Abstract
AbstractGraft-versus-host disease (GVHD) is a prominent barrier to allogeneic hematopoietic stem cell transplantation (AHSCT). Definitive diagnosis of GVHD is invasive, and biopsies of involved tissues pose a high risk of bleeding and infection. T cells are central to GVHD pathogenesis, and our previous studies in a chronic GVHD mouse model showed that alloreactive CD4+ T cells traffic to the target organs ahead of overt symptoms. Because increased glycolysis is an early feature of T-cell activation, we hypothesized that in vivo metabolic imaging of glycolysis would allow noninvasive detection of liver GVHD as activated CD4+ T cells traffic into the organ. Indeed, hyperpolarized 13C-pyruvate magnetic resonance imaging detected high rates of conversion of pyruvate to lactate in the liver ahead of animals becoming symptomatic, but not during subsequent overt chronic GVHD. Concomitantly, CD4+ T effector memory cells, the predominant pathogenic CD4+ T-cell subset, were confirmed to be highly glycolytic by transcriptomic, protein, metabolite, and ex vivo metabolic activity analyses. Preliminary data from single-cell sequencing of circulating T cells in patients undergoing AHSCT also suggested that increased glycolysis may be a feature of incipient acute GVHD. Metabolic imaging is being increasingly used in the clinic and may be useful in the post-AHSCT setting for noninvasive early detection of GVHD.
Highlights
Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative therapy for patients with aggressive hematologic malignancies, nonmalignant hematologic diseases, and a consolidation therapy for patients receiving chimeric antigen receptor T cells
Because activated CD41 T cells have been shown to have a distinct metabolic profile, including elevated glycolysis in settings of cancer and autoimmunity,[42,43,44] we focused on metabolites generated from pyruvate, the metabolite situated at the crossroads between aerobic glycolysis, the tricarboxylic acid (TCA) cycle, and amino acid metabolism (Figure 1C)
We found that phenotypically naive splenic CD41 T cells (Tn, CD44lowCCR71) in AHSCT recipients had three- to fourfold higher intracellular levels of lactate compared with allogeneic T effector memory (Tem), as well as CD41 T cells extracted from syngeneic recipients (Figure 1D)
Summary
Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative therapy for patients with aggressive hematologic malignancies, nonmalignant hematologic diseases, and a consolidation therapy for patients receiving chimeric antigen receptor T cells. Acute and chronic graft-versus-host disease (GVHD) following AHSCT are prevalent and morbid and may share pathophysiologic features. Acute GVHD (aGVHD) is the most significant risk factor for the development of chronic GVHD (cGVHD), and jointly they represent a major barrier to successful AHSCT.[1,2,3] In addition, GVHD of the liver and the gastrointestinal tract poses a particular diagnostic challenge.[4,5] Biopsies of these tissues are invasive, associated with serious bleeding and infection risks for the AHSCT recipient, and, diagnostic, do not inform treatment selection. Responses to therapy are difficult to assess and are being ascertained by tabulating and tracking the severity of clinical signs and symptoms.[2,4,5,6,7] Noninvasive objective approaches to diagnose and monitor GVHD are needed.[8]
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