In vivo kinetics and nonradioactive imaging of rapidly proliferating cells in graft-versus-host disease
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
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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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 1

CD4+ T cell pool size, composition, and distribution for normal mice and syngeneic (syn) and allogeneic (allo) hematopoietic stem cell transplant recipients.

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CD4+ T cell pool size, composition, and distribution for normal mice and...
CD4+ T cell numbers extracted from spleen, parenchymal liver, small intestine, flank skin, and blood were combined. (A) Graphic representation of the predominant CD4+ T cell subset distribution in syngeneic and allogeneic recipients at day +28. In the syngeneic setting, CD4+ T cells primarily found in lymphoid organs and of Tn phenotype. In the allogeneic setting, CD4+ T cells were primarily in target tissues (skin, liver, gut) and of Tem phenotype. (B) The mean total Tn cell number within the graft, normal mice, and syngeneic and allogeneic recipients at day +14 and +28. (C) The mean total Tem and Treg numbers within the graft, normal mice, and syngeneic and allogeneic recipients at day +14 and +28. (D) Treg/Tem ratio was > 1 in the graft, syngeneic recipients, and normal mice, while it was < 1 in cGVHD setting. (E) Treg/CD4+ TCON ratio vs. Treg/CD4+ Tem ratio for normal mice, and syngeneic and allogeneic recipients at day +28 in blood. Data are representative of more than 3 independent experiments. For panels B–E, n = 10; **P < 0.01, ***P < 0.001; Tukey’s test with 2-way ANOVA.