This work was supported by NIH 5R21HL127389-02, NIH 4T32HL007111-39, NIH R01HL134664, and DOE DE-SC0008947 grants, International Atomic Energy Agency, Vienna, Mayo Clinic Division of Nuclear Medicine, Department of Radiology, and Mayo Clinic Center for Regenerative Medicine, Rochester, MN. All figures were created using BioRender.com.

<ol>
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Authors have no financial competing interest but are the inventors of this technology (Patent # US20210330823A1).

Following are critical steps in the protocol that need optimization for effective cell radiolabeling. In protocol steps 1.2 and 1.3, depending on the volume of [89Zr]Zr(HPO4)2 or [89Zr]ZrCl4 employed, an appropriate volume (microliters) of base must be used; 1.0 M K2CO3 solution must be used for the neutralization of [89Zr]Zr(HPO4)2 and 1.0 M Na2CO3 solution for the neutralization of [8...

Stem cell and chimeric antigen receptor (CAR) T-cell therapies are gaining popularity and are under active investigation for the treatment of various diseases, such as myocardial failure1,2, retinal degeneration2, macular degeneration2, diabetes2, myocardial infarction3,4,5, and cancers6,7,8,9,10. Among the two plausible approaches of stem cell therapies, stem cells can either be directly engrafted on the disease site to cause a therapeutic response, or cause changes in the microenvironment of the disease site without adhering to the disease site to initiate an indirect therapeutic response. An indirect therapeutic response could cause changes in the microenvironment of the disease site by releasing factors that would repair or treat the disease5. These approaches of stem cell therapies could be evaluated by noninvasive imaging of radiolabeled stem cells. Noninvasive imaging could correlate the uptake of the radiolabeled cells on the disease site with a therapeutic response to decipher the direct versus indirect therapeutic response.
Additionally, immune cell-based therapies are being developed to treat various cancers using CAR T-cell6,7,8,9,10and dendritic cell immunotherapy11,12. Mechanistically, in CAR T-cell immunotherapy6,7,8,9,10, T-cells are engineered to express an epitope that binds to a specific antigen on tumors that needs to be treated. These engineered CAR T-cells, upon administration, bind to the specific antigen present on the tumor cells through an epitope-antigen interaction. After binding, the bound CAR T-cells undergo activation and then proliferate and release cytokines, which signals the immune system of the host to attack the tumor expressing the specific antigen. In contrast, in the case of dendritic cell therapies11,12, dendritic cells are engineered to present a specific cancer antigen on their surface. These engineered dendritic cells, when administered, home to the lymph nodes and bind to the T-cells in the lymph nodes. The T-cells, upon binding to the specific cancer antigens on the administered dendritic cells, undergo activation/proliferation and initiate an immune response of the host against the tumor expressing that specific antigen. Hence, the assessment of trafficking of administered CAR T-cells to a tumor site9,10 and homing of dendritic cells to the lymph nodes11,12 is possible by imaging radiolabeled CAR T-cells and dendritic cells to determine the efficacy of immunotherapy. Furthermore, noninvasive cell trafficking can help to better understand the therapeutic potential, clarify the direct versus indirect therapeutic response, and predict and monitor the therapeutic response of both stem cell and immune cell-based therapies.
Different imaging modalities for cell trafficking have been explored3,4,9,10,12, including optical imaging, magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), and positron emission tomography (PET). Each of these techniques has its own advantages and disadvantages. Among these, PET is the most promising modality due to its quantitative nature and high sensitivity, which are essential for the reliable quantification of cells in imaging-based cell trafficking3,4,9,10.
The positron-emitting radioisotope 89Zr, with a half-life of 78.4 h, is suitable for cell labeling. It allows PET imaging of cell trafficking for over 1 week and is readily produced by widely available, low-energy medical cyclotrons13,14,15,16,17. Additionally, an appropriately functionalized, p-isothiocyanatobenzyl-desferrioxamine (DFO-Bn-NCS) chelator is commercially available for the synthesis of a 89Zr-labeled, ready-to-use, cell labeling synthon, [89Zr]Zr-p-isothiocyanatobenzyl-desferrioxamine, also known as [89Zr]Zr-DBN18,19,20,21,22,23,24,25.&#160;The principle of [89Zr]Zr-DBN-mediated cell labeling is based on a reaction between primary amines of cell membrane proteins and the isothiocyanate (NCS) moiety of [89Zr]Zr-DBN to produce a stable covalent thiourea bond.
[89Zr]Zr-DBN-based cell labeling and imaging have been published to track a variety of different cells, including stem cells18,23,25, dendritic cells18, cardiopoietic stem cells19, decidual stromal cells20,&#160;bone marrow-derived macrophages20, peripheral blood mononuclear cells20, Jurkat/CAR T-cells21, hepatocytes22,24, and white blood cells25. The following protocol provides step-by-step methods of preparation and cell radiolabeling with [89Zr]Zr-DBN and describes changes that may be required in the radiolabeling protocol for a specific cell type. For greater clarity, the method of cell radiolabeling presented here is divided into four sections. The first section deals with the preparation of [89Zr]Zr-DBN by chelating 89Zr&#160;with DFO-Bn-NCS. The second section describes the preparation of a biocompatible formulation of [89Zr]Zr-DBN that can be readily used for cell radiolabeling. The third section covers the steps needed for the preconditioning of cells for radiolabeling. The preconditioning of cells involves washing the cells with protein-free phosphate buffered saline (PBS) and HEPES buffered Hanks balanced salt solution (H-HBSS) to remove external proteins, which might interfere or compete with the reaction of [89Zr]Zr-DBN with primary amines present on the cell surface proteins during radiolabeling. The final section provides steps involved in the actual radiolabeling of the cells and quality control analysis.

