Surgeon-dependent histopathological variations in minor alloantigen-mismatched mouse lung transplantation
Mitsuaki Kawashima,
Jillian D. Oliver,
Tatsuaki Watanabe,
Hisashi Oishi,
Ning Huang,
Chihiro Konoeda,
Shin Hirayama,
David M. Hwang,
Qixuan Li,
Ella Huszti,
Mingyao Liu,
Shaf Keshavjee,
Stephen Juvet,
Tereza Martinu
Affiliations
Mitsuaki Kawashima
Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, Ajmera Transplant Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
Jillian D. Oliver
Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, Ajmera Transplant Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
Tatsuaki Watanabe
Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, Ajmera Transplant Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
Hisashi Oishi
Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, Ajmera Transplant Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
Ning Huang
Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, Ajmera Transplant Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
Chihiro Konoeda
Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, Ajmera Transplant Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
Shin Hirayama
Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, Ajmera Transplant Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
David M. Hwang
Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Hospital, Toronto, Ontario, Canada
Qixuan Li
Biostatistics Research Unit, University Health Network, Toronto, Ontario, Canada
Ella Huszti
Biostatistics Research Unit, University Health Network, Toronto, Ontario, Canada
Mingyao Liu
Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, Ajmera Transplant Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
Shaf Keshavjee
Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, Ajmera Transplant Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
Stephen Juvet
Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, Ajmera Transplant Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Division of Respirology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
Tereza Martinu
Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, Ajmera Transplant Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Division of Respirology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Corresponding author: Tereza Martinu, Toronto Lung Transplant Program, University Health Network, University of Toronto, 585 University Ave, MARS-9092, Toronto, ON M5G 2N2, Canada.
Background: The mouse orthotopic single lung transplant (LTx) model is an important scientific tool to explore LTx immunology. C57BL/10J (B10, H-2b) to C57BL/6J (B6, H-2b) minor alloantigen-mismatched LTx exhibits mild acute rejection and chronic fibrosis, mimicking human LTx, where acute rejection is dampened by immunosuppressants and chronic lung allograft dysfunction (CLAD) develops over time. However, we have observed variations in allograft histology across experiments, which were not explained by animal vendor or experimental conditions. The purpose of this study was to evaluate those variations objectively. Methods: We performed a retrospective review of B10-to-B6 LTx performed in our laboratory 2012-2019. Only LTx without experimental interventions (eg, immunomodulatory agents or genetic modifications) examined at day 28 was eligible for this study. Mice from each surgeon were selected and divided into 3 groups to represent early, middle, and late timepoints in their mouse LTx experience (143 LTx from 5 surgeons). Histology from these LTx was graded in a randomized and blinded manner. Pathological variations and trajectories were graphed; logistic regression analyses were performed for statistical assessment. Results: Distribution and trajectories of pathological outcomes were significantly different across surgeons. In multivariable logistic regression analyses, surgeon was associated with pathological outcomes whereas case number was not. Longer warm ischemia time was associated with more severe pleural fibrosis. Conclusions: The B10 to B6 single LTx model can be a powerful tool to recapitulate CLAD-like histology. However, this is a challenging operation and surgeon-dependent variability in histopathological findings needs to be taken into account when designing experimental protocols.
