An imidazole modified lipid confers enhanced mRNA-LNP stability and strong immunization properties in mice and non-human primates.

The mRNA vaccine technology has promising applications to fight infectious diseases as demonstrated by the licensing of two mRNA-based vaccines, Comirnaty® (Pfizer/BioNtech) and Spikevax® (Moderna), in the context of the Covid-19 crisis. Safe and effective delivery systems are essential to the performance of these vaccines and lipid nanoparticles (LNPs) able to entrap, protect and deliver the mRNA in vivo are considered by many as the current "best in class". Nevertheless, current mRNA/LNP vaccine technology has still some limitations, one of them being thermostability, as evidenced by the ultracold distribution chain required for the licensed vaccines. We found that the thermostability of mRNA/LNP, could be improved by a novel imidazole modified lipid, DOG-IM4, in combination with standard helper lipids. DOG-IM4 comprises an ionizable head group consisting of imidazole, a dioleoyl lipid tail and a short flexible polyoxyethylene spacer between the head and tail. Here we describe the synthesis of DOG-IM4 and show that DOG-IM4 LNPs confer strong immunization properties to influenza HA mRNA in mice and macaques and a remarkable stability to the encapsulated mRNA when stored liquid in phosphate buffered saline at 4 °C. We speculate the increased stability to result from some specific attributes of the lipid's imidazole head group.

Göttingen Minipigs as a Model to Evaluate Longevity, Functionality, and Memory of Immune Response Induced by Pertussis Vaccines.

Evaluation of the short-term and long-term immunological responses in a preclinical model that simulates the targeted age population with a relevant vaccination schedule is essential for human vaccine development. A Göttingen minipig model was assessed, using pertussis vaccines, to demonstrate that vaccine antigen-specific humoral and cellular responses, including IgG titers, functional antibodies, Th polarization and memory B cells can be assessed in a longitudinal study. A vaccination schedule of priming with a whole cell (DTwP) or an acellular (DTaP) pertussis vaccine was applied in neonatal and infant minipigs followed by boosting with a Tdap acellular vaccine. Single cell RNAsequencing was used to explore the long-term maintenance of immune memory cells and their functionality for the first time in this animal model. DTaP but not DTwP vaccination induced pertussis toxin (PT) neutralizing antibodies. The cellular immune response was also characterized by a distinct Th polarization, with a Th-2-biased response for DTaP and a Th-1/Th-17-biased response for DTwP. No difference in the maintenance of pertussis-specific memory B cells was observed in DTaP- or DTwP-primed animals 6 months post Tdap boost. However, an increase in pertussis-specific T cells was still observed in DTaP primed minipigs, together with up-regulation of genes involved in antigen presentation and interferon pathways. Overall, the minipig model reproduced the humoral and cellular immune responses induced in humans by DTwP vs. DTaP priming, followed by Tdap boosting. Our data suggest that the Göttingen minipig is an attractive preclinical model to predict the long-term immunogenicity of human vaccines against Bordetella pertussis and potentially also vaccines against other pathogens.

Personality traits are associated with cognitive empathy in medical students but not with its evolution and interventions to improve it.

OBJECTIVE: Cognitive empathy might decrease during medical school. Factors associated with its evolution remain poorly understood, as well as whether such factors could moderate the effect of an intervention to preserve cognitive empathy. The aim was to explore the associations between personality traits and both cognitive empathy at baseline and its changes at follow-up. The possible effect of an intervention depended upon personality traits was also examined. METHODS: The cohort consisted of fourth year medical students and the associations between personality traits, using the Short Big Five Inventory, and cognitive empathy changes at 3-month, using the Jefferson Scale of Empathy-Student version (JSE-S), were examined. A randomization in two groups (Balint groups versus no intervention) allowed examining whether the effect of the intervention depended upon personality traits. Linear regressions were adjusted for gender, anticipated specialty choice, parental education, living status, financial insecurity, randomization group and baseline JSE-S. RESULTS: The cohort included 311 participants from October 2015 to December 2016 at Paris Diderot and Paris Descartes University. At follow-up, there was a JSE-S total score increase of 1.22(SD:9.10) in the intervention group, compared to a decrease of 1.64(SD:10.74) in the other group. Baseline JSE-S was positively associated with Extraversion and Conscientiousness and negatively with Neuroticism. In contrast, we found no associations between baseline personality traits and JSE-S change. There were no interactions between personality traits and randomization group. CONCLUSION: Although personality might be linked with cognitive empathy, medical students may benefit from strategies designed for improving cognitive empathy regardless of their personality.

