Communicating About Precision Transplantation Tools.

Purpose of review: Precision tools that ensure molecular compatibility can help prevent rejection and improve kidney transplantation outcomes. However, these tools will generate controversy because they are perceived to and can in fact impact equity in the ethics of allocation. They may also affect the extent to which physicians can advocate for their patient fiduciaries, as generally required by Canadian professional ethics and law. Sources of information: Electronic databases such as Google Scholar and PubMed were searched for peer-reviewed literature, and Google search engine was used to identify the news articles, jurisprudence, legal information, and other relevant websites cited. Methods: We discuss controversies precision transplantation tools will likely generate, consider what challenges will arise from their implementation, and provide recommendations of avenues and content for communication to address these issues. Key findings: Communication about the translation of new precision tools will be challenging as media portrayals of transplantation often focus on individual narratives about access to transplantation and fail to center the issues of utility, allocation, and rejection. Incomplete portrayals of this nature will need to be countered with explanations of how new precision tools can be of net benefit when implemented equitably, as maintaining trust in the donation and transplantation system is key. Limitations: Our manuscript focuses on precision medicine applications pertaining to the implementation of molecular compatibility in transplantation. Distinct communication content and avenues may need to be considered in other contexts. Implications: Clear, accurate, and strategic communication is key to managing translation of precision medicine tools. For this purpose, we provide detailed recommendations for stakeholder engagement, content, and avenues for communicating about precision transplantation tools.

Motif de la revue: Les outils de précision assurant la compatibilité moléculaire peuvent aider à prévenir le rejet et à améliorer les résultats de la transplantation rénale. Or, ces outils susciteront une controverse parce qu'ils sont perçus comme ayant une incidence sur l'équité dans l'éthique de l'allocation, et qu'ils peuvent effectivement en avoir une. Ces outils sont également susceptibles d'influer sur les limites au sein desquelles les médecins peuvent défendre les intérêts de leurs patients fiduciaires, comme l'exigent l'éthique professionnelle et le droit canadien. Sources: Des bases de données électroniques telles que Google Scholar et PubMed ont été consultées à la recherche de la documentation évaluée par des pairs. Le moteur de recherche Google a servi à répertorier les articles de presse, la jurisprudence, les informations juridiques et les autres sites Web pertinents cités. Méthodologie: Nous discutons des controverses qui seront vraisemblablement générées par les nouveaux outils de précision liés à la transplantation. Nous examinons également les défis qui découleront de leur mise en œuvre et nous formulons des recommandations sur les stratégies et le contenu à adopter dans les communications qui aborderont ces questions. Principales observations: La communication entourant l'application des nouveaux outils de précision posera un défi, car les représentations médiatiques de la transplantation se concentrent le plus souvent sur des récits individuels liés à l'accès à la transplantation, et ne mettent pas en lumière les problèmes liés à l'utilité, l'attribution et le rejet. Ces représentations incomplètes devront être contrebalancées par des explications sur la façon dont les nouveaux outils de précision pourront être bénéfiques s'ils sont mis en œuvre équitablement; car il est essentiel de maintenir la confiance dans le système de don et de transplantation. Limites: Notre article porte sur les applications de la médecine de précision en lien avec la mise en œuvre d'outils mesurant la compatibilité moléculaire en transplantation. Il faudra possiblement envisager des stratégies et un contenu de communication distincts dans d'autres contextes. Conclusion: Une stratégie de communication claire et précise est essentielle pour gérer l'application des outils de la médecine de précision. À cette fin, nous fournissons des recommandations détaillées sur l'engagement des intervenants, ainsi qu'en matière de contenu et de stratégies pour les communications liées aux nouveaux outils de précision en transplantation.

