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Surgical Director, Lung Transplantation
Mechanisms of Primary Graft Dysfunction followingLung Transplantation
Ankit Bharat MD FACS
PRIMARY GRAFT DYSFUNCTION• Incidence >50-70%
• Occurs within first 24 hours following transplant
• Characterized by respiratory failure
• Leading cause of short-term mortality
• Predominant cause of chronic lung allograft rejection
CM
Neut
NETosis
Alveolus
Interstitium
NCM
NeutPGDComplementary role in
neutrophil trafficking
“Garden-variety” ischemia-reperfusion injury
Bharat & Kreisel, Annals Thor Surg, 2018
Col VKAT
Pre-existing Autoimmunity& Autoantibodies
Col VKAT
Col VKAT
(Sequestered lung-restricted antigens in native lungs)
Teff
ISCHEMIA-REPERFUSIONCHRONIC INFLAMMATION
PGD
(Sequestered self-antigensin allograft exposed to host immune system)
Bharat & Kreisel, Annals Thor Surg, 2018
Autoantibody-mediated rejection mimicking PGD
PERFUSED HUMAN DONOR LUNGS CONTAIN MONOCYTES
Bharat et al, AJRCMB, Jan 2016
Zhikun et al, SCIENCE TM
Depletion of donor NCM abrogates neutrophil recruitment and ameliorates PGD
Donor PBS-lip Donor Clo-lip Nr4a1-/- donors
Nonclassical Monocyte (NCM)
Ly6ClowCX3CR1HighCCR2-
Monocyte subsets in mice and humans
Classical Monocyte (CM)
CCR2+Ly6ChighCX3CR1low
Depletion of recipient’s classical monocytes impairs neutrophil extravasation
Control Depletion of host CM
IL-1β production by host classical monocyte is necessary for neutrophil extravasation
WT donor IL1-R KO donor
Donor NCM initiate PGD
• Strategies to deplete NCM in donor lung? Role of EVLP
• NCM damage-associated molecular patterns (DAMPs)- ? Reduce allograft tissue ischemia
Increased levels of NCM in donor lungs from TBI or ECD donors
P<0.001
Human Mouse models
Fernandez et al, Under review
Nonclassical monocytes rapidly phagocytoseapoptotic endothelial cells in vitro
Cell Tracker Green
Cel
l Tra
cker
Red
81%19%
Confocal
9%91%
Confocal
Human NCMMurine NCM
Normal endothelial culture CMP-induced apoptosis
Acknowledgments
Pulmonary MedicineGR Scott Budinger
Alexander MisharinChing-I Chen
Alexandra McQuattie-Pimentel
Flow Cytometry CoreSuchitra Swaminathan
Comprehensive Transplant CenterMichael Abecassis
Bharat LabMahzad Akbarpour
Stephen ChiuHaiying SunElena Susan
Sheng-Xian JiaQiang Wu
Kreisel LabWenjun
Jim Hsiao