Impact of integrating objective structured clinical examination into academic student assessment: Large-scale experience in a French medical school.

PURPOSE: Objective structured clinical examinations (OSCE) evaluate clinical reasoning, communication skills, and interpersonal behavior during medical education. In France, clinical training has long relied on bedside clinical practice in academic hospitals. The need for a simulated teaching environment has recently emerged, due to the increasing number of students admitted to medical schools, and the necessity of objectively evaluating practical skills. This study aimed at investigating the relationships between OSCE grades and current evaluation modalities. METHODS: Three-hundred seventy-nine 4th-year students of University-of-Paris Medical School participated to the first large-scale OSCE at this institution, consisting in three OSCE stations (OSCE#1-3). OSCE#1 and #2 focused on cardiovascular clinical skills and competence, whereas OSCE#3 focused on relational skills while providing explanations before planned cholecystectomy. We investigated correlations of OSCE grades with multiple choice (MCQ)-based written examinations and evaluations of clinical skills and behavior (during hospital traineeships); OSCE grade distribution; and the impact of integrating OSCE grades into the current evaluation in terms of student ranking. RESULTS: The competence-oriented OSCE#1 and OSCE#2 grades correlated only with MCQ grades (r = 0.19, P<0.001) or traineeship skill grades (r = 0.17, P = 0.001), respectively, and not with traineeship behavior grades (P>0.75). Conversely, the behavior-oriented OSCE#3 grades correlated with traineeship skill and behavior grades (r = 0.19, P<0.001, and r = 0.12, P = 0.032), but not with MCQ grades (P = 0.09). The dispersion of OSCE grades was wider than for MCQ examinations (P<0.001). When OSCE grades were integrated to the final fourth-year grade with an incremental 10%, 20% or 40% coefficient, an increasing proportion of the 379 students had a ranking variation by ±50 ranks (P<0.001). This ranking change mainly affected students among the mid-50% of ranking. CONCLUSION: This large-scale French experience showed that OSCE designed to assess a combination of clinical competence and behavioral skills, increases the discriminatory capacity of current evaluations modalities in French medical schools.

Balint groups and narrative medicine compared to a control condition in promoting students' empathy.

BACKGROUND: The perceived importance of clinical empathy may decline among students during medical training. Several interventions have been shown to be effective in promoting or preserving medical students' empathic abilities, such as empathy skills training or Balint groups. Although narrative medicine training shares some features with these interventions, no randomized study to date examined the efficacy of narrative medicine training. This study aimed to assess the effects of Balint groups and narrative medicine training on clinical empathy measured by the self-rated Jefferson's School Empathy Scale - Medical Student (JSPE-MS©) among fourth-year medical students. METHODS: Students who gave their consent to participate were randomly allocated in equal proportion to Balint groups, narrative medicine training or to the control group. Participants in the intervention groups received either seven sessions of 1.5-h Balint groups or a 2-h lecture and five sessions of 1.5-h narrative medicine training from October 2015 to December 2015. The main outcome was the change in JSPE-MS© score from baseline to one week after the last session. RESULTS: Data from 362 out of 392 participants were analyzed: 117 in the control group, 125 in the Balint group and 120 in the narrative medicine group. The change in JSPE-MS© score from baseline to follow-up was significantly higher in the Balint group than in the control group [mean (SD): 0.27 (8.00) vs. -2,36 (11.41), t = 2.086, P = 0.038]. The change in JSPE-MS© score in the narrative medicine group [mean (SD): - 0.57 (8.76)] did not significantly differ from the changes in the control group (t = 1.355, P = 0.18) or the Balint group (t = 0.784, P = 0.43). Adjusting for participants' characteristics at baseline, Balint groups remained associated with better outcomes compared to the control group (ß = 2.673, P = 0.030). CONCLUSIONS: Balint groups may promote clinical empathy to some extent among medical students, at least in the short run.

Patient-Physician Agreement in Reporting and Prioritizing Existing Chronic Conditions.