<table><tbody><tr><td>Acetonitrile</td><td>Thermo Fisher Scientific, Inc., Waltham, MA, USA</td><td>A996-4</td><td></td></tr><tr><td>Alpha Minimum Essential Medium</td><td>Thermo Fisher Scientific, Inc., Waltham, MA, USA</td><td>12571063</td><td></td></tr><tr><td>Anion exchange column</td><td>Macherey-Nagel, Inc., D&amp;uuml;ren, Germany</td><td>731876</td><td>Chromafix 30-PS-HCO&lt;sub&gt;3&lt;/sub&gt;&amp;nbsp;SPE 45 mg cartridge</td></tr><tr><td>Conical centrifuge tubes (15 mL)</td><td>Corning Inc., Glendale, AZ, USA</td><td>352096</td><td>Falcon 15 mL high-clarity polypropylene (PP) conical centrifuge tubes</td></tr><tr><td>Dendritic cells</td><td>The American Type Culture Collection, Manassas, VA, USA</td><td>CRL-11904</td><td></td></tr><tr><td>DFO-Bn-NCS</td><td>Macrocyclics, Inc., Plano, TX, USA</td><td>B-705</td><td>p-SCN-Bn-Deferoxamine</td></tr><tr><td>DMSO</td><td>Sigma-Aldrich, Inc., St. Louis, MO</td><td>276855</td><td></td></tr><tr><td>Dose calibrator</td><td>Mirion Technologies (Capintec), Inc., Florham Park, NJ, USA</td><td>5130-3234</td><td>CRC -55tR Dose Calibrator&amp;nbsp;</td></tr><tr><td>Dulbecco&amp;rsquo;s modified Eagle&amp;rsquo;s medium&amp;nbsp;</td><td>The American Type Culture Collection, Manassas, VA, USA</td><td>30-2002</td><td></td></tr><tr><td>Fetal Bovine Serum (FBS)</td><td>The American Type Culture Collection, Manassas, VA, USA</td><td>30-2020</td><td></td></tr><tr><td>Hanks Balanced Salt solution (HBSS)</td><td>Thermo Fisher Scientific, Inc., Waltham, MA, USA</td><td>14025092</td><td>For preparation of H-HBSS</td></tr><tr><td>Hydrochloric Acid (trace metal basis grade)</td><td>Thermo Fisher Scientific, Inc., Waltham, MA, USA</td><td>A508P212</td><td></td></tr><tr><td>Melanoma cells</td><td>The American Type Culture Collection, Manassas, VA, USA</td><td>CRL-6475</td><td></td></tr><tr><td>Methanol</td><td>Sigma-Aldrich, Inc., St. Louis, MO</td><td>34860</td><td></td></tr><tr><td>Microcentrifuge tube</td><td>Eppendorf, Hamburg, Germany</td><td>30108442</td><td>Protein LoBind microcentrifuge tube</td></tr><tr><td>Murine GM-CSF</td><td>R&amp;amp;D Systems, Inc., Minneapolis, MN USA</td><td>415-ML-010</td><td></td></tr><tr><td>Penicillin/Streptomycin</td><td>Thermo Fisher Scientific, Inc., Waltham, MA, USA</td><td>15140-122</td><td></td></tr><tr><td>Phosphate Buffered Saline without Ca&lt;sup&gt;2+&lt;/sup&gt; and Mg&lt;sup&gt;2+&lt;/sup&gt;</td><td>Thermo Fisher Scientific, Inc., Waltham, MA, USA</td><td>10010023</td><td>For washing cells</td></tr><tr><td>Saline</td><td>Covidien LLC, Mansfield, MA, USA</td><td>1020</td><td>0.9% Sterile Saline Solution</td></tr><tr><td>Shaker&amp;nbsp;</td><td>Eppendorf, Hamburg, Germany</td><td>T1317</td><td>Thermomixer</td></tr><tr><td>Silica gel-rad-TLC paper sheet&amp;nbsp;</td><td>Agilent Technologies Inc., Santa Clara, CA, USA</td><td>SGI0001</td><td>iTLC-SG</td></tr></tbody></table>

