Chronic rejection of experimental lung allografts
Zusammenfassung der Projektergebnisse
The outcome of lung transplantation is poor. Bronchiolitis obliterans (BO), which is defined clinically as a decline in lung function post-transplantation, limits the long-term survival of graft recipients. The pathogenesis of BO is poorly understood and no effective therapies exist. Acute rejection episodes and infections are important risk factors for the development of BO. This leads to the hypothesis that reversible acute rejection predisposes the allograft to an excessive response to a second inflammatory stimulus resulting in BO. The aim of the project was to characterize a new experimental rat model for BOS. Experimental BOS involves allogeneic left lung transplantation, suboptimal immunosuppression and intratracheal application of the bacterial cell wall component lipopolysaccharide (LPS) four weeks after transplantation to mimic alloimmuneindependent pulmonary inflammation. Within three months post-transplantation, lung allografts treated with LPS are consistently remodeled. In contrast, in isografts and control-treated allografts chronic damage was rare. We characterized the histopathological changes during chronic rejection of rat lung allografts and found signs of moderate acute rejection before LPS application. Inflammation was dramatically increased in pulmonary allografts in response to LPS- application, but was markedly milder in isografts and right native lungs of graft recipients. Allograft remodeling started as early as 12 days after LPS-application. Three weeks post-transplantation, the histopathology of experimental lung allografts was characterized by fibrotic scar tissue surrounding arteries and bronchioles as well as fibrotic changes in alveolar walls. These changes closely resembled human end-stage BOS as revealed by a direct comparison of patient and experimental allografts. Allogeneic lung transplantation resulted in local but not in systemic Th1-type immune reactions, including over-expression of chemokines, which are known to predict human BOS, and in an increased expression of the Toll-like receptor system, which is needed to sense LPS. Surprisingly, LPS application did not further augment T cell alloreactivity. Instead, the innate immune system of the lung mounted an exaggerated response and destructive effector molcules were expressed. We conclude that our experimental model for BOS is of clinical relevance and will be a valuable tool to further elucidate the enigmatic pathogenesis of BOS. Our data already suggest that prevention of BOS might be accomplished by local rather than systemic suppression of Th1 cells in stable grafts and by controlling innate immunity during alloimmune-independent pulmonary inflammation.
Projektbezogene Publikationen (Auswahl)
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(2011) Protective role of Apolipoprotein E in an experimental model of acute renal allograft rejection. Transplant Int 24 (Suppl.3): 33
Zakrzewicz A, Atanasova S, Wilker S, Padberg W, Grau V
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(2012) A new experimental model for chronic lung allograft damage. Pneumologie 66: 384-385
Atanasova S, Evers A, Fuchs G, Petri K, Obert M, Fischer-Heuschkel A, Rabin L, Hirschburger M, Padberg W, Grau V
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(2013) A relevant experimental model for human Bronchiolitis Obliterans Syndrome. J Heart Lung Transplant 32:1131-1139
Atanasova S, Hirschburger M, Jonigk D, Obert M, Petri K, Evers A, Hecker A, Schmitz J, Kaufmann A, Wilhelm J, Chakraborty T, Warnecke G, Gottlieb J, Padberg W, Grau V
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(2013). Apolipoprotein E attenuates acute rejection of experimental renal allografts. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI)
Zakrzewicz A, Atanasova S, Zakrzewicz D, Fuchs-Moll G, Wilker S, Petri K, Padberg W, Grau V
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(2013). ATP-mediated inflammasome activation is efficiently inhibited by acetylcholine . Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI)
Kuellmar M, Hecker A, Wilker S, Atanasova S, Zakrzewicz A, Meixner M, Kaufmann A, Kummer W, Padberg W, Grau V
