title: Myeloperoxidase-rich Ly-6C+ myeloid cells infiltrate allografts and contribute to an imaging signature of organ rejection in mice.
abstract: Rates of graft rejection are high among recipients of heart transplants. The onset and progression of clinically significant heart transplant rejection are currently monitored by serial biopsy, but this approach is highly invasive and lacks sensitivity. Here, we have developed what we believe to be a new technique to measure organ rejection noninvasively that involves the exploration of tissue-infiltrating leukocytes as biomarker sources for diagnostic imaging. Specifically, we profiled the myeloid response in a murine model of heart transplantation with the aim of defining and validating an imaging signature of graft rejection. Ly-6Chi monocytes, which promote inflammation, accumulated progressively in allografts but only transiently in isografts. Ly-6Clo monocytes, which help resolve inflammation, did not accumulate, although they composed the majority of the few remaining monocytes in isografts. The persistence of Ly-6Chi monocytes in allografts prompted us to screen for a Ly-6Chi monocyte-associated imaging marker. Low-density array data revealed that Ly-6Chi monocytes express 10-fold higher levels of myeloperoxidase (MPO) than Ly-6Clo monocytes. Noninvasive magnetic resonance imaging of MPO with an MPO-activatable Gd-chelate revealed a spatially defined T1-weighted signal in rejected allografts but not in isografts or MPO-deficient allograft recipients. Flow cytometry, enzymography, and histology validated the approach by mapping MPO activity to Ly-6Chi monocytes and neutrophils. Thus, MPO imaging represents a potential alternative to the current invasive clinical standard by which transplants are monitored.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
authors.forename: Moritz
authors.initials: M
authors.lastname: Wildgruber
authors.forename: Takuya
authors.initials: T
authors.lastname: Ueno
authors.forename: Jose-Luiz
authors.initials: JL
authors.lastname: Figueiredo
authors.forename: Peter
authors.initials: P
authors.lastname: Panizzi
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Zhang
authors.forename: James R
authors.initials: JR
authors.lastname: Stone
authors.forename: Elisenda
authors.initials: E
authors.lastname: Rodriguez
authors.forename: John W
authors.initials: JW
authors.lastname: Chen
authors.forename: Mikael J
authors.initials: MJ
authors.lastname: Pittet
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
mesh_terms: D000818:Animals; D003952:Diagnostic Imaging; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology*; D007958:Leukocyte Count; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology* / Q000502:physiology*; D022423:Myeloid Cells / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D009195:Peroxidase / Q000276:immunology; D014185:Transplantation, Isogeneic / Q000276:immunology
chemical_list: D009195:Peroxidase