positron emission tomography imaging of cell trafficking: a method of cell radiolabeling

Stem cell and chimeric antigen receptor (CAR) T-cell therapies are emerging as promising therapeutics for organ regeneration and as immunotherapy for various cancers. Despite significant progress having been made in these areas, there is still more to be learned to better understand the pharmacokinetics and pharmacodynamics of the administered therapeutic cells in the living system. For noninvasive, in vivo tracking of cells with positron emission tomography (PET), a novel [89Zr]Zr-p-isothiocyanatobenzyl-desferrioxamine ([89Zr]Zr-DBN)-mediated cell radiolabeling method has been developed utilizing 89Zr (t1/2 78.4 h). The present protocol describes a [89Zr]Zr-DBN-mediated, ready-to-use, radiolabeling synthon for direct radiolabeling of variety of cells, including mesenchymal stem cells, lineage-guided cardiopoietic stem cells, liver regenerating hepatocytes, white blood cells, melanoma cells, and dendritic cells. The developed methodology enables noninvasive PET imaging of cell trafficking for up to 7 days post-administration without affecting the nature or the function of the radiolabeled cells. Additionally, this protocol describes a stepwise method for the radiosynthesis of [89Zr]Zr-DBN, biocompatible formulation of [89Zr]Zr-DBN, preparation of cells for radiolabeling, and finally the radiolabeling of cells with [89Zr]Zr-DBN, including all the intricate details needed for the successful radiolabeling of cells.

The representative results presented in this manuscript were compiled from the previous [89Zr]Zr-DBN synthesis and cell radiolabeling studies18,19,22,23,24,25. In brief, 89Zr can be successfully complexed with DFO-Bn-NCS in ~30-60 min at 25-37 &#176;C using 7.5-15 &#181;g of DFO-Bn-NCS (Table 2</...

