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Salas JR, Ryan KM, Trias AO, Chen BY, Guemes M, Galic Z, Schultz KA, Clark PM. Blocking Deoxycytidine Kinase in Activated Lymphocytes Depletes Deoxycytidine Triphosphate Pools and Alters Cell Cycle Kinetics to Yield Less Disease in a Mouse Multiple Sclerosis Model. Immunology 2025; 174:247-263. [PMID: 39710854 DOI: 10.1111/imm.13885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 10/18/2024] [Accepted: 11/29/2024] [Indexed: 12/24/2024] Open
Abstract
Autoreactive, aberrantly activated lymphocytes that target myelin antigens in the central nervous system (CNS) are primary drivers of the autoimmune disease multiple sclerosis (MS). Proliferating cells including activated lymphocytes require deoxyribonucleoside triphosphates (dNTPs) for DNA replication. dNTPs can be synthesised via the de novo pathway from precursors such as glucose and amino acids or the deoxyribonucleoside salvage pathway from extracellular deoxyribonucleosides. Deoxycytidine kinase (dCK) is the rate-limiting enzyme in the salvage pathway. In prior work, we showed that targeting dCK with the small molecule inhibitor TRE-515 limits clinical symptoms in two myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) mouse models of MS and decreases the levels of activated CD4 T and B lymphocytes in vivo. However, whether targeting dCK limits disease in additional EAE models and how targeting dCK directly impacts activated and proliferating CD4 T and B cells has yet to be determined. Here, we show that dCK is activated in the lymph nodes and spleen in an EAE model induced by amino acids 139-151 of the proteolipid protein (PLP139-151) that is driven by CD4 T and B cells and is characterised by acute disease followed by disease remission. Treating this model with TRE-515 limits clinical symptoms and decreases the levels of activated CD4 T and B cells. In culture, CD4 T and B cells induce deoxyribonucleoside salvage following activation, and TRE-515 directly blocks CD4 T and B cell activation-induced proliferation and activation marker expression. TRE-515 decreases deoxycytidine triphosphate (dCTP) and deoxythymidine triphosphate (dTTP) pools and increases the length of time cells spend in S phase of the cell cycle without inducing a replication stress response in B cells. Our results suggest that dCK activity is required to supply needed dNTPs and to enable rapid cell division following lymphocyte activation against autoantigens in EAE mouse models.
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Affiliation(s)
- Jessica R Salas
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California, USA
- Crump Institute for Molecular Imaging, UCLA, Los Angeles, California, USA
| | - K M Ryan
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California, USA
- Crump Institute for Molecular Imaging, UCLA, Los Angeles, California, USA
| | - Alyssa O Trias
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California, USA
- Crump Institute for Molecular Imaging, UCLA, Los Angeles, California, USA
| | - Bao Ying Chen
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California, USA
- Crump Institute for Molecular Imaging, UCLA, Los Angeles, California, USA
| | - Miriam Guemes
- Department of Medicine, UCLA, Los Angeles, California, USA
| | - Zoran Galic
- Department of Medicine, UCLA, Los Angeles, California, USA
| | | | - Peter M Clark
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California, USA
- Crump Institute for Molecular Imaging, UCLA, Los Angeles, California, USA
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2
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Chen BY, Salas JR, Trias AO, Rodriguez AP, Tsang JE, Guemes M, Le TM, Galic Z, Shepard HM, Steinman L, Nathanson DA, Czernin J, Witte ON, Radu CG, Schultz KA, Clark PM. Targeting deoxycytidine kinase improves symptoms in mouse models of multiple sclerosis. Immunology 2023; 168:152-169. [PMID: 35986643 PMCID: PMC9844239 DOI: 10.1111/imm.13569] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 08/12/2022] [Indexed: 01/19/2023] Open
Abstract
Multiple sclerosis (MS) is an autoimmune disease driven by lymphocyte activation against myelin autoantigens in the central nervous system leading to demyelination and neurodegeneration. The deoxyribonucleoside salvage pathway with the rate-limiting enzyme deoxycytidine kinase (dCK) captures extracellular deoxyribonucleosides for use in intracellular deoxyribonucleotide metabolism. Previous studies have shown that deoxyribonucleoside salvage activity is enriched in lymphocytes and required for early lymphocyte development. However, specific roles for the deoxyribonucleoside salvage pathway and dCK in autoimmune diseases such as MS are unknown. Here we demonstrate that dCK activity is necessary for the development of clinical symptoms in the MOG35-55 and MOG1-125 experimental autoimmune encephalomyelitis (EAE) mouse models of MS. During EAE disease, deoxyribonucleoside salvage activity is elevated in the spleen and lymph nodes. Targeting dCK with the small molecule dCK inhibitor TRE-515 limits disease severity when treatments are started at disease induction or when symptoms first appear. EAE mice treated with TRE-515 have significantly fewer infiltrating leukocytes in the spinal cord, and TRE-515 blocks activation-induced B and T cell proliferation and MOG35-55 -specific T cell expansion without affecting innate immune cells or naïve T and B cell populations. Our results demonstrate that targeting dCK limits symptoms in EAE mice and suggest that dCK activity is required for MOG35-55 -specific lymphocyte activation-induced proliferation.