Dialysis and Transplant Considerations in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the fourth leading cause of kidney replacement therapy. Unfortunately, the need for dialysis or kidney transplantation is a foreseeable outcome for many patients affected by ADPKD. We review some of the unique issues that should be considered in the management of patients with ADPKD who require dialysis or kidney transplantation. The choice of dialysis modality may be influenced by the enlarged kidneys and liver, but peritoneal dialysis should not be excluded as an option, as studies do not consistently show that there is an increased risk for technique failure or peritonitis. The optimal kidney replacement therapy option remains kidney transplantation; however, nephrectomy may be needed if there is insufficient space for the allograft. Living donor candidates from at-risk families need to be excluded from carrying the disease either by diagnostic imaging criteria or genetic testing. Other potential transplant issues, such as malignancy and cardiovascular and metabolic risks, should also be recognized. Despite these issues, patients with ADPKD requiring dialysis or kidney transplantation generally have more favorable outcomes as compared to those with other causes of chronic kidney disease. Further studies are still needed to personalize the therapeutic approach for those receiving kidney replacement therapy and eventually improve clinical outcomes.

Health Services Use and Outcomes for Hospital Admissions With a Major Cardiovascular Event Recorded in Health Care Administrative Data in Patients Receiving Maintenance Hemodialysis: A Retrospective Cohort Study.

Background: Administrative data are used in studies of hemodialysis care to report cardiovascular-related hospitalizations. Showing recorded events are associated with significant health care resource use and poor outcomes would confirm that administrative data algorithms identify clinically meaningful events. Objective: The objective of this study was to describe the 30-day health service use and outcomes when a hospital admission with myocardial infarction, congestive heart failure, or ischemic stroke is recorded in administrative databases. Design: This is a retrospective review of linked administrative data. Patients and Setting: Patients receiving maintenance in-center hemodialysis in Ontario, Canada, between April 1, 2013, and March 31, 2017, were included. Measurements: Records from linked health care databases at ICES in Ontario, Canada were considered. We identified hospital admission with the most responsible diagnosis recorded as myocardial infarction, congestive heart failure, or ischemic stroke. We then assessed the frequency of common tests, procedures, consultations, post-discharge outpatient drug prescriptions, and outcomes within 30 days following the hospital admission. Methods: We used descriptive statistics to summarize results using counts and percentages for categorical variables and means with standard deviations or medians with quartile ranges for continuous variables. Results: There were 14 368 patients who received maintenance hemodialysis between April 1, 2013, and March 31, 2017. The number of events per 1000 person-years was 33.5 for hospital admissions with myocardial infarction, 34.2 for congestive heart failure, and 12.9 for ischemic stroke. The median (25th, 75th percentile) duration of hospital stay was 5 (3-10) days for myocardial infarction, 4 (2-8) days for congestive heart failure, and 9 (4-18) days for ischemic stroke. The chance of death within 30 days was 21% for myocardial infarction, 11% for congestive heart failure, and 19% for ischemic stroke. Limitations: Events, procedures, and tests recorded in administrative data can be misclassified compared with medical charts. Conclusions: In patients receiving maintenance hemodialysis, hospital admissions of major cardiovascular events routinely recorded in health administrative databases are associated with significant use of health service resources and poor health outcomes.