Watch this Scientific Journal Video about Positron Emission Tomography Imaging of Cell Trafficking: A Method of Cell Radiolabeling at JoVE.com

Positron Emission Tomography Imaging of Cell Trafficking: A Method of Cell Radiolabeling

Presented here is a protocol to radiolabel cells with a positron emission tomography (PET) radioisotope, 89Zr (t1/2 78.4 h), using a ready-to-use radiolabeling synthon, [89Zr]Zr-p-isothiocyanatobenzyl-desferrioxamine ([89Zr]Zr-DBN). Radiolabeling cells with [89Zr]Zr-DBN allows noninvasive tracking and imaging of administered radiolabeled cells in the body with PET for up to 7 days post-administration.

Stem cell and chimeric antigen receptor (CAR) T-cell therapies are emerging as promising therapeutics for organ regeneration and as immunotherapy for ...

positron-emission-tomography-imaging-cell-trafficking-method-cell

Research

JoVE Journal

Cancer Research

1.6K Views.  Mayo Clinic. Dit protocol beschrijft een stapsgewijze methode voor het radioactief labelen van cellen en zirkonium-89-DBN en de niet-invasieve tracking ervan door PET. Deze techniek biedt ook een betrouwbare en stabiele methode voor het radioactief labelen van cellen door een covalente conjugatie van zirkonium-89-DBN naar de primaire middelen van de celoppervlakte-eiwitten. Artsen en wetenschappers die werken met celtherapieën voor neurologische aandoeningen en verschillende vormen van kanker zullen dit ...

Video: Positron Emission Tomography Imaging of Cell Trafficking: A Method of Cell Radiolabeling

Radiolabeling and Quantification of Cellular Levels of Phosphoinositides by High Performance Liquid Chromatography-coupled Flow Scintillation

Phosphoinositides (PtdInsPs) are essential signaling lipids responsible for recruiting specific effectors and conferring organelles with molecular identity and function. Each of the seven PtdInsPs varies in their distribution and abundance, which are tightly regulated by specific kinases and phosphatases. The abundance of PtdInsPs can change abruptly in response to various signaling events or disturbance of the regulatory machinery. To understand how these events lead to changes in the amount of PtdInsPs and their resulting impact, it is important to quantify PtdInsP levels before and after a signaling event or between control and abnormal conditions. However, due to their low abundance and similarity, quantifying the relative amounts of each PtdInsP can be challenging. This article describes a method for quantifying PtdInsP levels by metabolically labeling cells with 3H-myo-inositol, which is incorporated into PtdInsPs. Phospholipids are then precipitated and deacylated. The resulting soluble 3H-glycero-inositides are further extracted, separated by high-performance liquid chromatography (HPLC), and detected by flow scintillation. The labeling and processing of yeast samples is described in detail, as well as the instrumental setup for the HPLC and flow scintillator. Despite losing structural information regarding acyl chain content, this method is sensitive and can be optimized to concurrently quantify all seven PtdInsPs in cells.

Phosphoinositides are signaling lipids whose relative abundance rapidly changes in response to various stimuli. This article describes a method to measure the abundance of phosphoinositides by metabolically labeling cells with 3H-myo-inositol, followed by extraction and deacylation. Extracted glycero-inositides are then separated by high-performance liquid chromatography and quantified by flow scintillation.

Phosphoinositides (PtdInsPs) are essential signaling lipids responsible for recruiting specific effectors and conferring organelles with molecular ...

Chemistry

Dynamic Imaging of Chimeric Antigen Receptor T Cells with [18F]Tetrafluoroborate Positron Emission Tomography/Computed Tomography

T cells genetically engineered to express chimeric antigen receptors (CAR) have shown unprecedented results in pivotal clinical trials for patients with B cell malignancies or multiple myeloma (MM). However, numerous obstacles limit the efficacy and prohibit the widespread use of CAR T cell therapies due to poor trafficking and infiltration into tumor sites as well as lack of persistence in vivo. Moreover, life-threatening toxicities, such as cytokine release syndrome or neurotoxicity, are major concerns. Efficient and sensitive imaging and tracking of CAR T cells enables the evaluation of T cell trafficking, expansion, and in vivo characterization and allows the development of strategies to overcome the current limitations of CAR T cell therapy. This paper describes the methodology for incorporating the sodium iodide symporter (NIS) in CAR T cells and for CAR T cell imaging using [18F]tetrafluoroborate-positron emission tomography ([18F]TFB-PET) in preclinical models. The methods described in this protocol can be applied to other CAR constructs and target genes in addition to the ones used for this study.