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Affiliation(s)
- Bao Ying Chen
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
- Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA
| | - Jessica R. Salas
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
- Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA
| | - Alyssa O. Trias
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
- Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA
| | - Arely Perez Rodriguez
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
- Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA
| | - Jonathan E. Tsang
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Miriam Guemes
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Thuc M. Le
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
- Ahmanson Translational Imaging Division, University of California, Los Angeles, Los Angeles, CA, USA
| | - Zoran Galic
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | | | - Lawrence Steinman
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - David A. Nathanson
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
- Ahmanson Translational Imaging Division, University of California, Los Angeles, Los Angeles, CA, USA
| | - Johannes Czernin
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
- Ahmanson Translational Imaging Division, University of California, Los Angeles, Los Angeles, CA, USA
| | - Owen N. Witte
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA
| | - Caius G. Radu
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
- Ahmanson Translational Imaging Division, University of California, Los Angeles, Los Angeles, CA, USA
| | | | - Peter M. Clark
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
- Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA
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3
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Fooladi M, Shirazi A, Sheikhzadeh P, Amirrashedi M, Ghahramani F, Cheki M, Khoobi M. Investigating the attenuating effect of telmisartan against radiation-induced intestinal injury using 18F-FDG micro-PET imaging. Int J Radiat Biol 2022; 99:446-458. [PMID: 35930426 DOI: 10.1080/09553002.2022.2110295] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Abstract
BACKGROUND AND OBJECTIVE This study was aimed to investigate the ability of 18F-Fluro-deoxy-glucose (18F-FDG)-based micro-positron emission tomography (microPET) imaging to evaluate the efficacy of telmisartan, a highly selective angiotensin II receptor antagonist (ARA), in intestinal tissue recovery process after in vivo irradiation. METHODS Male Balb/c mice were randomly divided into four groups of control, telmisartan, irradiation, and telmisartan + irradiation. A solution of telmisartan in phosphate-buffered saline (PBS) was administered orally at 12 mg/kg body weight for seven consecutive days prior to whole body exposing to a single sub-lethal dose of 5 Gy X-rays. The mice were imaged using 18F-FDG microPET at 9 and 30 days post-irradiation. The 18F-FDG uptake in jejunum was determined according to the mean standardized uptake value (SUVmean) index. Tissues were also processed in similar time points for histological analysis. RESULTS The 18F-FDG microPET imaging confirmed the efficacy of telmisartan as a potent attenuating agent for ionizing radiation-induced injury of intestine in mice model. The results were also in line with the histological analysis indicating that pretreatment with telmisartan reduced damage to the villi, crypts, and intestinal mucosa compared with irradiated and non-treated group from day 9 to 30 after irradiation. CONCLUSION The results revealed that 18F-FDG microPET imaging could be a good candidate to replace time-consuming and invasive biological techniques for screening of radioprotective agents. These findings were also confirmed by histological examinations which indicated that telmisartan can effectively attenuates radiation injury caused by ionizing-irradiation.
