Terry Samantha Y A, Koenders Marije I, Franssen Gerben M, Nayak Tapan K, Freimoser-Grundschober Anne, Klein Christian, Oyen Wim J, Boerman Otto C, Laverman Peter
Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Department of Imaging Chemistry and Biology, King's College London, London, United Kingdom
Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
J Nucl Med. 2016 Mar;57(3):467-72. doi: 10.2967/jnumed.115.162628. Epub 2015 Dec 3.
Rheumatoid arthritis is an autoimmune disease resulting in chronic synovial inflammation. Molecular imaging could be used to monitor therapy response, thus enabling tailored therapy regimens and enhancing therapeutic outcome. Here, we hypothesized that response to etanercept could be monitored by radionuclide imaging in arthritic mice. We tested 3 different targets, namely fibroblast activation protein (FAP), macrophages, and integrin αvβ3.
Male DBA/1J mice with collagen-induced arthritis were treated with etanercept. SPECT/CT scans were acquired at 1, 24, and 48 h after injection of (111)In-RGD2 (integrin αvβ3), (111)In-anti-F4/80-A3-1 (antimurine macrophage antibody), or (111)In-28H1 (anti-FAP antibody), respectively, with nonspecific controls included. Mice were dissected after the last scan, and scans were analyzed quantitatively and were correlated with macroscopic scoring.
Experimental arthritis was imaged with (111)In-28H1 (anti-FAP), (111)In-anti-F4/80-A3-1, and (111)In-RGD2. Tracer uptake in joints correlated with arthritis score. Treatment decreased joint uptake of tracers from 23 ± 15, 8 ± 4, and 2 ± 1 percentage injected dose per gram (%ID/g) to 11 ± 11 (P < 0.001), 4 ± 4 (P < 0.001), and 1 ± 0.2 %ID/g (P < 0.01) for (111)In-28H1, (111)In-anti-F4/80-A3-1, and (111)In-RGD2, respectively. Arthritis-to-blood ratios (in mice with arthritis score 2 per joint) were higher for (111)In-28H1 (5.5 ± 1; excluding values > 25), (111)In-anti-F4/80-A3-1 (10.4 ± 4), and (111)In-RGD2 (7.2 ± 1) than for control (111)In-DP47GS (0.7 ± 0.5; P = 0.002), (111)In-rat IgG2b (0.5 ± 0.2; P = 0.002), or coinjection of excess RGD2 (3.5), indicating specific uptake of all tracers in arthritic joints.
(111)In-28H1, (111)In-anti-F4/80-A3-1, and (111)In-RGD2 can be used to specifically monitor the response to therapy in experimental arthritis at the molecular level. Further studies, however, still need to be performed.
类风湿性关节炎是一种导致慢性滑膜炎的自身免疫性疾病。分子成像可用于监测治疗反应，从而实现个性化治疗方案并提高治疗效果。在此，我们假设在关节炎小鼠中，可通过放射性核素成像监测对依那西普的反应。我们测试了3个不同靶点，即成纤维细胞活化蛋白（FAP）、巨噬细胞和整合素αvβ3。
用依那西普治疗胶原诱导性关节炎的雄性DBA/1J小鼠。分别在注射（111）铟-RGD2（整合素αvβ3）、（111）铟-抗F4/80-A3-1（抗鼠巨噬细胞抗体）或（111）铟-28H1（抗FAP抗体）后1、24和48小时进行SPECT/CT扫描，包括非特异性对照。在最后一次扫描后解剖小鼠，并对扫描结果进行定量分析，并与宏观评分相关联。
实验性关节炎可用（111）铟-28H1（抗FAP）、（111）铟-抗F4/80-A3-1和（111）铟-RGD2成像。关节内示踪剂摄取与关节炎评分相关。治疗后，（111）铟-28H1、（111）铟-抗F4/80-A3-1和（111）铟-RGD2的关节示踪剂摄取分别从每克注射剂量的23±15、8±4和2±1百分比注射剂量（%ID/g）降至11±11（P<0.001）、4±4（P<0.001）和1±0.2%ID/g（P<0.01）。（每关节关节炎评分为2的小鼠）（111）铟-28H1（5.5±1；排除>25的值）、（111）铟-抗F4/80-A3-1（10.4±4）和（111）铟-RGD2（7.2±1）的关节炎与血液比值高于对照（111）铟-DP47GS（0.7±0.5；P=0.002）、（111）铟-大鼠IgG2b（0.5±0.2；P=0.002）或过量RGD2共注射（3.5），表明所有示踪剂在关节炎关节中均有特异性摄取。
（111）铟-28H1、（111）铟-抗F4/80-A3-1和（111）铟-RGD2可用于在分子水平特异性监测实验性关节炎的治疗反应。然而，仍需进行进一步研究。
