Dataset Information

¹⁸F-FAC PET Selectively Images Liver-Infiltrating CD4 and CD8 T Cells in a Mouse Model of Autoimmune Hepatitis.

ABSTRACT: Immune cell-mediated attack on the liver is a defining feature of autoimmune hepatitis and hepatic allograft rejection. Despite an assortment of diagnostic tools, invasive biopsies remain the only method for identifying immune cells in the liver. We evaluated whether PET imaging with radiotracers that quantify immune activation (¹⁸F-FDG and ¹⁸F-1-(2'-deoxy-2'-fluoro-arabinofuranosyl)cytosine [¹⁸F-FAC]) and hepatocyte biology (¹⁸F-2-deoxy-2-fluoroarabinose [¹⁸F-DFA]) can visualize and quantify liver-infiltrating immune cells and hepatocyte inflammation, respectively, in a preclinical model of autoimmune hepatitis. Methods: Mice treated with concanavalin A (ConA) to induce a model of autoimmune hepatitis or vehicle were imaged with ¹⁸F-FDG, ¹⁸F-FAC, and ¹⁸F-DFA PET. Immunohistochemistry, digital autoradiography, and ex vivo accumulation assays were used to localize areas of altered radiotracer accumulation in the liver. For comparison, mice treated with an adenovirus to induce a viral hepatitis were imaged with ¹⁸F-FDG, ¹⁸F-FAC, and ¹⁸F-DFA PET. ¹⁸F-FAC PET was performed on mice treated with ConA and vehicle or with ConA and dexamethasone. Biopsy samples of patients with autoimmune hepatitis were immunostained for deoxycytidine kinase. Results: Hepatic accumulation of ¹⁸F-FDG and ¹⁸F-FAC was 173% and 61% higher, respectively, and hepatic accumulation of ¹⁸F-DFA was 41% lower, in a mouse model of autoimmune hepatitis than in control mice. Increased hepatic ¹⁸F-FDG accumulation was localized to infiltrating leukocytes and inflamed sinusoidal endothelial cells, increased hepatic ¹⁸F-FAC accumulation was concentrated in infiltrating CD4 and CD8 cells, and decreased hepatic ¹⁸F-DFA accumulation was apparent in hepatocytes throughout the liver. In contrast, viral hepatitis increased hepatic ¹⁸F-FDG accumulation by 109% and decreased hepatic ¹⁸F-DFA accumulation by 20% but had no effect on hepatic ¹⁸F-FAC accumulation (nonsignificant 2% decrease). ¹⁸F-FAC PET provided a noninvasive biomarker of the efficacy of dexamethasone for treating the autoimmune hepatitis model. Infiltrating leukocytes in liver biopsy samples from patients with autoimmune hepatitis express high levels of deoxycytidine kinase, a rate-limiting enzyme in the accumulation of ¹⁸F-FAC. Conclusion: Our data suggest that PET can be used to noninvasively visualize activated leukocytes and inflamed hepatocytes in a mouse model of autoimmune hepatitis.

SUBMITTER: Salas JR

PROVIDER: S-EPMC6167535 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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18F-FAC PET Selectively Images Liver-Infiltrating CD4 and CD8 T Cells in a Mouse Model of Autoimmune Hepatitis.

Salas Jessica R JR Chen Bao Ying BY Wong Alicia A Cheng Donghui D Van Arnam John S JS Witte Owen N ON Clark Peter M PM

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20180426 10

Immune cell-mediated attack on the liver is a defining feature of autoimmune hepatitis and hepatic allograft rejection. Despite an assortment of diagnostic tools, invasive biopsies remain the only method for identifying immune cells in the liver. We evaluated whether PET imaging with radiotracers that quantify immune activation (18F-FDG and 18F-1-(2'-deoxy-2'-fluoro-arabinofuranosyl)cytosine [18F-FAC]) and hepatocyte biology (18F-2-deoxy-2-fluoroarabin ...[more]

PMID: 29700125

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Project description:Brain-infiltrating leukocytes contribute to multiple sclerosis (MS) and autoimmune encephalomyelitis and likely play a role in traumatic brain injury, seizure, and stroke. Brain-infiltrating leukocytes are also primary targets for MS disease-modifying therapies. However, no method exists for noninvasively visualizing these cells in a living organism. 1-(2'-deoxy-2'-18F-fluoroarabinofuranosyl) cytosine (18F-FAC) is a PET radiotracer that measures deoxyribonucleoside salvage and accumulates preferentially in immune cells. We hypothesized that 18F-FAC PET could noninvasively image brain-infiltrating leukocytes. Methods: Healthy mice were imaged with 18F-FAC PET to quantify if this radiotracer crosses the blood-brain barrier (BBB). Experimental autoimmune encephalomyelitis (EAE) is a mouse disease model with brain-infiltrating leukocytes. To determine whether 18F-FAC accumulates in brain-infiltrating leukocytes, EAE mice were analyzed with 18F-FAC PET, digital autoradiography, and immunohistochemistry, and deoxyribonucleoside salvage activity in brain-infiltrating leukocytes was analyzed ex vivo. Fingolimod-treated EAE mice were imaged with 18F-FAC PET to assess if this approach can monitor the effect of an immunomodulatory drug on brain-infiltrating leukocytes. PET scans of individuals injected with 2-chloro-2'-deoxy-2'-18F-fluoro-9-?-d-arabinofuranosyl-adenine (18F-CFA), a PET radiotracer that measures deoxyribonucleoside salvage in humans, were analyzed to evaluate whether 18F-CFA crosses the human BBB. Results: 18F-FAC accumulates in the healthy mouse brain at levels similar to 18F-FAC in the blood (2.54 ± 0.2 and 3.04 ± 0.3 percentage injected dose per gram, respectively) indicating that 18F-FAC crosses the BBB. EAE mice accumulate 18F-FAC in the brain at 180% of the levels of control mice. Brain 18F-FAC accumulation localizes to periventricular regions with significant leukocyte infiltration, and deoxyribonucleoside salvage activity is present at similar levels in brain-infiltrating T and innate immune cells. These data suggest that 18F-FAC accumulates in brain-infiltrating leukocytes in this model. Fingolimod-treated EAE mice accumulate 18F-FAC in the brain at 37% lower levels than control-treated EAE mice, demonstrating that 18F-FAC PET can monitor therapeutic interventions in this mouse model. 18F-CFA accumulates in the human brain at 15% of blood levels (0.08 ± 0.01 and 0.54 ± 0.07 SUV, respectively), indicating that 18F-CFA does not cross the BBB in humans. Conclusion: 18F-FAC PET can visualize brain-infiltrating leukocytes in a mouse MS model and can monitor the response of these cells to an immunomodulatory drug. Translating this strategy into humans will require exploring additional radiotracers.

