Although lung transplant rejection has traditionally been thought to occur as a result of host adaptive immuneresponses to alloantigens present in the donor lung, the lung is unique among transplanted organs in itsconstant exposures to environmental stimuli and in its intrinsic innate host defenses. Toll-like receptors(TLRs) expressed on pulmonary cells provide the first line of host defense against foreign pathogens andenvironmental challenges. Our preliminary results demonstrate that polymorphisms of TLR4, which diminishinnate responsiveness, also diminish susceptibility to the development of acute rejection. These TLR4polymorphisms also lead to a reduction in the severity of bronchiolitis obliterans syndrome (BOS), a conditionof chronic allograft rejection associated with airflow obstruction and airway obliteration. Based on theseobservations we hypothesize that activation of innate immunity through TLRs in the transplanted lungpromotes the adaptive alloimmune response that leads to acute rejection and BOS. Further support for thishypothesis is provided by the observation that aerosolized challenge with lipopolysaccharide (IPS), aprototypic trigger of innate immunity, leads to the development of pathological lesions of acute rejection andlymphocytic bronchiolitis in mice that have undergone allogenic bone marrow transplant (BMT). In thisproject we will specifically test the hypothesis that polymorphisms in human TLRs and in related genestranscriptionally activated by LPS regulate the innate response to lung transplant and determine susceptibilityto acute rejection and BOS in the following aims:
Aim 1 will identify polymorphic variants in TLRs and relatedinnate molecules.
Aim 2 will identify polymorphic variations in human candidate genes derivedexperimentally from differential gene expression studies of LPS induced lung rejection in mice.
Aim 3 willgenotype 800 lung transplant recipients and their donors for polymorphic variants in candidate genes.
Aim 4 will determine if allelic variants in candidate genes among lung transplant recipients or their donorssignificantly alters the risk for acute rejection or BOS. Completion of these aims will significantly increase ourunderstanding of innate immune regulation of lung transplant rejection and will provide a basis for thedevelopment of innovative therapeutic strategies to prevent lung transplant rejection. This project will interactwith all cores and include investigations of the TLRs (activated by hyaluronic acid, Project 3) and surfactantproteins A and D (Project 1) in regulating the development of lung transplant rejection.
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