PURPOSE: In this study, we aimed to assess (1) the agreement between patient self-reports and general practitioner (GP) reports of the chronic conditions affecting the patients and (2) the agreement between patients and GPs on health priorities in a primary care setting. METHOD: Patients were recruited in the Parisian area of France by a convenience sample of GPs; eligibility criteria required that the GP was the patient's listed primary care provider for at least 12 months. Participants were asked to report all the patient's current chronic conditions by using a previously developed list of 124 chronic conditions and write a list of up to 3 priority conditions. RESULTS: From April to May 2017, 233 patients were recruited from 16 GP practices. Agreement between the number of conditions reported by patients and by GPs was moderate (intraclass correlation coefficient 0.59, 95% CI, 0.50 to 0.69). Agreement between patient self-reports and GP reports of each chronic condition ranged from very good (eg, κ = 0.85 for hypothyroidism) to poor (eg, κ = 0.12 for chronic anxiety disorder). Among the 153 patient-GP pairs for which both the patient and GP wrote a priority list, 45 (29.4%) of patients' first priorities did not appear anywhere on the corresponding GPs' lists, and 19 (12.4%) pairs had no matching priority condition. CONCLUSIONS: Agreement between patients and their GPs varied widely depending on the diseases reported. Low agreement on health priorities suggests a need for improvement to ensure better alignment between patient and physician perspectives.

Promoting empathy among medical students: A two-site randomized controlled study.

OBJECTIVE: To assess the effects of Balint groups on empathy measured by the Consultation And Relational Empathy Measure (CARE) scale rated by standardized patients during objective structured clinical examination and self-rated Jefferson's School Empathy Scale - Medical Student (JSPE-MS©) among fourth-year medical students. METHODS: A two-site randomized controlled trial were planned, from October 2015 to December 2015 at Paris Diderot and Paris Descartes University, France. Eligible students were fourth-year students who gave their consent to participate. Participants were allocated in equal proportion to the intervention group or to the control group. Participants in the intervention group received a training of 7 sessions of 1.5-hour Balint groups, over 3months. The main outcomes were CARE and the JSPE-MS© scores at follow-up. RESULTS: Data from 299 out of 352 randomized participants were analyzed: 155 in the intervention group and 144 in the control group, with no differences in baseline measures. There was no significant difference in CARE score at follow-up between the two groups (P=0.49). The intervention group displayed significantly higher JSPE-MS© score at follow-up than the control group [Mean (SD): 111.9 (10.6) versus 107.7 (12.7), P=0.002]. The JSPE-MS© score increased from baseline to follow-up in the intervention group, whereas it decreased in the control group [1.5 (9.1) versus -1.8 (10.8), P=0.006]. CONCLUSIONS: Balint groups may contribute to promote clinical empathy among medical students. TRIAL REGISTRATION: NCT02681380.

'Intern life': a longitudinal study of burnout, empathy, and coping strategies used by French GPs in training.

BACKGROUND: More than half of French medical GP trainees (GPTs) suffer from burnout. AIM: To define and follow the evolution of risk factors, such as empathy and coping strategies, associated with burnout in this population. DESIGN & SETTING: Prospective longitudinal study involving volunteers of 577 Parisian university GPTs in 2012. METHOD: Self-reported anonymous online questionnaires were sent three times every 6 months to all participants. Stress was measured using the Intern-Life scale and burnout using the Maslach Inventory, and anxiety and depression measured using the Hospital Anxiety and Depression Scale (HADS). Sociodemographic, professional, and personal data, including coping strategies and measures of empathy were also collected. RESULTS: In total 343 questionnaires were fully completed at baseline (T0): 304 were usable at baseline, 169 were usable at 6 months (T1) and 174 at 1 year (T2). Stress rates decreased sharply between T1 (scores 42.96) and T2 (17.08), while scores for burnout remained relatively stable: more than 13% of GPTs had high scores in all three dimensions of burnout. Depersonalisation increased from 61% (T1) to 66% (T2). One hundred and four paired samples were analysed between T0 and T1, and between T1 and T2. Emotion-centred coping was associated with emotional exhaustion (P<0.05), while professional support reduced it. Experiences of aggression increased depersonalisation (P<0.05). Social support, problem-centred coping, perspective-taking empathy, and professional support improved the sense of personal accomplishment (P<0.05). CONCLUSION: Tools to help GPTs are available but are underused. More training in doctor-patient relationships and understanding of medical hidden curricula are necessary to decrease burnout among GPTs and improve their wellbeing and patient care.

Exclusion of patients with concomitant chronic conditions in ongoing randomised controlled trials targeting 10 common chronic conditions and registered at ClinicalTrials.gov: a systematic review of registration details.