Contexte: Les données administratives sont utilisées pour signaler les hospitalisations liées aux maladies cardiovasculaires dans les études portant sur les soins en hémodialyse. Montrer que les événements signalés sont associés à une utilisation importante des ressources en santé et à une évolution défavorable confirmerait que les algorithmes de données administratives identifient les événements cliniquement significatifs. Objectif: Décrire les interventions et l'évolution de l'état de santé sur une période de 30 jours lorsqu'une hospitalisation pour infarctus du myocarde, insuffisance cardiaque congestive ou accident vasculaire cérébral (AVC) ischémique est enregistrée dans les bases de données administratives. Type d'étude: Revue rétrospective de bases de données administratives couplées. Sujets et cadre de l'étude: Patients sous hémodialyse chronique en milieu hospitalier en Ontario (Canada) entre le 1er avril 2013 et le 31 mars 2017. Mesures: Les dossiers provenant des bases de données couplées de l'ICES en Ontario (Canada). Nous avons répertorié les hospitalisations dont le diagnostic principal enregistré était un infarctus du myocarde, une insuffisance cardiaque congestive ou un AVC ischémique. Nous avons ensuite évalué la fréquence des examens, des procédures, des consultations, des ordonnances de médicaments en consultation externe après la sortie de l'hôpital et des résultats dans les 30 jours suivant l'hospitalisation. Méthodologie: Nous avons utilisé des statistiques descriptives pour résumer les résultats. Des décomptes et pourcentages ont été utilisés pour les variables catégoriques; des moyennes avec écarts-types ou des médianes avec des intervalles de quartiles ont été utilisées pour les variables continues. Résultats: En tout, il y avait 14 368 patients sous hémodialyse chronique entre le 1er avril 2013 et le 31 mars 2017. Le nombre d'événements par 1 000 années-personnes était de 33,5 pour les hospitalisations avec infarctus du myocarde, de 34,2 avec insuffisance cardiaque congestive et de 12,9 pour AVC ischémique. La durée médiane (25e, 75e percentile) de l'hospitalisation était de 5 (3 à 10) jours pour l'infarctus du myocarde, de 4 (2 à 8) jours pour l'insuffisance cardiaque congestive et de 9 (4 à 18) jours pour l'AVC ischémique. Le risque de décès dans les 30 jours était de 21 % pour l'infarctus du myocarde, de 11 % pour l'insuffisance cardiaque congestive et de 19 % pour l'AVC ischémique. Limites: Les événements, les procédures et les examens enregistrés dans les bases de données administratives peuvent être sujets à des erreurs de classification par rapport aux dossiers médicaux. Conclusion: Chez les patients sous hémodialyse chronique, les hospitalisations enregistrées dans les bases de données administratives à la suite d'événements cardiovasculaires majeurs sont associées à une utilisation importante des ressources en santé et à une évolution défavorable de l'état de santé.

Albuminuria, Reduced Kidney Function, and the Risk of ST - and non-ST-segment-elevation myocardial infarction.

Background Chronic kidney disease is a recognized independent risk factor for cardiovascular disease, but whether the risks of ST-segment-elevation myocardial infarction ( STEMI ) and non-ST-segment-elevation myocardial infarction ( NSTEMI ) differ in the chronic kidney disease population is unknown. Methods and Results Using administrative data from Ontario, Canada, we examined patients ≥66 years of age with an outpatient estimated glomerular filtration rate ( eGFR ) and albuminuria measure for incident myocardial infarction from 2002 to 2015. Adjusted Fine and Gray subdistribution hazard models accounting for the competing risk of death were used. In 248 438 patients with 1.2 million person-years of follow-up, STEMI , NSTEMI , and death occurred in 1436 (0.58%), 4431 (1.78%), and 30 015 (12.08%) patients, respectively. The highest level of albumin-to-creatinine ratio (>30 mg/mmol) was associated with a 2-fold higher adjusted risk of both STEMI and NSTEMI among patients with eGFR ≥60 mL/(min·1.73 m2) compared to albumin-to-creatinine ratio <3 mg/mmol. The lowest level of eGFR (<30 mL/[min·1.73 m2]) was not associated with higher STEMI risk but with a 4-fold higher risk of NSTEMI compared to those with eGFR ≥60 mL/(min·1.73 m2). The lowest eGFR (<30 mL/[min·1.73 m2]) and highest albumin-to-creatinine ratio (>30 mg/mmol) were associated with a greater than 4-fold higher risk of both STEMI and NSTEMI (subdistribution hazard models [95% confidence interval] 4.53 [3.30-6.21] and 4.42 [3.67-5.32], respectively) compared to albumin-to-creatinine ratio <3 mg/mmol and eGFR ≥60 mL/(min·1.73 m2). Conclusions Elevations in albuminuria are associated with a higher risk of both NSTEMI and STEMI , regardless of kidney function, whereas reduced kidney function alone is associated with a higher NSTEMI risk.

The Risk of Adverse Events in Patients With Polycystic Kidney Disease With Advanced Chronic Kidney Disease.