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Affiliation(s)
- Masoomeh Fooladi
- Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Shirazi
- Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Peyman Sheikhzadeh
- Department of Nuclear Medicine, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahsa Amirrashedi
- Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Molecular and Cellular Imaging, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ghahramani
- Radiotherapy-Oncology Center, Yas Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Cheki
- Department of Medical Imaging and Radiation Sciences, Faculty of Paramedicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mehdi Khoobi
- Biomaterials Group, Pharmaceutical Sciences Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.,Department of Radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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Cornelissen B, Knight JC, Mukherjee S, Evangelista L, Xavier C, Caobelli F, Del Vecchio S, Rbah-Vidal L, Barbet J, de Jong M, van Leeuwen FWB. Translational molecular imaging in exocrine pancreatic cancer. Eur J Nucl Med Mol Imaging 2018; 45:2442-2455. [PMID: 30225616 PMCID: PMC6208802 DOI: 10.1007/s00259-018-4146-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 08/22/2018] [Indexed: 02/06/2023]
Abstract
Effective treatment for pancreatic cancer remains challenging, particularly the treatment of pancreatic ductal adenocarcinoma (PDAC), which makes up more than 95% of all pancreatic cancers. Late diagnosis and failure of chemotherapy and radiotherapy are all too common, and many patients die soon after diagnosis. Here, we make the case for the increased use of molecular imaging in PDAC preclinical research and in patient management.
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Affiliation(s)
- Bart Cornelissen
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, Oxford University, Oxford, UK.
| | - James C Knight
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, Oxford University, Oxford, UK
| | - Somnath Mukherjee
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, Oxford University, Oxford, UK
| | | | | | - Federico Caobelli
- Department of Radiology, Universitätsspital Basel, Basel, Switzerland
| | | | - Latifa Rbah-Vidal
- CRCINA, INSERM, CNRS, Université d'Angers, Université de Nantes, Nantes, France
| | - Jacques Barbet
- CRCINA, INSERM, CNRS, Université d'Angers, Université de Nantes, Nantes, France
| | - Marion de Jong
- Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Fijs W B van Leeuwen
- Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands
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Salas JR, Chen BY, Wong A, Cheng D, Van Arnam JS, Witte ON, Clark PM. 18F-FAC PET Selectively Images Liver-Infiltrating CD4 and CD8 T Cells in a Mouse Model of Autoimmune Hepatitis. J Nucl Med 2018; 59:1616-1623. [PMID: 29700125 DOI: 10.2967/jnumed.118.210328] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 04/23/2018] [Indexed: 12/17/2022] Open
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.
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Affiliation(s)
- Jessica R Salas
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California.,Crump Institute for Molecular Imaging, UCLA, Los Angeles, California
| | - Bao Ying Chen
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California.,Crump Institute for Molecular Imaging, UCLA, Los Angeles, California
| | - Alicia Wong
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California.,Crump Institute for Molecular Imaging, UCLA, Los Angeles, California
| | - Donghui Cheng
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, California
| | - John S Van Arnam
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and
| | - Owen N Witte
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California.,Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, California.,Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, California
| | - Peter M Clark
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California .,Crump Institute for Molecular Imaging, UCLA, Los Angeles, California.,Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, California
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6
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Antonios JP, Soto H, Everson RG, Moughon DL, Wang AC, Orpilla J, Radu C, Ellingson BM, Lee JT, Cloughesy T, Phelps ME, Czernin J, Liau LM, Prins RM. Detection of immune responses after immunotherapy in glioblastoma using PET and MRI. Proc Natl Acad Sci U S A 2017; 114:10220-10225. [PMID: 28874539 PMCID: PMC5617282 DOI: 10.1073/pnas.1706689114] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Contrast-enhanced MRI is typically used to follow treatment response and progression in patients with glioblastoma (GBM). However, differentiating tumor progression from pseudoprogression remains a clinical dilemma largely unmitigated by current advances in imaging techniques. Noninvasive imaging techniques capable of distinguishing these two conditions could play an important role in the clinical management of patients with GBM and other brain malignancies. We hypothesized that PET probes for deoxycytidine kinase (dCK) could be used to differentiate immune inflammatory responses from other sources of contrast-enhancement on MRI. Orthotopic malignant gliomas were established in syngeneic immunocompetent mice and then treated with dendritic cell (DC) vaccination and/or PD-1 mAb blockade. Mice were then imaged with [18F]-FAC PET/CT and MRI with i.v. contrast. The ratio of contrast enhancement on MRI to normalized PET probe uptake, which we term the immunotherapeutic response index, delineated specific regions of immune inflammatory activity. On postmortem examination, FACS-based enumeration of intracranial tumor-infiltrating lymphocytes directly correlated with quantitative [18F]-FAC PET probe uptake. Three patients with GBM undergoing treatment with tumor lysate-pulsed DC vaccination and PD-1 mAb blockade were also imaged before and after therapy using MRI and a clinical PET probe for dCK. Unlike in mice, [18F]-FAC is rapidly catabolized in humans; thus, we used another dCK PET probe, [18F]-clofarabine ([18F]-CFA), that may be more clinically relevant. Enhanced [18F]-CFA PET probe accumulation was identified in tumor and secondary lymphoid organs after immunotherapy. Our findings identify a noninvasive modality capable of imaging the host antitumor immune response against intracranial tumors.