Dynamic Imaging of Chimeric Antigen Receptor T Cells with [18F]Tetrafluoroborate Positron Emission Tomography/Computed Tomography

This protocol describes the methodology for non-invasively tracking T cells genetically engineered to express chimeric antigen receptors in vivo with a clinically available platform.

T cells genetically engineered to express chimeric antigen receptors (CAR) have shown unprecedented results in pivotal clinical trials for patients with B ...

Radiosynthesis and PET/CT Imaging of 68Ga-Labelled Nanobody in Xenograft Models

Radiosynthesis, Quality Control, and Small Animal Positron Emission Tomography Imaging of 68Ga-Labelled Nano Molecules

Small animal Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) imaging techniques are crucial in preclinical cancer research, necessitating meticulous attention to radiotracer synthesis, quality assurance, and in vivo injection protocols. This study presents a comprehensive workflow tailored to enhance the robustness and reproducibility of small animal PET experiments. The synthesis process in the radiochemistry laboratory using 68Ga is detailed, highlighting stringent quality control and assurance protocols for each radiotracer production. Parameters such as concentration, molar activity, pH, and purity are rigorously monitored, aligning with standards applicable to human studies. This methodology introduces streamlined syringe preparation and a custom-designed 30G cannula for precise intravenous injections into mice. Monitoring of animal health during scanning, including temperature and heart rate, ensures their well-being throughout the procedure. Dosages for PET and SPECT scans are predetermined to balance data acquisition with minimizing radiation exposure to animals and researchers. Similarly, CT scans employ pre-programmed settings to limit radiation exposure, especially pertinent in long-term studies assessing treatment effects. By optimizing these steps, the workflow aims to standardize procedures, reduce variability, and enhance the quality of small animal PET/SPECT/CT imaging. This resource provides valuable insights for researchers seeking to improve the accuracy and reliability of preclinical investigations in molecular imaging, ultimately advancing the field.

This paper describes the radiosynthesis, formulation, quality control of a new radiolabeled probe (i.e., 68Ga-labeled nanobody NM-02), and its use for small animal PET/CT imaging in a xenograft model.

Small animal Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) imaging techniques are crucial in preclinical ...

Murine Lymphocyte Labeling by 64Cu-Antibody Receptor Targeting for In Vivo Cell Trafficking by PET/CT

This protocol illustrates the production of 64Cu and the chelator conjugation/radiolabeling of a monoclonal antibody (mAb) followed by murine lymphocyte cell culture and 64Cu-antibody receptor targeting of the cells. In vitro evaluation of the radiolabel and non-invasive in vivo cell tracking in an animal model of an airway delayed-type hypersensitivity reaction (DTHR) by PET/CT are described.
In detail, the conjugation of a mAb with the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) is shown. Following the production of radioactive 64Cu, radiolabeling of the DOTA-conjugated mAb is described. Next, the expansion of chicken ovalbumin (cOVA)-specific CD4+ interferon (IFN)-&#947;-producing T helper cells (cOVA-TH1) and the subsequent radiolabeling of the cOVA-TH1 cells are depicted. Various in vitro techniques are presented to evaluate the effects of 64Cu-radiolabeling on the cells, such as the determination of cell viability by trypan blue exclusion, the staining for apoptosis with Annexin V for flow cytometry, and the assessment of functionality by IFN-&#947; enzyme-linked immunosorbent assay (ELISA). Furthermore, the determination of the radioactive uptake into the cells and the labeling stability are described in detail. This protocol further describes how to perform cell tracking studies in an animal model for an airway DTHR and, therefore, the induction of cOVA-induced acute airway DHTR in BALB/c mice is included. Finally, a robust PET/CT workflow including image acquisition, reconstruction, and analysis is presented.
The 64Cu-antibody receptor targeting approach with subsequent receptor internalization provides high specificity and stability, reduced cellular toxicity, and low efflux rates compared to common PET-tracers for cell labeling, e.g.64Cu-pyruvaldehyde bis(N4-methylthiosemicarbazone) (64Cu-PTSM). Finally, our approach enables non-invasive in vivo cell tracking by PET/CT with an optimal signal-to-background ratio for 48 h. This experimental approach can be transferred to different animal models and cell types with membrane-bound receptors that are internalized.

