Metabolic MRI for In Vivo Detection of Graft-Versus-Host Disease in a Pre-Clinical Model

Abstract

Chronic graft-versus-host disease (cGVHD) remains a prominent barrier preventing successful allogeneic hematopoietic stem cell transplantation (AHSCT). Diagnosis of cGVHD is challenging since biopsies of the involved tissues are associated with bleeding and infection risks. In the absence of biopsy specimens, clinicians rely on subjective clinical scoring for cGVHD diagnosis and monitoring of therapeutic responses. Our previous studies in the pre-clinical cGVHD mouse model demonstrated that the primary cellular mediators of cGVHD, alloreactive donor-derived CD4+ T cells, are distributed to target rather than lymphoid organs. This is in direct contrast to syngeneic HSCT recipients (matched host and donor pairings) where T cells are primarily localized to lymphoid organs. Our prospective metabolic screening and ex vivo metabolic profiling of CD4+ T cell subsets indicated that effector memory T cells (Tem) preferentially utilize aerobic glycolysis. Thus, we hypothesized that visualization of tissues exhibiting high rates of glycolysis could allow in vivo detection of cGVHD in the affected organs since they are infiltrated by alloreactive glycolytic Tem cells. In order to test this, we initiated metabolic magnetic resonance imaging (MRI) in the minor antigen mismatched HSCT mouse model. Following administration of 13C-pyruvate, we measured the conversion of the glycolytic end product, pyruvate, into lactate as a means of evaluating glycolytic rates in target organs. Indeed, hyperpolarized 13C-pyruvate MRI of the liver and gut distinguished allogeneic versus syngeneic HSCT recipients, prior to the development of clinically evident cGVHD. This imaging approach is amenable to clinical translation to potentially allow for cGVHD diagnosis and disease monitoring in patients.