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Affiliation(s)
- Joseph P Antonios
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
| | - Horacio Soto
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
| | - Richard G Everson
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
| | - Diana L Moughon
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
| | - Anthony C Wang
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
| | - Joey Orpilla
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
| | - Caius Radu
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
- The Crump Institute for Molecular Imaging, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
| | - Benjamin M Ellingson
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
- Department of Radiology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
| | - Jason T Lee
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
- The Crump Institute for Molecular Imaging, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
| | - Timothy Cloughesy
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
- Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
| | - Michael E Phelps
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095;
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
- The Crump Institute for Molecular Imaging, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
| | - Johannes Czernin
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
- The Crump Institute for Molecular Imaging, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
| | - Linda M Liau
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
- Brain Research Institute, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
| | - Robert M Prins
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095;
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
- Brain Research Institute, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
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Caobelli F, Evangelista L, Quartuccio N, Familiari D, Altini C, Castello A, Cucinotta M, Di Dato R, Ferrari C, Kokomani A, Laghai I, Laudicella R, Migliari S, Orsini F, Pignata SA, Popescu C, Puta E, Ricci M, Seghezzi S, Sindoni A, Sollini M, Sturiale L, Svyridenka A, Vergura V, Alongi P, Young AIMN Working Group. Role of molecular imaging in the management of patients affected by inflammatory bowel disease: State-of-the-art. World J Radiol 2016; 8:829-845. [PMID: 27843542 PMCID: PMC5084061 DOI: 10.4329/wjr.v8.i10.829] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 06/30/2016] [Accepted: 08/29/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To present the current state-of-the art of molecular imaging in the management of patients affected by inflammatory bowel disease (IBD).
METHODS A systematic review of the literature was performed in order to find important original articles on the role of molecular imaging in the management of patients affected by IBD. The search was updated until February 2016 and limited to articles in English.
RESULTS Fifty-five original articles were included in this review, highlighting the role of single photon emission tomography and positron emission tomography.
CONCLUSION To date, molecular imaging represents a useful tool to detect active disease in IBD. However, the available data need to be validated in prospective multicenter studies on larger patient samples.
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8
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Kaaru E, Bianchi A, Wunder A, Rasche V, Stiller D. Molecular Imaging in Preclinical Models of IBD with Nuclear Imaging Techniques: State-of-the-Art and Perspectives. Inflamm Bowel Dis 2016; 22:2491-8. [PMID: 27580387 DOI: 10.1097/mib.0000000000000904] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is characterized by chronic unregulated inflammation of the intestinal mucosa of the gastrointestinal tract. To date, this pathology has no cure. Colonoscopy and biopsies are the current gold standard diagnostic tools. However, being a chronic disease, IBD requires continuous follow-up to check for disease progress, treatment response, and remission. Unfortunately, these 2 diagnostic procedures are invasive and generally unable to show the cellular and molecular changes that take place in vivo. In this context, it is clear that there is a strong need for optimized noninvasive imaging techniques able to overcome the aforementioned limitations. This review aims to bring to light the scientific advancements that have been achieved so far in nuclear medicine in relation to tracking of immune cells involved in the preclinical models of IBD. In particular, this review will explore the advantages and limitations of the radiopharmaceuticals that aim to track whole cells like neutrophils, those that involve the radiolabeling of immune cell substrates or available human IBD medical therapies, and those that aim to track cell signaling molecules (e.g., cytokines and cell adhesion molecules). After a detailed critical summary of the state-of-the art, the challenges and perspectives of molecular imaging applied to IBD studies will be analyzed. Special attention will be paid to the translational potential of the described techniques and on the potential impact of these innovative approaches on the drug discovery pipelines and their contribution to the evolution of personalized medicine.
