Lung recipients suffer from shorter life spans and higher rejection rates when compared to other solid organ recipients. Neutrophilia is associated with graft injury but it remains unclear how neutrophils regulate adaptive immune response that control lung transplant tolerance. Recent reports from our laboratory show neutrophils trigger acute rejection by direct interactions between CD11c+ antigen presenting cells and T lymphocytes. However, how neutrophils control chronic rejection, the major cause of death of lung recipients who have had their grafts for more than one year, remains largely unknown. Using a new model of mouse orthotopic lung transplantation and novel intravital imaging techniques new data from our lab indicates that both high neutrophilia and the complete lack of neutrophils promotes chronic rejection in response to airway epithelial injury. Moreover, neutrophils are required to induce immunosuppression-mediated tolerance. In this proposal we will define mechanisms by which neutrophils differentially regulate rejection and tolerance. We have 3 specific aims.
In Aim 1 we will define neutrophil activity that promotes tolerance through analyzing trafficking patterns that promote the removal of injured cells, which we hypothesize prevents chronic rejection. We also determine if the homing of central memory CD8+ T cells to lung allografts, which we have recently shown promotes the induction of immunosuppression-mediated tolerance, is dependent on neutrophils.
In Aim 2 we hypothesize that high neutrophilia triggers chronic rejection through altering the stability of bronchus associated lymphoid tissue, an ectopic lymphoid aggregates that we have shown is associated with tolerance.
In Aim 3, we determine if neutrophils extracellular trap (NET) generation is associated with worse primary graft dysfunction in clinical lung transplant recipients and chronic rejection in the mouse lung transplant model.
Lung transplant recipient is an established therapy for patients suffering from end stage lung disease. However, lung transplant recipient survival is poor compared to recipients of other solid organs. A major obstacle to survival is bronchiolitis obliterans syndrome (BOS). Using novel models of lung transplantation we propose to study how neutrophils regulate the development of BOS.
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