Murine Lymphocyte Labeling by 64Cu-Antibody Receptor Targeting for In Vivo  Cell Trafficking by PET/CT

Following the preparation of a 64Cu-modified monoclonal antibody binding to a transgenic murine T cell receptor, T cells are radiolabeled in vivo, analyzed for viability, functionality, labeling stability and apoptosis, and adoptively transferred into mice with an airway delayed-type hypersensitivity reaction for non-invasive imaging by positron emission tomography/computed tomography (PET/CT).

This protocol illustrates the production of 64Cu and the chelator conjugation/radiolabeling of a monoclonal antibody (mAb) followed by murine lymphocyte ...

Immunology and Infection

Efficient Synthesis of Carbon-11 Radiotracers Using the Loop Method Methylation

Enhancing Efficiency and Radiolabeling Yields of Carbon-11 Radioligands for Clinical Research Using the Loop Method

A successful positron emission tomography imaging program involving carbon-11 radiotracers demands fast, efficient, and reliable synthesis methods, requiring an on-site cyclotron and radiochemistry group, as well as clinical staff trained to operate under the unique constraints of the carbon-11 radionuclide. This study examines the merits and advantages of a captive solvent &#39;loop method&#39; of radiolabeling four tracers with the carbon-11 radionuclide, producing the radioligands [11C]ER-176, [11C]MRB, [11C]mHED, and [11C]PiB.
The &#39;loop method&#39; is compared against the traditional reactor-based method of carbon-11 methylation in the course of synthesizing the same radiotracers on the identical automated platform. Further, a complete overview of the clinical research preparation of the [11C]ER-176 radiotracer is presented. As demonstrated by the production of [11C]ER-176, the captive solvent &#39;loop method&#39; of heterogeneous alkylation proved to be more efficient, with excellent radiochemical purity (99.6 &#177; 0.6%, n = 25), higher and more consistent radiochemical yield (end of synthesis (EOS) = 5.4 &#177; 2.2 GBq, n = 25) compared to the reactor method (EOS = 1.6 &#177; 0.5 GBq, n = 6), increased molar activity (loop method = 194 &#177; 66 GBq/&#181;mol, n = 25; reactor method = 132 &#177; 78 GBq/&#181;mol, n = 6), along with an average 5 min shorter reaction sequence.

This protocol presents a detailed procedure to prepare four carbon-11 radiotracers by way of the &#8220;loop method&#8221; [11C]methylation. We describe the procedure to synthesize [11C]ER-176, &#160;with data for three additional radiotracers: [11C]MRB, [11C]mHED, and [11C]PiB. The loop method provides an efficient synthesis with increased radiochemical yields against traditional reaction vessel [11C]methylation.

A successful positron emission tomography imaging program involving carbon-11 radiotracers demands fast, efficient, and reliable synthesis methods, ...

Fluorescence-Activated Cell Sorting-Radioligand Treated Tissue (FACS-RTT) to Determine the Cellular Origin of Radioactive Signal

