In vivo kinetics and nonradioactive imaging of rapidly proliferating cells in graft-versus-host disease
Nataliya P. Buxbaum, … , Remy J. Bosselut, Ronald E. Gress
Nataliya P. Buxbaum, … , Remy J. Bosselut, Ronald E. Gress
Published June 15, 2017
Citation Information: JCI Insight. 2017;2(12):e92851. https://doi.org/10.1172/jci.insight.92851.
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Resource and Technical Advance Immunology Transplantation

In vivo kinetics and nonradioactive imaging of rapidly proliferating cells in graft-versus-host disease

Abstract

Hematopoietic stem cell transplantation (HSCT) offers a cure for cancers that are refractory to chemotherapy and radiation. Most HSCT recipients develop chronic graft-versus-host disease (cGVHD), a systemic alloimmune attack on host organs. Diagnosis is based on clinical signs and symptoms, as biopsies are risky. T cells are central to the biology of cGVHD. We found that a low Treg/CD4+ T effector memory (Tem) ratio in circulation, lymphoid, and target organs identified early and established mouse cGVHD. Using deuterated water labeling to measure multicompartment in vivo kinetics of these subsets, we show robust Tem and Treg proliferation in lymphoid and target organs, while Tregs undergo apoptosis in target organs. Since deuterium enrichment into DNA serves as a proxy for cell proliferation, we developed a whole-body clinically relevant deuterium MRI approach to nonradioactively detect cGVHD and potentially allow imaging of other diseases characterized by rapidly proliferating cells.

Authors

Nataliya P. Buxbaum, Donald E. Farthing, Natella Maglakelidze, Martin Lizak, Hellmut Merkle, Andrea C. Carpenter, Brittany U. Oliver, Veena Kapoor, Ehydel Castro, Gregory A. Swan, Liliane M. dos Santos, Nicolas J. Bouladoux, Catherine V. Bare, Francis A. Flomerfelt, Michael A. Eckhaus, William G. Telford, Yasmine Belkaid, Remy J. Bosselut, Ronald E. Gress

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Figure 6

In vivo deuterium labeling followed by deuterium MRI (dMRI) facilitates diagnosis of chronic graft vs.

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In vivo deuterium labeling followed by deuterium MRI (dMRI) facilitates ...
host disease (cGVHD) in the target organ in allogeneic (allo) hematopoietic stem cell transplant (HSCT) recipients. (A and C) Proton (anatomical) MRI and dMRI (B and D) obtained with Bruker 9.7T magnet on day +28 following syngeneic HSCT (A and B) and allogeneic HSCT (C and D) after 21 days (day +7 to +28) of 2H2O labeling to total body water of 5%. For each mouse, 3 coronal slices 3 mm in thickness were obtained through the midabdomen (covering liver and spleen); 5% 2H2O phantom was imaged to provide a reference deuterium signal. (E) Normalized deuterium signal (nDS) in the liver at day +14 was significantly higher in allogeneic recipients compared with syngeneic, while the unaffected tissue (muscle) nDS did not differ between cohorts, shown in F. For E and F, data are representative of 1 experiment (n = 3 per cohort). (G) nDS in the liver at day +28 was significantly higher in allogeneic recipients compared with syngeneic, while the muscle nDS did not differ between cohorts, shown in H. For G and H, data representative of 2 independent experiments (n = 4 and 3 for allo and syn, respectively). For panels E–H, *P < 0.05, ***P < 0.001; 2-sample, 2-tailed, unequal variance t test.