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Affiliation(s)
- Eric Kaaru
- *Target Discovery Research Department, In-Vivo Imaging Laboratory, Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach an der Riss, Germany; †Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach an der Riss, Germany; ‡Core Facility Small Animal Imaging, Ulm University, Ulm, Germany; and §Internal Medicine II, University Hospital Ulm, Ulm, Germany
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[18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity. Proc Natl Acad Sci U S A 2016; 113:4027-32. [PMID: 27035974 DOI: 10.1073/pnas.1524212113] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Deoxycytidine kinase (dCK), a rate-limiting enzyme in the cytosolic deoxyribonucleoside (dN) salvage pathway, is an important therapeutic and positron emission tomography (PET) imaging target in cancer. PET probes for dCK have been developed and are effective in mice but have suboptimal specificity and sensitivity in humans. To identify a more suitable probe for clinical dCK PET imaging, we compared the selectivity of two candidate compounds-[(18)F]Clofarabine; 2-chloro-2'-deoxy-2'-[(18)F]fluoro-9-β-d-arabinofuranosyl-adenine ([(18)F]CFA) and 2'-deoxy-2'-[(18)F]fluoro-9-β-d-arabinofuranosyl-guanine ([(18)F]F-AraG)-for dCK and deoxyguanosine kinase (dGK), a dCK-related mitochondrial enzyme. We demonstrate that, in the tracer concentration range used for PET imaging, [(18)F]CFA is primarily a substrate for dCK, with minimal cross-reactivity. In contrast, [(18)F]F-AraG is a better substrate for dGK than for dCK. [(18)F]CFA accumulation in leukemia cells correlated with dCK expression and was abrogated by treatment with a dCK inhibitor. Although [(18)F]CFA uptake was reduced by deoxycytidine (dC) competition, this inhibition required high dC concentrations present in murine, but not human, plasma. Expression of cytidine deaminase, a dC-catabolizing enzyme, in leukemia cells both in cell culture and in mice reduced the competition between dC and [(18)F]CFA, leading to increased dCK-dependent probe accumulation. First-in-human, to our knowledge, [(18)F]CFA PET/CT studies showed probe accumulation in tissues with high dCK expression: e.g., hematopoietic bone marrow and secondary lymphoid organs. The selectivity of [(18)F]CFA for dCK and its favorable biodistribution in humans justify further studies to validate [(18)F]CFA PET as a new cancer biomarker for treatment stratification and monitoring.
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Brückner M, Lenz P, Mücke MM, Gohar F, Willeke P, Domagk D, Bettenworth D. Diagnostic imaging advances in murine models of colitis. World J Gastroenterol 2016; 22:996-1007. [PMID: 26811642 PMCID: PMC4716050 DOI: 10.3748/wjg.v22.i3.996] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 09/09/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis are chronic-remittent inflammatory disorders of the gastrointestinal tract still evoking challenging clinical diagnostic and therapeutic situations. Murine models of experimental colitis are a vital component of research into human IBD concerning questions of its complex pathogenesis or the evaluation of potential new drugs. To monitor the course of colitis, to the present day, classical parameters like histological tissue alterations or analysis of mucosal cytokine/chemokine expression often require euthanasia of animals. Recent advances mean revolutionary non-invasive imaging techniques for in vivo murine colitis diagnostics are increasingly available. These novel and emerging imaging techniques not only allow direct visualization of intestinal inflammation, but also enable molecular imaging and targeting of specific alterations of the inflamed murine mucosa. For the first time, in vivo imaging techniques allow for longitudinal examinations and evaluation of intra-individual therapeutic response. This review discusses the latest developments in the different fields of ultrasound, molecularly targeted contrast agent ultrasound, fluorescence endoscopy, confocal laser endomicroscopy as well as tomographic imaging with magnetic resonance imaging, computed tomography and fluorescence-mediated tomography, discussing their individual limitations and potential future diagnostic applications in the management of human patients with IBD.
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Abstract
Nanotechnology has the potential to increase the selectivity and potency of chemical, physical, and biological approaches for eliciting cancer cell death while minimizing collateral toxicity to nonmalignant cells. Materials on the nanoscale are increasingly being targeted to cancer cells with great specificity through both active and passive targeting. In this review, we summarize recent literature that has broken new ground in the use of nanotechnology for cancer treatment with an emphasis on targeted drug delivery.