OBJECTIVES: To systematically assess registration details of ongoing randomised controlled trials (RCTs) targeting 10 common chronic conditions and registered at ClinicalTrials.gov and to determine the prevalence of (1) trial records excluding patients with concomitant chronic condition(s) and (2) those specifically targeting patients with concomitant chronic conditions. DESIGN: Systematic review of trial registration records. DATA SOURCES: ClinicalTrials.gov register. STUDY SELECTION: All ongoing RCTs registered from 1 January 2014 to 31 January 2015 that assessed an intervention targeting adults with coronary heart disease (CHD), hypertension, heart failure, stroke/transient ischaemic attack, atrial fibrillation, type 2 diabetes, chronic obstructive pulmonary disease, painful condition, depression and dementia with a target sample size ≥100. DATA EXTRACTION: From the trial registration records, 2 researchers independently recorded the trial characteristics and the number of exclusion criteria and determined whether patients with concomitant chronic conditions were excluded or specifically targeted. RESULTS: Among 319 ongoing RCTs, despite the high prevalence of the concomitant chronic conditions, patients with these conditions were excluded in 251 trials (79%). For example, although 91% of patients with CHD had a concomitant chronic condition, 69% of trials targeting such patients excluded patients with concomitant chronic condition(s). When considering the co-occurrence of 2 chronic conditions, 31% of patients with chronic pain also had depression, but 58% of the trials targeting patients with chronic pain excluded patients with depression. Only 37 trials (12%) assessed interventions specifically targeting patients with concomitant chronic conditions; 31 (84%) excluded patients with concomitant chronic condition(s). CONCLUSIONS: Despite widespread multimorbidity, more than three-quarters of ongoing trials assessing interventions for patients with chronic conditions excluded patients with concomitant chronic conditions.

Potential workload in applying clinical practice guidelines for patients with chronic conditions and multimorbidity: a systematic analysis.

OBJECTIVES: To describe the potential workload for patients with multimorbidity when applying existing clinical practice guidelines. DESIGN: Systematic analysis of clinical practice guidelines for chronic conditions and simulation modelling approach. DATA SOURCES: National Guideline Clearinghouse index of US clinical practice guidelines. STUDY SELECTION: We identified the most recent guidelines for adults with 1 of 6 prevalent chronic conditions in primary care (ie hypertension, diabetes, coronary heart disease (CHD), chronic obstructive pulmonary disease (COPD), osteoarthritis and depression). DATA EXTRACTION: From the guidelines, we extracted all recommended health-related activities (HRAs) such as drug management, self-monitoring, visits to the doctor, laboratory tests and changes of lifestyle for a patient aged 45-64 years with moderate severity of conditions. SIMULATION MODELLING APPROACH: For each HRA identified, we performed a literature review to determine the potential workload in terms of time spent on this HRA. Then, we used a simulation modelling approach to estimate the potential workload needed to comply with these recommended HRAs for patients with several of these chronic conditions. RESULTS: Depending on the concomitant chronic condition, patients with 3 chronic conditions complying with all the guidelines would have to take a minimum of 6 to a maximum of 13 medications per day, visit a health caregiver a minimum of 1.2 to a maximum of 5.9 times per month and spend a mean (SD) of 49.6 (27.3) to 71.0 (34.5) h/month in HRAs. The potential workload increased greatly with increasing number of concomitant conditions, rising to 18 medications per day, 6.6 visits per month and 80.7 (35.8) h/month in HRAs for patients with 6 chronic conditions.

Suspected community-acquired pneumonia in an ambulatory setting (CAPA): a French prospective observational cohort study in general practice.

BACKGROUND: Few studies have addressed the pragmatic management of ambulatory patients with suspected community-acquired pneumonia (CAP) using a precise description of the disease with or without chest X-ray (X-ray) evidence. AIMS: To describe the characteristics, clinical findings, additional investigations and disease progression in patients with suspected CAP managed by French General Practitioners (GPs). METHODS: The patients included were older than 18 years, with signs or symptoms suggestive of CAP associated with recent-onset unilateral crackles on auscultation or a new opacity on X-ray. They were followed for up to 6 weeks. Descriptive analyses of all patients and according to their management with X-rays were carried out. RESULTS: From September 2011 to July 2012, 886 patients have been consulted by 267 GPs. Among them, 278 (31%) were older than 65 years and 337 (38%) were at increased risk for invasive pneumococcal disease. At presentation, the three most common symptoms, cough (94%), fever (93%), and weakness or myalgia (81%), were all observed in 70% of patients. Unilateral crackles were observed in 77% of patients. Among patients with positive radiography (64%), 36% had no unilateral crackles. A null CRB-65 score was obtained in 62% of patients. Most patients (94%) initially received antibiotics and experienced uncomplicated disease progression regardless of their management with X-rays. Finally, 7% of patients were hospitalised and 0.3% died. CONCLUSIONS: Most patients consulting GPs for suspected CAP had the three following most common symptoms: cough, fever, and weakness or myalgia. More than a third of them were at increased risk for invasive pneumococcal disease. With or without X-rays, most patients received antibiotics and experienced uncomplicated disease progression.

