Fluorine labelling of therapeutic human tolerogenic dendritic cells for 19F-magnetic resonance imaging

Abstract

Tolerogenic dendritic cell (tolDC) therapies aim to restore self-tolerance in patients suffering from autoimmune diseases. Phase 1 clinical trials with tolDC have shown the feasibility and safety of this approach, but have also highlighted a lack of understanding of their distribution in vivo. Fluorine-19 magnetic resonance imaging (19F-MRI) promises an attractive cell tracking method because it allows for detection of 19F-labelled cells in a non-invasive and longitudinal manner. Here, we tested the suitability of nanoparticles containing 19F (19F-NP) for labelling of therapeutic human tolDC for detection by 19F-MRI. We found that tolDC readily endocytosed 19F-NP with acceptable effects on cell viability and yield. The MRI signal-to-noise ratios obtained are more than sufficient for detection of the administered tolDC dose (10 million cells) at the injection site in vivo, depending on the tissue depth and the rate of cell dispersal. Importantly, 19F-NP labelling did not revert tolDC into immunogenic DC, as confirmed by their low expression of typical mature DC surface markers (CD83, CD86), low secretion of pro-inflammatory IL-12p70, and low capacity to induce IFN-γ in allogeneic CD4+ T cells. In addition, the capacity of tolDC to secrete anti-inflammatory IL-10 was not diminished by 19F-NP labelling. We conclude that 19F-NP is a suitable imaging agent for tolDC. With currently available technologies, this imaging approach does not yet approach the sensitivity required to detect small numbers of migrating cells, but could have important utility for determining the accuracy of injecting tolDC into the desired target tissue and their efflux rate.

In vivotracking of adenoviral-transduced iron oxide-labeled bone marrow-derived dendritic cells using magnetic particle imaging

“…This is the first in vivo MPI study that employed multichannel joint image reconstruction with a focused FOV for image acquisition and represents an important step forward in establishing MPI as a non-invasive imaging modality capable of tracking the fate of injected DC to serve as a surrogate marker of therapeutic effectiveness. Recently, DC-based therapies have garnered much interest within combination cancer immunotherapy in autoimmune and transplantation settings [58] as well as in infectious disease settings such as SARS-CoV-2 [59]. Regardless of disease setting, non-invasive and quantifiable imaging is required for cell-based immunotherapies to be successful.…”

In vivo tracking of adenoviral-transduced iron oxide-labeled bone marrow-derived dendritic cells using magnetic particle imaging

“…In conclusion, this is the first in vivo MPI study that employed multichannel joint image reconstruction with a focused FOV for image acquisition and represents an important step forward in establishing MPI as a noninvasive imaging modality capable of tracking the fate of injected DC to serve as a surrogate marker of therapeutic effectiveness. Recently, DC-based therapies have garnered much interest within combination cancer immunotherapy in autoimmune and transplantation settings [ 59 ] as well as in infectious disease settings such as SARS-CoV-2 [ 60 ]. Regardless of disease setting, noninvasive and quantifiable imaging is required for cell-based immunotherapies to be successful.…”

Challenges in tolerogenic dendritic cell therapy for autoimmune diseases: the route of administration

“…For example, compared to mature moDCs, tolDCs generated with Dexa and the active form of VitD3 have substantially reduced expression of CCR7 and therefore a limited capacity to migrate in a CCR7-dependent manner [ 53 ]. Indeed, these tolDCs failed to migrate towards the draining lymph node after administration into an inflamed knee joint of a RA patient, as determined by imaging of 111 Indium-labelled tolDCs [ 54 ] This observation possibly explains the local but not systemic effects of tolDC administration [ 39 ]. It is therefore crucial to improve our understanding of the biodistribution of tolDCs after administration via different routes and how this relates to their immunomodulatory actions.…”

“…In the tolDC field, we (Hilkens and colleagues) have recently tested the labelling of therapeutic human tolDCs with nanoparticles containing 19 F ( 19 F-NP) for detection by 19 F-MRI [ 54 ]. We found that tolDCs readily endocytosed 19 F-NP with acceptable effects on cell viability and yield and, importantly, without affecting the tolerogenic features of the cells.…”