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Monitoring the efficacy of dendritic cell vaccination by early detection of (99m) Tc-HMPAO-labelled CD4(+) T cells.

ABSTRACT: DC vaccines have been used to induce tumour-specific cytotoxic T cells . However, this approach to cancer immunotherapy has had limited success. To be successful, injected DCs need to migrate to the LNs where they can stimulate effector T cells . We and others have previously demonstrated by MRI that tumour antigen-pulsed-DCs labelled ex vivo with superparamagnetic iron oxide nanoparticles migrated to the draining LNs and are capable of activating antigen-specific T cells . The results from our study demonstrated that ex vivo superparamagnetic iron oxide nanoparticles-labelled and OVA-pulsed DCs prime cytotoxic CD8(+) T-cell responses to protect against a B16-OVA tumour challenge. In the clinic, a possible noninvasive surrogate marker for efficacy of DC vaccination is to image the specific migration and accumulation of T cells following DC vaccination.

SUBMITTER: Sharif-Paghaleh E

PROVIDER: S-EPMC4211358 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Monitoring the efficacy of dendritic cell vaccination by early detection of (99m) Tc-HMPAO-labelled CD4(+) T cells.

Sharif-Paghaleh Ehsan E Leech John J Sunassee Kavitha K Ali Niwa N Sagoo Pervinder P Lechler Robert I RI Smyth Lesley A LA Lombardi Giovanna G Mullen Gregory E GE

European journal of immunology 20140414 7

DC vaccines have been used to induce tumour-specific cytotoxic T cells . However, this approach to cancer immunotherapy has had limited success. To be successful, injected DCs need to migrate to the LNs where they can stimulate effector T cells . We and others have previously demonstrated by MRI that tumour antigen-pulsed-DCs labelled ex vivo with superparamagnetic iron oxide nanoparticles migrated to the draining LNs and are capable of activating antigen-specific T cells . The results from our ...[more]

PMID: 24643793

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Project description:PurposeSentinel lymph node (SLN) biopsy has proven to reliably stage the clinically negative neck in early-stage oral squamous cell carcinoma (OSCC). [99mTc]Tc-tilmanocept may be of benefit in OSCC with complex lymphatic drainage patterns and close spatial relation to SLNs.MethodsA prospective within-patient evaluation study was designed to compare [99mTc]Tc-tilmanocept with [99mTc]Tc-nanocolloid for SLN detection. A total of 20 patients with early-stage OSCC were included, who underwent lymphoscintigraphy with both tracers. Both lymphoscintigraphic images of each patient were evaluated for SLN detection and radiotracer distribution at 2-4 h post-injection.ResultsThe injection site's remaining radioactivity was significantly lower for [99mTc]Tc-tilmanocept (29.9%), compared with [99mTc]Tc-nanocolloid (60.9%; p < 0.001). Radioactive uptake in SLNs was significantly lower for [99mTc]Tc-tilmanocept (1.95%) compared with [99mTc]Tc-nanocolloid (3.16%; p = 0.010). No significant difference was seen in SLN to injection site ratio in radioactivity between [99mTc]Tc-tilmanocept (0.066) and [99mTc]Tc-nanocolloid (0.054; p = 0.232). A median of 3.0 and 2.5 SLNs were identified with [99mTc]Tc-tilmanocept and [99mTc]Tc-nanocolloid, respectively (p = 0.297). Radioactive uptake in higher echelon nodes was not significantly different between [99mTc]Tc-tilmanocept (0.57%) and [99mTc]Tc-nanocolloid (0.86%) (p = 0.052). A median of 2.0 and 2.5 higher echelon nodes was identified with [99mTc]Tc-tilmanocept and [99mTc]Tc-nanocolloid, respectively (p = 0.083).Conclusion[99mTc]Tc-tilmanocept had a higher injection site clearance, but at the same time a lower uptake in the SLN, resulting in an SLN to injection site ratio, which was not significantly different from [99mTc]Tc-nanocolloid. The relatively low-radioactive uptake in SLNs of [99mTc]Tc-tilmanocept may limit intraoperative detection of SLNs, but can be overcome by a higher injection dose.

Project description:ObjectiveSingle-photon emission computed tomography (SPECT) with the tracer 99m Tc-HMPAO is a method to visualize the cerebral hyperperfusion during an epileptic seizure and thus localize the epileptogenic zone and seizure propagation. Subtraction of interictal from Ictal SPECT Co-registered to MRI (SISCOM) visualizes areas with relative increases in cerebral blood flow. The purpose of this retrospective study is to explore the added value of visualizing areas of hypoperfusion as well as hyperperfusion, so-called reversed SISCOM.MethodsFifty-six patients operated for epilepsy who had been investigated with SISCOM were included in the analysis. The patients were divided into two groups based on seizure duration after tracer injection, above or below 30 s. The preoperative SISCOM description was compared to the area of resection and given a concordance score. The 56 SISCOM were recalculated visualizing also areas of hypoperfusion and again compared to the site of resection using the same scale of concordance. The reversed SISCOM were categorized into three subgroups: "Altered Conclusion," "Confirmed Conclusion," and "Adds Nothing." If an area of hyperperfusion had an area of hypoperfusion in close proximity, it was re-interpreted as noise, thus possibly altering the conclusion. If the areas of hypoperfusion were in the opposite hemisphere it was interpreted as confirming factor. Further the concordance scores from conventional SISCOM and reversed SISCOM was compared to surgical outcome to explore the difference in sensitivity, positive predictive value (PPV), and odds ratio.ResultsIn approximately half of the cases reversed SISCOM added additional value, meaning either altered the conclusion or confirmed the conclusion. The sensitivity, PPV, and odds ratio was also better in the subgroup of long, >30 s seizure duration after injection, and got worse in the group with short, <30 s seizure duration after injection.SignificanceAdding reversed SISCOM performed better than conventional SISCOM at predicting good surgical outcome.

