Class Switchings><Impairment><Inflammation><Inflammatory><Injury><Innate Immunity><Intercrines><Intracellular Communication and Signaling><Investigation><Ischemia><Ischemia-Reperfusion Injury><Isoantibodies><Isotype Switching><Isotype Switchings><Kidney Grafting><Kidney Transplantation><Kidney Transplants><Knowledge><Ligands><Location><Lymphoblast Transformation><Lymphocyte Activation><Lymphocyte Stimulation><Lymphocyte Transformation><MHC Class II><MHC Class II Genes><MHC Class II Molecule><MHC Class II Protein><MHC class II antigen><Major Histocompatibility Complex Class II><Mediating><Mice><Mice Mammals><Modern Man><Murine><Mus><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Organ Donor><Organ Transplantation><Organ Transplants><Outcome><Pathogenicity><Patients><Prevention><Production><Receptor Protein><Renal Grafting><Renal Transplantation><Renal Transplants><Reperfusion Damage><Reperfusion Injury><Risk><Risk Factors><Role><SIS cytokines><Series><Signal Transduction><Signal Transduction Systems><Signaling><Source><Spleen><Spleen Reticuloendothelial System><Structure of germinal center of lymph node><Subcellular Process><T-Cells><T-Lymphocyte><Testing><Therapeutic Intervention><Time><Transplant Recipients><Transplantation><Vascularization><accessory cell><activated B cells><adaptive immune response><adaptive immunity><alloimmunity><antibody rejection><antibody-mediated rejection><assault><biological signal transduction><cadaveric><cadavers><cardiovascular disorder><cell adhesion protein><cell biology><chemoattractant cytokine><chemokine><chronic kidney disease><cytokine><exosome><extracellular vesicles><graft failure><high risk><immunogen><improved outcome><inhibiting antibody><injuries><injury to tissue><intervention therapy><isoimmunity><kidney allograft><kidney tx><mortality><mouse model><murine model><organ allograft><organ graft><organ xenograft><pathogen><post-transplant><post-transplantation><posttransplant><posttransplantation><receptor><renal allograft><response><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><thymus derived lymphocyte><tissue injury><trafficking><transplant><transplant patient>