Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall D1
Introduction: Organ fibrosis and vasculopathy are major causes of chronic cardiac allograft failure. Resident (donor-derived) fibroblasts are thought to be mainly responsible for excessive production of matrix proteins. We recently showed that basophils, as producers of pro-fibrotic cytokines, trigger the production of various connective tissue elements by fibroblasts in chronic allograft fibrosis. Little is known about the role of IL-3, a strong activator of basophils, in organ fibrosis.
Method: We have studied this question in a fully MHC mismatched model of heart transplantation with transient depletion of CD4+ cells to largely prevent acute rejection. This model is characterized by myocardial infiltration of leukocytes and development of interstitial fibrosis and allograft vasculopathy within 20 days. In order to study the role of IL-3 for the development of allograft fibrosis, we used IL-3+/- and IL-3-/- recipient mice. Before transplantation basophils were depleted with an mAb against FcεR1, the high affinity IgE-receptor, or with an antibody against anti-CD200R3. Fibroblasts were identified by flow cytometry (CD45– Collagen-type-1+ cells) and via immunohistochemistry (by expression of αSMA).
Results: IL-3 was produced in large quantities in allogeneic transplanted hearts compared to syngeneic controls. Diminished production of IL-3 in recipient mice during development of organ fibrosis reduced vasculopathy and deposition of Collagen-type-1. We demonstrate that fibrotic remodelling of chronically rejected allografts is a process involving the IL-3 dependent activation of basophils and infiltration into the allograft with production of pro-fibrotic cytokines and the subsequent activation of resident fibroblasts leading to destruction of the normal tissue architecture.
Conclusion: We show that IL-3 is important for activation of fibroblasts and production of matrix proteins leading to chronic allograft tissue fibrosis and vasculopathy. IL-3 activates pro-fibrotic signalling pathways and basophils. Hence, IL-3 represents a promising target for future therapies to prevent chronic allograft fibrosis.
CITATION INFORMATION: Schiechl-Brachner G, Rodriguez Gomez M, Renner K, Buchtler S, Schmidbauer K, Halbritter D, Neumayer S, Talke Y, Bruehl H, Mack M. IL-3 Contributes to Development of Basophil-Triggered Cardiac Allograft Fibrosis Development. Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Schiechl-Brachner G, Gomez MRodriguez, Renner K, Buchtler S, Schmidbauer K, Halbritter D, Neumayer S, Talke Y, Bruehl H, Mack M. IL-3 Contributes to Development of Basophil-Triggered Cardiac Allograft Fibrosis Development. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/il-3-contributes-to-development-of-basophil-triggered-cardiac-allograft-fibrosis-development/. Accessed January 19, 2020.
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