BACKGROUND: Polycystic kidney disease (PKD) leads to progressive chronic kidney disease (CKD) with a subsequent risk of adverse events such as cardiac disease, infections, end-stage kidney disease (ESKD), and mortality. OBJECTIVES: To determine the risks of CKD-related adverse outcomes in patients with PKD compared with patients without PKD. SETTING: Canadian study of prediction of death, dialysis and interim cardiovascular events (CanPREDDICT) was a prospective pan-Canadian cohort study from 2008-2013 involving 28 facilities with adjudicated outcomes. PATIENTS: Adult CKD patients (estimated glomerular filtration rate [eGFR] = 15-45 mL/min/1.73 m2) under the care of a nephrologist. MEASUREMENTS: Polycystic kidney disease as identified by the treating physician. METHODS: Patients with PKD (PKD) and non-PKD were propensity score (PS) matched (1:4) using demographics, comorbidities, and laboratory values. We used conditional Cox proportional hazards models to examine the risk of cardiac disease (defined as coronary artery disease or congestive heart failure), infection, ESKD, or all-cause mortality in patients with PKD compared with no PKD. RESULTS: Among a total of 2370 patients, 105 with PKD were matched with 416 without PKD with a baseline mean age and eGFR of 62.6 years and 27.8 mL/min, respectively. During 1680 person-years of follow time (median follow-up: 3.8 years), there were a total of 43 cardiac, 83 ESKD, 117 infectious, and 39 all-cause mortality events. PKD was associated with a higher risk of cardiac events (9.5% vs 7.9%, hazard ratio [HR] = 1.46, 95% confidence interval [CI] = 1.04-2.04) and ESKD (25.7% vs 13.5%, HR = 2.00, 95% CI = 1.33-3.01), and with similar risks for infection (21.9% vs 22.6%, HR = 1.16, 95% CI = 0.75-1.82) or all-cause mortality (6.7% vs 7.7%, HR = 0.87, 95% CI = 0.40-1.91) compared with non-PKD. There were no differences in the types of infections (urinary, respiratory, hematologic, or other) between the 2 groups (P = .585). CONCLUSIONS: Patients with PKD with advanced CKD are at a potentially higher risk of ESKD and cardiac events compared with patients without PKD. These findings, if confirmed in larger cohorts, suggest that monitoring and treatment for adverse outcomes in patients with PKD, especially related to cardiac disease, may be beneficial.

CONTEXTE: La maladie polykystique des reins (MPR) mène à l'insuffisance rénale chronique (IRC) progressive, laquelle augmente à son tour la probabilité d'apparition de pathologies subséquentes, notamment cardiopathie, infections et insuffisance rénale terminale (IRT), ainsi que le risque de décès du patient. OBJECTIFS DE L'ÉTUDE: L'étude visait à évaluer le risque de survenue d'une pathologie associée à l'IRC chez les patients atteints d'une MPR en comparaison avec les patients non atteints d'une MPR. CADRE ET TYPE D'ÉTUDE: Il s'agit d'une étude de cohorte prospective pancanadienne, la CanPREDDICT (Canadian Study of Prediction of Death, Dialysis and Interim Cardiovascular Events). L'étude s'est tenue entre 2008 et 2013 au sein de 28 établissements, et les issues étaient rigoureusement définies et jugées par un comité. PARTICIPANTS: Des patients adultes atteints d'IRC (DFGe = 15-45 mL/min/1,73 m2) suivis par un néphrologue. MESURE: La maladie polykystique des reins (MPR) telle que diagnostiquée par le médecin traitant. MÉTHODOLOGIE: Le jumelage des patients atteints de la maladie polykystique rénale autosomique dominante (MPRAD) avec les sujets contrôles s'est fait sur la base du score de propension dans un rapport d'un pour quatre (1:4). Les autres critères employés pour le jumelage étaient le profil démographique des patients, leurs comorbidités et leurs résultats de laboratoire. Des modèles conditionnels des risques proportionnels de Cox ont été utilisés pour évaluer le risquei) de développer une cardiopathie (coronopathie ou insuffisance cardiaque congestive) ouii) une infection ouiii) une évolution vers l'IRT, de même queiv) le risque de mortalité (toutes causes confondues), dans les deux groupes de patients. RÉSULTATS: Parmi les 2 370 participants, 105 atteints de MPR ont été jumelés à 416 patients non atteints. L'âge initial moyen des participants était de 62,6 ans et leur DFGe moyen se situait à 27,8 mL/min/1,73 m2. Au cours des 1 680 années-personnes de suivi (suivi moyen de 3,8 ans par patient), on a répertorié 43 cas de cardiopathie et 117 cas d'infection; 83 patients ont développé une IRT et 39 sont décédés (toutes causes confondues). La MPR a été associée à un risque plus élevé de cardiopathie (9,5 % [MPR] c. 7,9 % [non MPR]; RR : 1,46; IC à 95 % : 1,04-2,04) et d'évolution vers l'IRT (25,7 % [MPR] c. 13,5 % [non MPR]; RR : 2,00; IC à 95 % : 1,33-3,01) par rapport aux patients non atteints. Les risques d'infection (21,9 % [MPR] c. 22,6 % [non MPR]; RR : 1,16; IC à 95 % : 0,75-1,82) et de mortalité toutes causes confondues (6,7 % [MPR] c. 7,7 % [non MPR]; RR : 0,87; IC à 95 %; 0,40-1,91) se sont toutefois avérés similaires dans les deux groupes. De plus, aucune différence n'a été observée selon le type d'infection (urinaire, respiratoire, hématologique ou autre) entre les deux groupes (P = 0,585). CONCLUSION: Les patients atteints d'un stade avancé d'IRC et d'une MPR sont plus à risque d'évoluer vers l'IRT ou de développer une cardiopathie que les patients non atteints d'une MPR. Ces résultats, s'ils sont confirmés par des études sur cohortes plus nombreuses, suggèrent que le suivi et le traitement des pathologies associés à la MPR sur la santé des patients, particulièrement la cardiopathie, pourraient s'avérer bénéfiques.