Glial cells probably have a considerable implication in the pathophysiology of neurodegenerative disorders, such as Alzheimer's disease (AD). Their alterations are perhaps associated with a pro-inflammatory state. The TgF344-AD rat strain has been designed to express human APP and human PS1&#916;E9 genes, encoding for amyloid proteins A&#946;-40 and A&#946;-42 and displays amyloid pathology and cognitive deficits with aging. The TgF344-AD rat model is used in this study to evaluate the cellular origin of the 18 kDa translocator protein (TSPO, a marker of glial cell activation) binding, and the 5HT2A-receptor (5HT2AR) serotonin receptor levels that are possibly disrupted in AD. The technique presented here is Fluorescence-Activated Cell Sorting to Radioligand Treated Tissue (FACS-RTT), a quantitative cell-type-specific technique complementary to in vivo PET or SPECT or ex vivo/in vitro autoradiography techniques. It quantifies the same radiolabeled tracer used prior for imaging, using a &#947; counter after cytometry cell sorting. This allows determining the cellular origin of the radiolabeled protein with high cellular specificity and sensitivity. For example, studies with FACS-RTT showed that (i) the increase in TSPO binding was associated with microglia in a rat model of lipopolysaccharide (LPS)-induced neuroinflammation, (ii) an increase in TSPO binding at 12- and 18-months was associated with astrocytes first, and then microglia in the TgF344-AD rats compared to wild type (WT) rats, and (iii) the striatal density of 5HT2AR decreases in astrocytes at 18 months in the same rat AD model. Interestingly, this technique can be extended to virtually all radiotracers.

Fluorescence-Activated Cell Sorting-Radioligand Treated Tissue FACS-RTT to Determine the Cellular Origin of Radioactive Signal

Fluorescence-Activated Cell Sorting-Radioligand Treated Tissue (FACS-RTT) is a powerful tool to study the role of the 18 kDa translocator protein or Serotonin 5HT2A-receptor expression in Alzheimer&#39;s Disease at a cellular scale. This protocol describes the ex-vivo application of FACS-RTT in the TgF344-AD rat model.

Glial cells probably have a considerable implication in the pathophysiology of neurodegenerative disorders, such as Alzheimer's disease (AD). Their ...

Neuroscience

Tracking Drug-induced Changes in Receptor Post-internalization Trafficking by Colocalizational Analysis

The intracellular trafficking of receptors is a collection of complex and highly controlled processes. Receptor trafficking modulates signaling and overall cell responsiveness to ligands and is, itself, influenced by intra- and extracellular conditions, including ligand-induced signaling. Optimized for use with monolayer-plated cultured cells, but extendable to free-floating tissue slices, this protocol uses immunolabelling and colocalizational analysis to track changes in intracellular receptor trafficking following both chronic/prolonged and acute interventions, including exogenous drug treatment. After drug treatment, cells are double-immunolabelled for the receptor and for markers for the intracellular compartments of interest. Sequential confocal microscopy is then used to capture two-channel photomicrographs of individual cells, which are subjected to computerized colocalizational analysis to yield quantitative colocalization scores. These scores are normalized to permit pooling of independent replicates prior to statistical analysis. Representative photomicrographs may also be processed to generate illustrative figures. Here, we describe a powerful and flexible technique for quantitatively assessing induced receptor trafficking.

Receptor trafficking modulates signaling and cell responsiveness to ligands and is, itself, responsive to cell conditions, including ligand-induced signaling. Here, we describe a powerful and flexible technique for quantitatively assessing drug-induced receptor trafficking using immunolabeling and colocalizational analysis.

The intracellular trafficking of receptors is a collection of complex and highly controlled processes. Receptor trafficking modulates signaling and ...

