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Principal Investigator: Mark Eugene Snyder
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $715,793
Funding agency: National Heart Lung and Blood Institute
Project Summary
Lung transplantation remains the only definitive treatment for many patients with end stage lung disease.
However, the outcomes after lung transplant are meager when compared to other solid organ transplants, with
a median survival of only 6 years. The major limiting factor to long-term survival after lung transplantation is the
high incidence of chronic lung allograft dysfunction (CLAD), a progressive form of a lung allograft failure
associated with high morbidity and mortality affecting half of all transplant recipients by 5 years. Episodes of
acute cellular rejection, a T cell mediated allo-immune inflammation of the lung allograft, are associated with
increased risk of CLAD. Our group previously showed that T cells recruited to the lung during acute cellular
rejection persist within the allograft as tissue resident memory T cells (TRM) and that these TRM migrate to the
airways, the site of tissue pathology in CLAD. The focus of this application is to identify whether lung allograft
TRM are alloreactive and how TRM may interact with their local environment to contribute to the development of
CLAD. Importantly, our preliminary data suggests that systemic immune modulators do not impact lung TRM in
the same way that they effect circulating immune cells. This application plans to advance our understanding of
how commonly used immunosuppressants, like alemtuzumab, basiliximab, glucocorticoids, and cyclosporine
impact the phenotype, function, and persistence of lung TRM compared to circulating T cells. Our research aims
include: 1) Identify the alloreactive potential of recipient-derived allograft TRM in lung transplant recipients with
and without CLAD; 2) Establish the role of lung resident myeloid cells in the maintenance of alloreactive recipient-
derived lung TRM; and 3) Determine the impact of systemic and inhaled immune modulators on lung TRM
persistence and function. The results of these investigations explore a mechanism where alloreactive T cells
contribute to CLAD and elucidate how existing immune modulators impact TRM phenotype and function.
Terms: <Acute><Affect><Airway Fibrosis><Airway scar><Allografting><Anatomic Sites><Anatomic structures><Anatomy><Anti-Rejection Therapy><Antigenic Determinants><Assay><B7-H1><B7H1><Binding Determinants><Bioassay><Biological Assay><Biopsy><Body Tissues><Bronchiolitis><Bronchiolitis Obliterans><CD274><CD58><CD58 gene><Cell Body><Cell Communication><Cell Interaction><Cell Locomotion><Cell Migration><Cell Movement><Cell-to-Cell Interaction><Cells><Cellular Migration><Cellular Motility><Chronic><Ciclosporin><Circulation><Clonal Expansion><Computational toolkit><CsA><Cyclosporin A><Cyclosporine><Cyclosporine A><Data><Development><Dysfunction><Environment><Epitopes><Exudative Bronchiolitis><Failure><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Functional disorder><Gene Transcription><Genetic Transcription><Glucocorticoids><Grafting Procedure><Grippe><Human><Immune><Immunes><Immunomodulators><Immunosuppressants><Immunosuppressive Agents><Immunosuppressive Therapy><Immunosuppressive drug><Immunosuppressive treatment><In Vitro><Incidence><Influenza><Inhalation><Inhaling><Injury><Intervention><Intervention Strategies><Investigation><LFA-3><LFA3 Gene><Lead><Lesion><Life><Lung><Lung Diseases><Lung Grafting><Lung Inflammation><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung Tissue Fibrosis><Lung Transplantation><Lymphatic cell><Lymphocyte><Lymphocyte Function-Associated Antigen 3 Gene><Lymphocytic><MHC Receptor><MSK2 Gene><Macrophage><Maintenance><Major Histocompatibility Complex Receptor><Mediating><MoAb CD52><Modeling><Modern Man><Modification><Monoclonal Antibody CD52><Morbidity><Morbidity - disease rate><Myelogenous><Myeloid><Myeloid Cells><Mφ><Non-Polyadenylated RNA><Organ><Organ Transplantation><Organ Transplants><Outcome><PD-L1><PDL-1><PDL1><Pathologic><Pathology><Patients><Pb element><Peptides><Perfusion><Phenotype><Physiopathology><Pneumonitis><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Proliferative Bronchiolitis><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Fibrosis><Pulmonary Graft><Pulmonary Inflammation><Pulmonary Transplant><Pulmonary Transplantation><R-Series Research Projects><R01 Mechanism><R01 Program><RNA><RNA Expression><RNA Gene Products><Receptor Signaling><Research><Research Grants><Research Project Grants><Research Projects><Respiratory fibrosis><Ribonucleic Acid><Risk><Risk Factors><Role><Sandimmun><SangCya><Site><Solid><Specificity><Structure of parenchyma of lung><Syndrome><T cell infiltration><T cell receptor repertoire sequencing><T cell receptor sequencing><T memory cell><T-Cell Antigen Receptors><T-Cell Receptor><T-Cells><T-Lymphocyte><TCR repertoire sequencing><TCR sequencing><TCR-seq><TCRseq><Therapeutic><Therapeutic immunosuppression><Tissues><Transcription><Transplant Recipients><Validation><Viral><airway epithelium inflammation><airway inflammation><alemtuzumab><artificial immunosuppression><basiliximab><cell motility><computational toolbox><computational tools><computational toolset><computerized tools><cross reactivity><developmental><disease of the lung><disorder of the lung><experience><fibrosis in the lung><flow cytophotometry><heavy metal Pb><heavy metal lead><immune modulators><immune suppressive agent><immune suppressor><immunosuppression therapy><immunosuppressive substance><immunosuppressor><improved><injuries><interventional strategy><lung allograft><lung disorder><lung fibrosis><lung transplant><lymph cell><memory T lymphocyte><migration><mortality><neoral><organ allograft><organ graft><organ xenograft><pathogen><pathophysiology><programmed cell death ligand 1><programmed cell death protein ligand 1><protein death-ligand 1><pulmonary><recruit><resident memory T cell><respiratory inflammation><respiratory tract inflammation><retransplantation><sandimmune><scRNA-seq><screening><screenings><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><thymus derived lymphocyte><tissue resident memory T cell><transplant patient><validations>