Project description:BackgroundObstructive sleep apnea-hypopnea syndrome (OSAHS) could cause systematic inflammation including pulmonary inflammatory response, whereas the influence of OSAHS in pulmonary clearance ability remains unknown. The main pathophysiological feature of OSAHS is chronic intermittent hypoxia (CIH). The goal of this study is to clarify the airway clearance of particulate matter (PM) in CIH mice, and to explore the potential mechanism.MethodsBalb/c mice were divided into a CIH group and a control group, exposed to intermittent hypoxia and air chamber, respectively. A radioactive probe, 99mTc labeled PM, was endotracheally inserted into the mice at 10 mg/kg, with a starting dose of 800 μCi. The change of radioactive dose reserved in the lung was observed using single-photon emission computed tomography/computed tomography (SPECT/CT) and reconstructed data were analyzed. Special airway resistance (sRaw) of mice was measured by non-invasive airway mechanics sites. Lung resistive load (RL), elastic resistance, and compliance were measured by a multichannel physiological signal system. Lung injury was judged by hematoxylin-eosin staining and histologic score. Change in mucus secretion was determined using periodic acid-Schiff staining and enzyme-linked immunosorbent assay. Fresh lung tissue was used for real-time polymerase chain reaction and western blot analysis to explore related change of inflammation and signaling molecules and potential mechanical pathway.ResultsMice in the CIH group had higher PM radioactive deposit than the control group (93.37±3.44 μCi vs. 65.98±2.61 μCi). The average radiation dose in the lung was elevated (0.0005 μCi/mm3 vs. 0.0001383 μCi/mm3). Mice in the CIH group have higher value of sRaw, RL, and elastic resistance, whereas pulmonary compliance decreased compared to the control group (2.13±0.29 mL/cmH2O vs. 5.37±1.02 mL/cmH2O). The CIH group showed a higher histopathological score. Several genes associated with mucin secretion such as chemokine (C-X-C motif) ligand 1 (CXCL1), Clara Cell Secretory Protein 16 (CC16), macrophage inflammatory protein 2 (MIP-2), chloride channel regulator 1 (Gob5), and mucin 5AC (MUC5AC) showed elevated expression. Phosphatidylinostol-3-kinase/serine/threonine-specific protein kinase (PI3K/AKT) pathway was activated in the CIH group.ConclusionsCIH decreased pulmonary clearance of PM and increased lung airway resistance, which may be related to inflammatory response and mucus hypersecretion in the lung.

Project description:Dendritic cells (DCs) generated in vitro to present tumour antigens have been injected in cancer patients to boost in vivo anti-tumour immune responses. This approach to cancer immunotherapy has had limited success. For anti-tumour therapy, delivery and subsequent migration of DCs to lymph nodes leading to effective stimulation of effector T cells is thought to be essential. The ability to non-invasively monitor the fate of adoptively transferred DCs in vivo using magnetic resonance imaging (MRI) is an important clinical tool to correlate their in vivo behavior with response to treatment. Previous reports of superparamagnetic iron oxides (SPIOs) labelling of different cell types, including DCs, have indicated varying detrimental effects on cell viability, migration, differentiation and immune function. Here we describe an optimised labelling procedure using a short incubation time and low concentration of clinically used SPIO Endorem to successfully track murine DC migration in vivo using MRI in a mouse tumour model. First, intracellular labelling of bone marrow derived DCs was monitored in vitro using electron microscopy and MRI relaxometry. Second, the in vitro characterisation of SPIO labelled DCs demonstrated that viability, phenotype and functions were comparable to unlabelled DCs. Third, ex vivo SPIO labelled DCs, when injected subcutaneously, allowed for the longitudinal monitoring by MR imaging of their migration in vivo. Fourth, the SPIO DCs induced the proliferation of adoptively transferred CD4(+) T cells but, most importantly, they primed cytotoxic CD8(+) T cell responses to protect against a B16-Ova tumour challenge. Finally, using anatomical information from the MR images, the immigration of DCs was confirmed by the increase in lymph node size post-DC injection. These results demonstrate that the SPIO labelling protocol developed in this study is not detrimental for DC function in vitro and in vivo has potential clinical application in monitoring therapeutic DCs in patients with cancer.

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Monitoring the efficacy of dendritic cell vaccination by early detection of (99m) Tc-HMPAO-labelled CD4(+) T cells.

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Monitoring the efficacy of dendritic cell vaccination by early detection of (99m) Tc-HMPAO-labelled CD4(+) T cells.

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