Project description:The notion that T cell insulitis increases as type 1 diabetes (T1D) develops is unsurprising, however, the quantitative analysis of CD4+ and CD8+ T cells within the islet mass is complex and limited with standard approaches. Optical microscopy is an important and widely used method to evaluate immune cell infiltration into pancreatic islets of Langerhans for the study of disease progression or therapeutic efficacy in murine T1D. However, the accuracy of this approach is often limited by subjective and potentially biased qualitative assessment of immune cell subsets. In addition, attempts at quantitative measurements require significant time for manual analysis and often involve sophisticated and expensive imaging software. In this study, we developed and illustrate here a streamlined analytical strategy for the rapid, automated and unbiased investigation of islet area and immune cell infiltration within (insulitis) and around (peri-insulitis) pancreatic islets. To this end, we demonstrate swift and accurate detection of islet borders by modeling cross-sectional islet areas with convex polygons (convex hulls) surrounding islet-associated insulin-producing β cell and glucagon-producing α cell fluorescent signals. To accomplish this, we used a macro produced with the freeware software ImageJ equipped with the Fiji Is Just ImageJ (FIJI) image processing package. Our image analysis procedure allows for direct quantification and statistical determination of islet area and infiltration in a reproducible manner, with location-specific data that more accurately reflect islet areas as insulitis proceeds throughout T1D. Using this approach, we quantified the islet area infiltrated with CD4+ and CD8+ T cells allowing statistical comparison between different age groups of non-obese diabetic (NOD) mice progressing towards T1D. We found significantly more CD4+ and CD8+ T cells infiltrating the convex hull-defined islet mass of 13-week-old non-diabetic and 17-week-old diabetic NOD mice compared to 4-week-old NOD mice. We also determined a significant and measurable loss of islet mass in mice that developed T1D. This approach will be helpful for the location-dependent quantitative calculation of islet mass and cellular infiltration during T1D pathogenesis and can be combined with other markers of inflammation or activation in future studies.

Project description:PurposeTo investigate the performance of pretreatment fluorine 18 (18F) fluorodeoxyglucose PET/CT radiomics in predicting severe immune-related adverse events (irSAEs) among patients with advanced non-small cell lung cancer (NSCLC) treated with immunotherapy, which is important in optimizing treatment plans and alleviating future complications with early interventions.Materials and methodsThe retrospective arm of this study included 146 patients with histologically confirmed stage IIIB-IV NSCLC who were treated with immune checkpoint blockade between June 2011 and December 2017 and who were split into training (n = 97) and test (n = 49) cohorts. A prospective validation arm enrolled 48 patients before initiation of immunotherapy between January 2018 and June 2019 as an independent test cohort. Radiomics features extracted from baseline (preimmunotherapy treatment) PET, CT, and PET/CT fusion images were used to generate a radiomics score (RS) to quantify patient risk for developing irSAEs by an improved least absolute shrinkage and selection operator method. Weighted multivariable logistic regression analysis was then used to develop a nomogram model to predict irSAEs, which was assessed by its calibration, discrimination, and clinical usefulness.ResultsThe radiomics nomogram, incorporating the RS, type of immune checkpoint blockade, and dosing schedule, was able to predict patients with and without irSAEs with area under the receiver operating characteristic curve of 0.92 (95% confidence interval [CI]: 0.86, 0.98), 0.92 (95% CI: 0.86, 0.99), and 0.88 (95% CI: 0.78, 0.97) in the training, test, and prospective validation cohorts, respectively. Decision curve analysis showed that the radiomics nomogram model had the highest overall net benefit.ConclusionA high RS is a significant risk factor for development of irSAEs, demonstrating the value of PET/CT images in predicting irSAEs. By the identification, at baseline, of patients with NSCLC most likely to have irSAEs, treatment plans can be optimized before initiation of immunotherapy.Supplemental material is available for this article.© RSNA, 2020See also the commentary by Yousefi.

Dataset Information

¹⁸F-FAC PET Selectively Images Liver-Infiltrating CD4 and CD8 T Cells in a Mouse Model of Autoimmune Hepatitis.

Publications

<sup>18</sup>F-FAC PET Selectively Images Liver-Infiltrating CD4 and CD8 T Cells in a Mouse Model of Autoimmune Hepatitis.

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