TY - JOUR
T1 - Transcripts associated with chronic lung allograft dysfunction in transbronchial biopsies of lung transplants
AU - Parkes, Michael D.
AU - Halloran, Kieran
AU - Hirji, Alim
AU - Pon, Shane
AU - Weinkauf, Justin
AU - Timofte, Irina L.
AU - Snell, Greg I.
AU - Westall, Glen P.
AU - Havlin, Jan
AU - Lischke, Robert
AU - Zajacová, Andrea
AU - Hachem, Ramsey
AU - Kreisel, Daniel
AU - Levine, Deborah
AU - Kubisa, Bartosz
AU - Piotrowska, Maria
AU - Juvet, Stephen
AU - Keshavjee, Shaf
AU - Jaksch, Peter
AU - Klepetko, Walter
AU - Halloran, Philip F.
N1 - Funding Information:
This research has been principally supported by grants from Genome Canada, Canada Foundation for Innovation, the University of Alberta Hospital Foundation, the Alberta Ministry of Advanced Education and Technology, the Mendez National Institute of Transplantation Foundation, and Industrial Research Assistance Program. Partial support was also provided by funding from a licensing agreement with the One Lambda division of Thermo Fisher. Dr. Halloran held a Canada Research Chair in Transplant Immunology until 2008 and currently holds the Muttart Chair in Clinical Immunology.
Publisher Copyright:
© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.
PY - 2022/4
Y1 - 2022/4
N2 - Transplanted lungs suffer worse outcomes than other organ transplants with many developing chronic lung allograft dysfunction (CLAD), diagnosed by physiologic changes. Histology of transbronchial biopsies (TBB) yields little insight, and the molecular basis of CLAD is not defined. We hypothesized that gene expression in TBBs would reveal the nature of CLAD and distinguish CLAD from changes due simply to time posttransplant. Whole-genome mRNA profiling was performed with microarrays in 498 prospectively collected TBBs from the INTERLUNG study, 90 diagnosed as CLAD. Time was associated with increased expression of inflammation genes, for example, CD1E and immunoglobulins. After correcting for time, CLAD manifested not as inflammation but as parenchymal response-to-wounding, with increased expression of genes such as HIF1A, SERPINE2, and IGF1 that are increased in many injury and disease states and cancers, associated with development, angiogenesis, and epithelial response-to-wounding in pathway analysis. Fibrillar collagen genes were increased in CLAD, indicating matrix changes, and normal transcripts were decreased—dedifferentiation. Gene-based classifiers predicted CLAD with AUC 0.70 (no time-correction) and 0.87 (time-corrected). CLAD related gene sets and classifiers were strongly prognostic for graft failure and correlated with CLAD stage. Thus, in TBBs, molecular changes indicate that CLAD primarily reflects severe parenchymal injury-induced changes and dedifferentiation. (Figure presented.).
AB - Transplanted lungs suffer worse outcomes than other organ transplants with many developing chronic lung allograft dysfunction (CLAD), diagnosed by physiologic changes. Histology of transbronchial biopsies (TBB) yields little insight, and the molecular basis of CLAD is not defined. We hypothesized that gene expression in TBBs would reveal the nature of CLAD and distinguish CLAD from changes due simply to time posttransplant. Whole-genome mRNA profiling was performed with microarrays in 498 prospectively collected TBBs from the INTERLUNG study, 90 diagnosed as CLAD. Time was associated with increased expression of inflammation genes, for example, CD1E and immunoglobulins. After correcting for time, CLAD manifested not as inflammation but as parenchymal response-to-wounding, with increased expression of genes such as HIF1A, SERPINE2, and IGF1 that are increased in many injury and disease states and cancers, associated with development, angiogenesis, and epithelial response-to-wounding in pathway analysis. Fibrillar collagen genes were increased in CLAD, indicating matrix changes, and normal transcripts were decreased—dedifferentiation. Gene-based classifiers predicted CLAD with AUC 0.70 (no time-correction) and 0.87 (time-corrected). CLAD related gene sets and classifiers were strongly prognostic for graft failure and correlated with CLAD stage. Thus, in TBBs, molecular changes indicate that CLAD primarily reflects severe parenchymal injury-induced changes and dedifferentiation. (Figure presented.).
KW - basic (laboratory) research / science
KW - biopsy
KW - lung (allograft) function / dysfunction
KW - lung failure / injury
KW - lung transplantation / pulmonology
KW - rejection
UR - http://www.scopus.com/inward/record.url?scp=85121349455&partnerID=8YFLogxK
U2 - 10.1111/ajt.16895
DO - 10.1111/ajt.16895
M3 - Article
C2 - 34850543
AN - SCOPUS:85121349455
SN - 1600-6135
VL - 22
SP - 1054
EP - 1072
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 4
ER -