Origins of R2* orientation dependence in gray and white matter.

Estimates of the apparent transverse relaxation rate (R2*) can be used to quantify important properties of biological tissue. Surprisingly, the mechanism of R2* dependence on tissue orientation is not well understood. The primary goal of this paper was to characterize orientation dependence of R2* in gray and white matter and relate it to independent measurements of two other susceptibility based parameters: the local Larmor frequency shift (fL) and quantitative volume magnetic susceptibility (Δχ). Through this comparative analysis we calculated scaling relations quantifying R2' (reversible contribution to the transverse relaxation rate from local field inhomogeneities) in a voxel given measurements of the local Larmor frequency shift. R2' is a measure of both perturber geometry and density and is related to tissue microstructure. Additionally, two methods (the Generalized Lorentzian model and iterative dipole inversion) for calculating Δχ were compared in gray and white matter. The value of Δχ derived from fitting the Generalized Lorentzian model was then connected to the observed R2* orientation dependence using image-registered optical density measurements from histochemical staining. Our results demonstrate that the R2* and fL of white and cortical gray matter are well described by a sinusoidal dependence on the orientation of the tissue and a linear dependence on the volume fraction of myelin in the tissue. In deep brain gray matter structures, where there is no obvious symmetry axis, R2* and fL have no orientation dependence but retain a linear dependence on tissue iron concentration and hence Δχ.

Temporal changes in monocyte and macrophage subsets and microglial macrophages following spinal cord injury in the Lys-Egfp-ki mouse model.

The role of hematogenous (hMΦ) and microglial (mMΦ) macrophages following spinal cord injury (SCI) remains unclear as they are not distinguished easily from each other in the lesion area. We have recently described the temporal and spatial response to SCI of each MΦ population using the lys-EGFP-ki mouse that enables EGFP(+) hMΦ to be distinguished from EGFP(-) mMΦ at the lesion site. In the present study, we characterized the response of monocyte and hMΦ subsets and mMΦ to SCI. We describe, for the first time, the responses of circulating classical (pro-inflammatory) and non-classical monocyte subsets to SCI. Additionally, we show the presence of classical and non-classical hMΦ at the SCI lesion. Importantly, we demonstrate that the 'classical pro-inflammatory' hMΦ respond in the acute (1d, 3d) stages of SCI while the 'non-classical' hMΦ respond in the sub-acute (7d, 14d) phase of SCI. At later time points (6weeks post injury) classical hMΦ return to the injury site. Our study offers new insight into the cellular inflammatory response that occurs after SCI and suggests that the timing and targets of anti-inflammatory therapies may be crucial to maximize neuroprotection at the acute and more chronic stages of SCI.

