The nature of chronic rejection after lung transplantation: a murine orthotopic lung transplant study

Abstract

Chronic rejection; Lung transplantation; Mouse model

Rechazo crónico; Trasplante de pulmón; Modelo de ratón

Rebuig crònic; Trasplantament de pulmó; Model de ratolí

Introduction: Chronic rejection is a major complication post-transplantation. Within lung transplantation, chronic rejection was considered as airway centred. Chronic Lung Allograft Dysfunction (CLAD), defined to cover all late chronic complications, makes it more difficult to understand chronic rejection from an immunological perspective. This study investigated the true nature, timing and location of chronic rejection as a whole, within mouse lung transplantation. Methods: 40 mice underwent an orthotopic left lung transplantation, were sacrificed at day 70 and evaluated by histology and in vivo µCT. For timing and location of rejection, extra grafts were sacrificed at day 7, 35, 56 and investigated by ex vivo µCT or single cell RNA (scRNA) profiling. Results: Chronic rejection originated as innate inflammation around small arteries evolving toward adaptive organization with subsequent end-arterial fibrosis and obliterans. Subsequently, venous and pleural infiltration appeared, followed by airway related bronchiolar folding and rarely bronchiolitis obliterans was observed. Ex vivo µCT and scRNA profiling validated the time, location and sequence of events with endothelial destruction and activation as primary onset. Conclusion: Against the current belief, chronic rejection in lung transplantation may start as an arterial response, followed by responses in venules, pleura, and, only in the late stage, bronchioles, as may be seen in some but not all patients with CLAD.

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. BV, WJ, and GG-R are supported by KU Leuven (C16/19/005; C24/15/030). DEVR is supported by the Broere Foundation. SM and RV are Senior Clinical Research Fellows of the Research Foundation Flanders (FWO; 12G8715N) and are supported by a UZ Leuven research grant (STG15/023). JK, ArV, and VG are Junior Research Fellows of the Research Foundation Flanders (1198920N and 1102020N). SM is supported by grants from UZ Leuven (KOOR) and KU Leuven (C1 funding). GV acknowledges funding by KU Leuven IF (C24/17/061 and STG/15/024).