Increased T Cell Glucose Uptake Reflects Acute Rejection in Lung Grafts

Abstract

Although T cells are required for acute lung rejection, other graft-infiltrating cells such as neutrophils accumulate in allografts and are also high glucose utilizers. Positron emission tomography (PET) with the glucose probe [18F]fluorodeoxyglucose ([18F]FDG) has been employed to image solid organ acute rejection, but the sources of glucose utilization remain undefined. Using a mouse model of orthotopic lung transplantation, we analyzed glucose probe uptake in the grafts of syngeneic and allogeneic recipients with or without immunosuppression treatment. Pulmonary microPET scans demonstrated significantly higher [18F]FDG uptake in rejecting allografts when compared to transplanted lungs of either immunosuppressed or syngeneic recipients. [18F]FDG uptake was also markedly attenuated following T cell depletion therapy in lung recipients with ongoing acute rejection. Flow-cytometric analysis using the fluorescent deoxyglucose analog 2-NBDG revealed that T cells, and in particular CD8+ T cells, were the largest glucose utilizers in acutely rejecting lung grafts followed by neutrophils and antigen presenting cells. These data indicate that imaging modalities tailored toward assessing T cell metabolism may be useful in identifying acute rejection in lung recipients

Eosinophils promote inducible NOS–mediated lung allograft acceptance

“…Orthotopic transplantation of a left lung allograft was carried out according to our previous reports (4,11,42,44). To achieve allograft acceptance, mice were treated either with double CSB of the CD28/B7 and the CD40/CD40L pathways as previously described (11,45) or with high-dose cyclosporine A and low-dose methylprednisolone as previously described (16).…”

“…Quantitative analysis of accepting left lung allografts revealed an increase in both the relative percentage and total number of lung-infiltrating eosinophils over that in resting lungs ( Figure 3B). Such eosinophil influx was evident, with graft acceptance induced by CSB as well as cyclosporine (CsA) and low-dose methylprednisolone (MP) (16) (Figure 3B). Thus, despite the prevailing notion that eosinophils promote deleterious inflammatory responses in the lung, eosinophils represent the dominant iNOS-producing cells in the lung allograft, and pulmonary eosinophilia is associated with allograft acceptance.…”

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…This model is a suitable platform to evaluate new diagnostic modalities for AR. For example, fluorodeoxyglucose PET (FDG-PET) can be used to monitor acute lung allograft rejection owing to a high rate of metabolism of graft-infiltrating T cells (65). Thus, the orthotopic mouse lung transplant model is an effective experimental platform to study mechanisms that contribute to AR, test noninvasive diagnostic modalities as well as to study immune tolerance (66), and evaluate strategies to prevent or treat this complication.…”

Imaging Pulmonary Inflammation

“…However, 18 F-FDG also accumulates in macrophages (13), lymphocytes (14,15), and eosinophils (16,17). The increased 18 F-FDG uptake in these activated cell types supports various functions related to their specific immune responses, including cytokine-induced activation of neutrophils and eosinophils (18,19), antigen receptor-mediated activation of lymphocytes (15,20), and polarization state changes in macrophages (21). Structural cells within the lungs also increase glucose utilization during inflammation (22,23).…”

“…Initial studies using 18 F-FDG to image lung inflammation focused on measuring neutrophilic recruitment (11,12). However, 18 F-FDG also accumulates in macrophages (13), lymphocytes (14,15), and eosinophils (16,17). The increased 18 F-FDG uptake in these activated cell types supports various functions related to their specific immune responses, including cytokine-induced activation of neutrophils and eosinophils (18,19), antigen receptor-mediated activation of lymphocytes (15,20), and polarization state changes in macrophages (21).…”