Abstract
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Objectives: Macrophages play a critical role in atherosclerotic plaque progression, but existing strategies for imaging arterial inflammation in humans lack macrophage specificity. We investigated systemic administration of 99mTc-tilmanocept (TcTil), which specifically binds CD206+ macrophages, to image arterial inflammation and quantify macrophage infiltration in an index population of HIV-infected subjects with subclinical atherosclerosis.
Methods: a] The primary aim of the study was to determine the in vivo quantification of CD206+ aortic macrophage infiltration in humans non-invasively by thoracic single photon emission computed tomography (SPECT)/CT scanning following subcutaneous administration of TcTil. To contextualize the clinical significance of aortic TcTil uptake, cardiovascular imaging was performed - computed tomography angiography (CTA) scanning. Facilitating the identification of clinical parameters relating to aortic TcTil uptake, subjects underwent detailed history & blood testing for metabolic markers & markers of systemic immune activation. Initially, for the proof-of-concept phase of the study, 6 HIV-infected subjects w/ known subclinical atherosclerosis (prior CTA) were enrolled. Subsequently, for comparison, 3 non-HIV-infected subjects matched on Framingham Risk Score were enrolled. None of the subjects in either group had known current or prior clinical cardiovascular disease. The study was approved by the Massachusetts Gen. Hosp. Human Res Comm. IRB all subjects provided written informed consent. The study was registered on clinicaltrials.gov (NCT02542371). b] For both groups of study subjects (HIV-infected & non-HIV-infected), entry criteria included age 蠅 18 years. Exclusion criteria included history of myocardial infarction, stable or unstable angina, or coronary artery stenting or surgery; current treatment w/ prescription systemic steroids or anti-inflammatory/immune suppressant medical therapies; any recent treatment with statin therapy.
Results: High-level TcTil uptake was readily visible & detectable across 20.4% of the aortic surface volume among HIV-infected subjects compared to only 4.3% in a control population w/ similar CVD risk indices (P=0.009; Example - Figure 1)). Among all subjects, high-level aortic TcTil uptake related to total aortic plaque volume and the volume of non-calcified plaque (r = 0.78, P= 0.01). Moreover, TcTil uptake was robustly related to circulating levels of soluble CD14 (ρ=0.72, P=0.03), CD14+CD16- monocytes (ρ=0.77, P=0.02), CD8+ T cell count (ρ=0.73, P=0.02), and CD8+PD1+ T cells (ρ=0.72, P=0.03). Ex-vivo experiments on banked aortic tissue demonstrated increased CD206+ macrophage infiltration among HIV-infected subjects vs. controls (30.1±7.9 vs. 14.2±7.0 macrophages/mm2, P=0.0002) & significant tilmanocept co-localization w/ CD206+-staining macrophages.
Conclusion: Our findings represent a significant advance in functional imaging, utilizing a novel macrophage-specific molecular imaging strategy in humans to quantify arterial macrophage infiltration in relationship to plaque & immune indices in at-risk populations. This strategy may be useful to provide insights into immune-mediated mechanisms of atherogenesis, identify patients at risk for macrophage-mediated end organ damage, and enable future targeted delivery of immunomodulatory therapeutics. Research Support: Supported by NIH grants M01-RR-01066 and 1 UL1 RR025758-01 to the Harvard Clinical & Translational Science Ctr from the National Ctr for Res. Resources. Support was also received from NIH DKP30 045061. Supported in part by a NIH Med Res Investgr Training Award 8KL2TR000168-05 & by T32DK 007028. Navidea Biopharm. received a SBIR Grant 1 R43 HL127846-01 to support the study. $$graphic_540DA08D-165F-4EA7-BA6A-DF4CC59742FF$$