Biology

Imaging the Intracellular Trafficking of APP with Photoactivatable GFP

Beta-amyloid (A&#946;) is the major constituent of senile plaques found in the brains of Alzheimer&#8217;s disease patients. A&#946; is derived from the sequential cleavage of Amyloid Precursor Protein (APP) by &#946; and &#947;-secretases. Despite the importance of A&#946; to AD pathology, the subcellular localization of these cleavages is not well established. Work in our laboratory and others implicate the endosomal/lysosomal system in APP processing after internalization from the cell surface. However, the intracellular trafficking of APP is relatively understudied.
While cell-surface proteins are amendable to many labeling techniques, there are no simple methods for following the trafficking of membrane proteins from the Golgi. To this end, we created APP constructs that were tagged with photo-activatable GFP (paGFP) at the C-terminus. After synthesis, paGFP has low basal fluorescence, but it can be stimulated with 413 nm light to produce a strong, stable green fluorescence. By using the Golgi marker Galactosyl transferase coupled to Cyan Fluorescent Protein (GalT-CFP) as a target, we are able to accurately photoactivate APP in the trans-Golgi network. Photo-activated APP-paGFP can then be followed as it traffics to downstream compartments identified with fluorescently tagged compartment marker proteins for the early endosome (Rab5), the late endosome (Rab9) and the lysosome (LAMP1). Furthermore, using inhibitors to APP processing including chloroquine or the &#947;-secretase inhibitor L685, 458, we are able to perform pulse-chase experiments to examine the processing of APP in single cells.
We find that a large fraction of APP moves rapidly to the lysosome without appearing at the cell surface, and is then cleared from the lysosome by secretase-like cleavages. This technique demonstrates the utility of paGFP for following the trafficking and processing of intracellular proteins from the Golgi to downstream compartments.

While the transport of cell surface proteins is relatively easily studied, visualizing the trafficking of intracellular proteins is much more difficult. Here, we use constructs incorporating photoactivatable GFP and demonstrate a method to accurately follow the amyloid precursor protein from the Golgi apparatus to down-stream compartments and follow its clearance.

Beta-amyloid (A&#946;) is the major constituent of senile plaques found in the brains of Alzheimer&#8217;s disease patients. A&#946; is derived from the ...

Imaging CD19+ B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model using Positron Emission Tomography

Multiple sclerosis (MS) is the most common demyelinating central nervous system (CNS) disease affecting young adults, often resulting in neurological deficits and disability as the disease progresses. B lymphocytes play a complex and critical role in MS pathology and are the target of several therapeutics in clinical trials. Currently, there is no way to accurately select patients for specific anti-B cell therapies or to non-invasively quantify the effects of these treatments on B cell load in the CNS and peripheral organs. Positron emission tomography (PET) imaging has enormous potential to provide highly specific, quantitative information regarding the in vivo spatiotemporal distribution and burden of B cells in living subjects.
This paper reports methods to synthesize and employ a PET tracer specific for human CD19+ B cells in a well-established B cell-driven mouse model of MS, experimental autoimmune encephalomyelitis (EAE), which is induced with human recombinant myelin oligodendrocyte glycoprotein 1-125. Described here are optimized techniques to detect and quantify CD19+ B cells in the brain and spinal cord using in vivo PET imaging. Additionally, this paper reports streamlined methods for ex vivo gamma counting of disease-relevant organs, including bone marrow, spinal cord, and spleen, together with high-resolution autoradiography of CD19 tracer binding in CNS tissues.

Imaging CD19+ B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model using Positron Emission Tomography

This paper details methodology for radiolabeling a human-specific anti-CD19 monoclonal antibody and how to use it to quantify B cells in the central nervous system and peripheral tissues of a mouse model of multiple sclerosis using in vivo PET imaging, ex vivo gamma counting, and autoradiography approaches.

Multiple sclerosis (MS) is the most common demyelinating central nervous system (CNS) disease affecting young adults, often resulting in neurological ...

Labeling Murine T Helper Lymphocytes using Radiolabeled Monoclonal Antibodies

Source: Hoffmann, S. H. L., et al., <a href="https://app.jove.com/v/55270">Murine Lymphocyte Labeling by 64Cu-Antibody Receptor Targeting for In Vivo Cell Trafficking by PET/CT.</a> J. Vis. Exp. (2017)
In this video, we demonstrate the intracellular radiolabeling of T helper cells using radioactive isotope-conjugated monoclonal antibodies for non-invasive positron emission tomography imaging.

Source: Hoffmann, S. H. L., et al., Murine Lymphocyte Labeling by 64Cu-Antibody Receptor Targeting for In Vivo Cell Trafficking by PET/CT. J. Vis. Exp. ...

Positron Emission Tomography Imaging of Cell Trafficking: A Method of Cell Radiolabeling

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