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Affiliation(s)
- William H. Gmeiner
- Corresponding author: William H. Gmeiner, Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 21757, USA,
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Abstract
PET/CT imaging has become an important part of the evaluation of patients with many types of cancer. This imaging modality can also be used to image areas of active inflammation, such as those occurring in patients with active inflammatory bowel disease (IBD) (Crohn's disease and ulcerative colitis). The standard methods of determining a patient's disease activity are either indirect, such as blood and stool tests, or invasive, such as colonoscopy. FDG-PET imaging is a noninvasive, direct method of evaluating bowel inflammation and represents a significant advancement in the care of these patients. The PET/CT technique is very similar to that used for oncology imaging. Minor changes can be instituted to improve the accuracy, as well as to reduce the radiation exposure to the patient. This paper reviews the literature on the use of FDG-PET imaging in IBD in both the adult and pediatric populations. Future improvements in the technique should focus on decreasing the radiation dose to the patient and on decreasing the cost of the examination. The FDG-PET/CT technique is an excellent method for the noninvasive quantification of bowel inflammation in patients with IBD.
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Affiliation(s)
- Scott B Perlman
- The University of Wisconsin School of Medicine and Public Health, Madison, WI.
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Heylen M, Deleye S, De Man JG, Ruyssers NE, Vermeulen W, Stroobants S, Pelckmans PA, Moreels TG, Staelens S, De Winter BY. Colonoscopy and µPET/CT are valid techniques to monitor inflammation in the adoptive transfer colitis model in mice. Inflamm Bowel Dis 2013; 19:967-976. [PMID: 23407045 DOI: 10.1097/mib.0b013e3182802c7c] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND Preclinical in vivo research on inflammatory bowel diseases requires proper animal models and techniques allowing longitudinal monitoring of colonic inflammation without the need to kill animals. We evaluated colonoscopy and μ-positron emission tomography/computed tomography (μPET/CT) as monitoring tools in a model for chronic colitis in mice. METHODS Colitis was induced by adoptive transfer of CD4(+)CD25(-)CD62L(+) T cells in immunocompromised severe combined immunodeficient mice. Three study protocols were designed. In study 1, colonoscopy and µPET/CT were performed once, 4 weeks after transfer. In study 2 and study 3, colitis was sequentially followed up through colonoscopy (study 2) or colonoscopy plus µPET/CT (study 3). Each study included postmortem evaluation of colonic inflammation (macroscopy, microscopy, and myeloperoxidase activity). RESULTS In study 1, both colonoscopy and µPET/CT detected colitis 4 weeks after transfer. Study 2 showed a gradual increase in colonoscopic score from week 2 (1.4 ± 0.6) to week 8 (6.0 ± 1.1). In study 3, colitis was detected 2 weeks after transfer by µPET/CT (2.0 ± 0.4) but not by colonoscopy, whereas both techniques detected inflammation 4 and 6 weeks after transfer. Colonoscopy correlated with µPET/CT (r = 0.812, 0.884, and 0.781, respectively) and with postmortem analyses in all 3 studies. CONCLUSIONS Adoptive transfer of CD4(+)CD25(-)CD62L(+) T cells in severe combined immunodeficient mice results in a moderate chronic colitis. Evolution of colitis could be monitored over time by both colonoscopy and µPET/CT. µPET/CT seems to detect inflammation at an earlier time point than colonoscopy. Both techniques represent reliable and safe methods without the need to kill animals.