Tracking and evaluation of dendritic cell migration by cellular magnetic resonance imaging.

Cellular magnetic resonance imaging (MRI) is a means by which cells labeled ex vivo with a contrast agent can be detected and tracked over time in vivo. This technology provides a noninvasive method with which to assess cell-based therapies in vivo. Dendritic cell (DC)-based vaccines are a promising cancer immunotherapy, but its success is highly dependent on the injected DC migrating to a secondary lymphoid organ such as a nearby lymph node. There the DC can interact with T cells to elicit a tumor-specific immune response. It is important to verify DC migration in vivo using a noninvasive imaging modality, such as cellular MRI, so that important information regarding the anatomical location and persistence of the injected DC in a targeted lymph node can be provided. An understanding of DC biology is critical in ascertaining how to label DC with sufficient contrast agent to render them detectable by MRI. While iron oxide nanoparticles provide the best sensitivity for detection of DC in vivo, a clinical grade iron oxide agent is not currently available. A clinical grade (19) Fluorine-based perfluorcarbon nanoemulsion is available but is less sensitive, and its utility to detect DC migration in humans remains to be demonstrated using clinical scanners presently available. The ability to quantitatively track DC migration in vivo can provide important information as to whether different DC maturation and activation protocols result in improved DC migration efficiency which will determine the vaccine's immunogenicity and ultimately the tumor immunotherapy's outcome in humans.

Cellular MRI as a suitable, sensitive non-invasive modality for correlating in vivo migratory efficiencies of different dendritic cell populations with subsequent immunological outcomes.

The clinical application of dendritic cells (DC) as adjuvants in immunotherapies such as the cell-based cancer vaccine continues to gain interest. The overall efficacy of this emerging immunotherapy, however, remains low. Studies suggest the stage of maturation and activation of ex vivo-prepared DC immediately prior to patient administration is critical to subsequent DC migration in vivo, which ultimately affects overall vaccine efficacy. While it is possible to generate mature and activated DC ex vivo using various stimulatory cocktails, in the case of cancer patients, the qualitative and quantitative assessment of which DC stimulatory cocktail works most effectively to enhance subsequent DC migration in vivo is difficult. Thus, a non-invasive imaging modality capable of monitoring the real-time migration of DC in long-term studies is required. In this paper, we address whether cellular magnetic resonance imaging (MRI) is sufficiently sensitive to quantitatively detect differences in the migratory abilities of two different DC preparations: untreated (resting) versus ex vivo matured in a mouse model. In order to distinguish our ex vivo-generated DC of interest from surrounding tissues in magnetic resonance (MR) images, DC were labeled in vitro with the superparamagnetic iron oxide (SPIO) nanoparticle FeREX®. Characterization of DC phenotype and function following addition of a cytokine maturation cocktail and the toll-like receptor ligand CpG, both in the presence and in the absence of SPIO, were also carried out. Conventional histological techniques were used to verify the quantitative data obtained from MR images. This study provides important information relevant to tracking the in vivo migration of ex vivo-prepared and stimulated DC.

Cellular magnetic resonance imaging of monocyte-derived dendritic cell migration from healthy donors and cancer patients as assessed in a scid mouse model.

BACKGROUND AIMS. The use of dendritic cells (DC) as an adjuvant in cell-based immunotherapeutic cancer vaccines is a growing field of interest. A reliable and non-invasive method to track the fate of autologous DC following their administration to patients is required in order to confirm that clinically sufficient numbers are reaching the lymph node (LN). We demonstrate that an immunocompromised mouse model can be used to conduct translational studies employing cellular magnetic resonance imaging (MRI). Such studies can provide clinically relevant information regarding the migration potential of clinical-grade DC used in cancer immunotherapies. METHODS. Human monocyte-derived dendritic cells (mo-DC) were generated from negatively selected monocytes obtained from either healthy donors or cancer patients. DC were labeled with superparamagnetic iron oxide (SPIO) nanoparticles in order to track them in vivo in a CB17scid mouse model using cellular MRI. SPIO did not have any adverse effects on DC phenotype or function, independent of donor type. Cellular MRI readily detected migration of SPIO-loaded DC in CB17scid mice. No differences in migration were observed between DC obtained from healthy donors and those obtained from donors undergoing autologous stem cell transplant for cancer therapy. CONCLUSIONS. Cellular MRI provided semi-quantitative image data that corresponded with data obtained by digital morphometry, validating cellular MRI's potential to assess DC migration in DC-based cancer immunotherapy clinical trials.

