Reduction of PK11195 uptake observed in multiple sclerosis lesions after natalizumab initiation
Introduction
PET imaging in combination with the ligand [11C]PK11195 (PK) can be used to evaluate activated microglia and macrophages (MG/MΦ) in vivo (Banati, 2002). PK binds to the translocator protein (TSPO), which is expressed on the outer mitochondria membrane of activated MG/MΦ (Banati et al., 2000, Jucaite et al., 2012). Studies with PK confirmed the most prominent uptake within areas of increased inflammation, especially in enhancing lesions in multiple sclerosis (MS) patients (Debruyne et al., 2003), however most studies evaluating the binding of TSPO have been cross-sectional in design.
The innate immune system plays a pivotal role in the pathophysiology of MS, and important cell types involved in this process are resident microglia and blood-derived macrophages (Gandhi et al., 2010). In acute MS lesions, activated MG/MΦ are involved in demyelination and are the source of reactive nitrogen and oxygen species, which induces oxidative injury to mitochondria, oligodendrocytes and degenerating neurons (Fischer et al., 2012). Iron-containing pro-inflammatory MG/MΦ are present at the rim of chronic active MS lesions and at the site of ongoing demyelination (Mehta et al., 2013).
Natalizumab is a monoclonal antibody (AB) directed against VLA-4, an alpha-4 integrin expressed on leukocyte surfaces (Yednock et al., 1992). This protein interacts with its ligand, vascular cell adhesion molecule 1 (VCAM-1), which is located on endothelium, as well as on MG/MΦ and astrocytes (Chabot et al., 1997, Peterson et al., 2002). Blocking the VLA-4/VCAM-1 interaction decreases the influx of lymphocytes, reducing the effects of the adaptive immune response in the CNS, and subsequently the activation of microglia (del Pilar Martin et al., 2008, Waisman et al., 2015). In human studies, natalizumab therapy was shown to be highly effective for relapsing remitting MS (RRMS) with a significant reduction in relapse rates and MRI lesion activity (Miller et al., 2003, Johnson, 2007).
The current study aims to use PK11195-PET to evaluate the longitudinal uptake of PK11195 in a cohort of MS patients following the initiation of natalizumab treatment.
Section snippets
Human participants
This longitudinal study analyzed the degree of PK11195 uptake in natalizumab treated MS patients. The medication effect on PK11195 uptake was assessed over the period of 6 months (mo), using PK-PET imaging. Twenty-four patients with the diagnosis of RRMS or secondary progressive MS (SPMS) were enrolled in the study. However, the PET data from two participants had to be discarded because they were confounded by excessive motion, and four patients decided to withdraw consent. The eighteen
MS Patient cohort
This was a longitudinal, prospective study of PK11195 uptake in patients initiating natalizumab therapy. Patients were followed with MRI and PK-PET scans at baseline, 3mo and 6mo post natalizumab treatment. The eighteen patients utilized for this analysis are described in detail in Supplementary Table 1. Thirteen women and five men completed the study and mean age was 37.3 years. Mean disease duration, before starting natalizumab, was 8.2 years. The majority of patients were switching therapy
Discussion
We have shown a reduction in PK11195 uptake in MS patients following treatment with anti-VLA4 (natalizumab). We identify a longitudinal decrease of PK11195 uptake in EL, which was anticipated, however we also observe a decrease in this ligand's uptake in NEL. This study supports the potential utilization of PK-PET as an in vivo tool to assess the longitudinal effects of disease modifying agents in MS patients.
PK-PET imaging is a well-established method to assess CNS inflammation, and has been
Disclosures
Dr. Kaunzner received grant support from Biogen. Dr. Kang reports no disclosures. Ms. Monohan reports no disclosures. Dr. Kothari reports no disclosures. Dr. Nealon reports no disclosures. Dr. Perumal reports no disclosures. Dr. Vartanian is a speaker for Teva Neuroscience, has received honoraria for advising Genzyme, and has received grant support from the National MS society, Biogen, and Mallinckrodt. Dr. Kuceyeski reports no disclosures. Dr. Vallabhajosula reports no disclosures. Dr. Mozley
Study funding
Supported by Biogen.
Acknowledgements
We acknowledge Gulce Askin, MPH and Linda Gerber, Ph.D. for their support with the statistical analysis.
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