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Affiliation(s)
- Marthe Heylen
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium
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14
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Aarntzen EHJG, Srinivas M, Radu CG, Punt CJA, Boerman OC, Figdor CG, Oyen WJG, de Vries IJM. In vivo imaging of therapy-induced anti-cancer immune responses in humans. Cell Mol Life Sci 2012; 70:2237-57. [PMID: 23052208 PMCID: PMC3676735 DOI: 10.1007/s00018-012-1159-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2012] [Revised: 08/27/2012] [Accepted: 09/03/2012] [Indexed: 12/16/2022]
Abstract
Immunotherapy aims to re-engage and revitalize the immune system in the fight against cancer. Research over the past decades has shown that the relationship between the immune system and human cancer is complex, highly dynamic, and variable between individuals. Considering the complexity, enormous effort and costs involved in optimizing immunotherapeutic approaches, clinically applicable tools to monitor therapy-induced immune responses in vivo are most warranted. However, the development of such tools is complicated by the fact that a developing immune response encompasses several body compartments, e.g., peripheral tissues, lymph nodes, lymphatic and vascular systems, as well as the tumor site itself. Moreover, the cells that comprise the immune system are not static but constantly circulate through the vascular and lymphatic system. Molecular imaging is considered the favorite candidate to fulfill this task. The progress in imaging technologies and modalities has provided a versatile toolbox to address these issues. This review focuses on the detection of therapy-induced anticancer immune responses in vivo and provides a comprehensive overview of clinically available imaging techniques as well as perspectives on future developments. In the discussion, we will focus on issues that specifically relate to imaging of the immune system and we will discuss the strengths and limitations of the current clinical imaging techniques. The last section provides future directions that we envision to be crucial for further development.
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Affiliation(s)
- Erik H J G Aarntzen
- Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
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Patel MR, Chang YF, Chen IY, Bachmann MH, Yan X, Contag CH, Gambhir SS. Longitudinal, noninvasive imaging of T-cell effector function and proliferation in living subjects. Cancer Res 2010; 70:10141-9. [PMID: 21159636 PMCID: PMC3057959 DOI: 10.1158/0008-5472.can-10-1843] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Adoptive immunotherapy is evolving to assume an increasing role in treating cancer. Most imaging studies in adoptive immunotherapy to date have focused primarily on locating tumor-specific T cells rather than understanding their effector functions. In this study, we report the development of a noninvasive imaging strategy to monitor T-cell activation in living subjects by linking a reporter gene to the Granzyme B promoter (pGB), whose transcriptional activity is known to increase during T-cell activation. Because pGB is relatively weak and does not lead to sufficient reporter gene expression for noninvasive imaging, we specifically employed 2 signal amplification strategies, namely the Two Step Transcription Amplification (TSTA) strategy and the cytomegalovirus enhancer (CMVe) strategy, to maximize firefly luciferase reporter gene expression. Although both amplification strategies were capable of increasing pGB activity in activated primary murine splenocytes, only the level of bioluminescence activity achieved with the CMVe strategy was adequate for noninvasive imaging in mice. Using T cells transduced with a reporter vector containing the hybrid pGB-CMVe promoter, we were able to optically image T-cell effector function longitudinally in response to tumor antigens in living mice. This methodology has the potential to accelerate the study of adoptive immunotherapy in preclinical cancer models.
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Affiliation(s)
- Manishkumar R Patel
- Molecular Imaging Program at Stanford, Stanford University, Stanford, California 94305, USA
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Nair-Gill E, Wiltzius SM, Wei XX, Cheng D, Riedinger M, Radu CG, Witte ON. PET probes for distinct metabolic pathways have different cell specificities during immune responses in mice. J Clin Invest 2010; 120:2005-15. [PMID: 20484820 DOI: 10.1172/jci41250] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2009] [Accepted: 03/31/2010] [Indexed: 12/21/2022] Open
Abstract
Clinical tools that measure changes in immune cell metabolism would improve the diagnosis and treatment of immune dysfunction. PET, utilizing probes for specific metabolic processes, detects regions of immune activation in vivo. In this study we investigated the immune cell specificity of PET probes for two different metabolic pathways: [18F]-2-fluorodeoxyglucose ([18F]-FDG) for glycolysis and [18F]-2-fluoro-D-(arabinofuranosyl)cytosine ([18F]-FAC) for deoxycytidine salvage. We isolated innate and adaptive immune cells from tissues of mice challenged with a retrovirus-induced sarcoma and measured their ability to accumulate FDG and FAC. We determined that the two probes had distinct patterns of accumulation: FDG accumulated to the highest levels in innate immune cells, while FAC accumulated predominantly in CD8+ T cells in a manner that correlated with cellular proliferation. This study demonstrates that innate and adaptive cell types differ in glycolytic and deoxycytidine salvage demands during an immune response and that these differential metabolic requirements can be detected with specific PET probes. Our findings have implications for the interpretation of clinical PET scans that use [18F]-FDG or [18F]-FAC to assess immune function in vivo and suggest potential applications of metabolic PET to monitor the effects of targeted immune modulation.
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Affiliation(s)
- Evan Nair-Gill
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California, USA
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