Labelling dendritic cells with SPIO has implications for their subsequent in vivo migration as assessed with cellular MRI.

An optimized non-invasive imaging modality capable of tracking and quantifying in vivo DC migration in patients would provide clinicians with valuable information regarding therapeutic DC-based vaccine outcomes. Superparamagnetic iron oxide (SPIO) nanoparticles were used to label bone marrow-derived DC. In vivo DC migration was tracked and quantified non-invasively using cellular magnetic resonance imaging (MRI) in a mouse model. Labelling DC with SPIO reflects the kinetics of DC migration in vivo but appears to reduce overall DC migration, in part due to nanoparticle size. Magnetic separation of SPIO-labelled (SPIO(+)) DC from unlabelled (SPIO(-)) DC prior to injection improves SPIO(+) DC migration to the lymph node. Corresponding MR image data better correlate with the presence of DC in vivo; an improved immunological response is also seen. Cellular MRI is a viable, non-invasive imaging tool that can routinely track DC migration in vivo. Consideration should be given to optimizing MRI contrast agent-labelling of clinical-grade DC in order to accurately correlate DC fate to immunological outcomes in patients.

In vivo cellular MRI of dendritic cell migration using micrometer-sized iron oxide (MPIO) particles.

PURPOSE: This study seeks to assess the use of labeling with micron-sized iron oxide (MPIO) particles for the detection and quantification of the migration of dendritic cells (DCs) using cellular magnetic resonance imaging (MRI). PROCEDURES: DCs were labeled with red fluorescent MPIO particles for detection by cellular MRI and a green fluorescent membrane dye (PKH67) for histological detection. MPIO-labeled DCs or unlabeled control DCs were injected into mice footpads at two doses (0.1 × 10(6) and 1 × 10(6)). Images were acquired at 3 Tesla before DC injection and 2, 3, and 7 days post-DC injection. RESULTS: Labeling DCs with MPIO particles did not affect viability, but it did alter markers of DC activation and maturation. MRI and fluorescence microscopy allowed for the detection of MPIO-labeled DCs within the draining popliteal nodes after their injection into the footpad. CONCLUSIONS: This paper presents the first report of the successful use of fluorescent MPIO particles to label and track DC migration.

Semiquantitation of mouse dendritic cell migration in vivo using cellular MRI.

Despite recent therapeutic advances, including the introduction of novel cytostatic drugs and therapeutic antibodies, many cancer patients will experience recurrent or metastatic disease. Current treatment options, particularly for those patients with metastatic breast, prostate, or skin cancers, are complex and have limited curative potential. Recent clinical trials, however, have shown that cell-based therapeutic vaccines may be used to generate broad-based, antitumor immune responses. Dendritic cells (DC) have proved to be the most efficacious cellular component for therapeutic vaccines, serving as both the adjuvant and antigen delivery vehicle. At present it is not possible to noninvasively determine the fate of DC-based vaccines after their administration to human subjects. In this study, we demonstrate that in vitro-generated mouse DC can be readily labeled with superparamagnetic iron oxide nanoparticles, Feridex, without altering cell morphology, or their phenotypic and functional maturation. Feridex-labeling enables the detection of DC in vivo after their migration to draining lymph nodes using a 1.5 T clinical magnetic resonance scanner. In addition, we report a semiquantitative approach for analysis of magnetic resonance images and show that the Feridex-induced signal void volume, and fractional signal loss, correlates with the delivery and migration of small numbers of in vitro-generated DC. These findings, together with ongoing preclinical studies, are key to gaining information critical for improving the efficacy of therapeutic vaccines for the treatment cancer, and potentially, chronic infectious diseases.