Quality of life and illness perception in primary biliary cirrhosis: a controlled cross-sectional study.

OBJECTIVE: The aim of this study was to understand better the quality of life (QOL) and illness perception in women with primary biliary cirrhosis (PBC) through a comparison with women having diabetes. METHODS: One hundred and ninety-four women took part in this study: 130 with PBC, 64 with type 2 diabetes. They were administered the SF-12 to measure QOL and the Brief Illness Perception Questionnaire to assess representations of their illness. Analysis of covariance with bootstrapping was used to compare QOL and illness perception scores by controlling age and mean disease duration. RESULTS: Physical QOL was significantly worse for women with PBC than for women with diabetes. Women with PBC felt their disease would last longer and reported more symptoms and concerns related to their disease than women with diabetes. Significant differences were also observed for causes: women with PBC mainly reported autoimmune, emotional, unknown/unlucky and medical causes whereas women with diabetes reported mostly lifestyle and hereditary causes. Marginally significant differences were observed regarding consequences on daily life, feeling of control over the disease and emotional responses, which were shown to be worse in PBC. Mental QOL, treatment control and overall understanding of the disease was similar in both groups. CONCLUSIONS: This study shows that women with PBC have a worse QOL and somewhat different illness perception than women with diabetes. Further research could help understand PBC specificities better in order to improve patient care, especially if factors such as fatigue or rarity of the disease explain these results.

A comparative review of toll-like receptor 4 expression and functionality in different animal species.

Toll-like receptors (TLRs) belong to the pattern recognition receptor (PRR) family, a key component of the innate immune system. TLRs detect invading pathogens and initiate an immediate immune response to them, followed by a long-lasting adaptive immune response. Activation of TLRs leads to the synthesis of pro-inflammatory cytokines and chemokines and the expression of co-stimulatory molecules. TLR4 specifically recognizes bacterial lipopolysaccharide, along with several other components of pathogens and endogenous molecules produced during abnormal situations, such as tissue damage. Evolution across species can lead to substantial diversity in the TLR4's affinity and specificity to its ligands, the TLR4 gene and cellular expression patterns and tissue distribution. Consequently, TLR4 functions vary across different species. In recent years, the use of synthetic TLR agonists as adjuvants has emerged as a realistic therapeutic goal, notably for the development of vaccines against poorly immunogenic targets. Given that an adjuvanted vaccine must be assessed in pre-clinical animal models before being tested in humans, the extent to which an animal model represents and predicts the human condition is of particular importance. This review focuses on the current knowledge on the critical points of divergence between human and the mammalian species commonly used in vaccine research and development (non-human primate, mouse, rat, rabbit, swine, and dog), in terms of molecular, cellular, and functional properties of TLR4.

Reporting funding source or conflict of interest in abstracts of randomized controlled trials, no evidence of a large impact on general practitioners' confidence in conclusions, a three-arm randomized controlled trial.

BACKGROUND: Systematic reporting of funding sources is recommended in the CONSORT Statement for abstracts. However, no specific recommendation is related to the reporting of conflicts of interest (CoI). The objective was to compare physicians' confidence in the conclusions of abstracts of randomized controlled trials of pharmaceutical treatment indexed in PubMed. METHODS: We planned a three-arm parallel-group randomized trial. French general practitioners (GPs) were invited to participate and were blinded to the study's aim. We used a representative sample of 75 abstracts of pharmaceutical industry-funded randomized controlled trials published in 2010 and indexed in PubMed. Each abstract was standardized and reported in three formats: 1) no mention of the funding source or CoI; 2) reporting the funding source only; and 3) reporting the funding source and CoI. GPs were randomized according to a computerized randomization on a secure Internet system at a 1:1:1 ratio to assess one abstract among the three formats. The primary outcome was GPs' confidence in the abstract conclusions (0, not at all, to 10, completely confident). The study was planned to detect a large difference with an effect size of 0.5. RESULTS: Between October 2012 and June 2013, among 605 GPs contacted, 354 were randomized, 118 for each type of abstract. The mean difference (95% confidence interval) in GPs' confidence in abstract findings was 0.2 (-0.6; 1.0) (P = 0.84) for abstracts reporting the funding source only versus no funding source or CoI; -0.4 (-1.3; 0.4) (P = 0.39) for abstracts reporting the funding source and CoI versus no funding source and CoI; and -0.6 (-1.5; 0.2) (P = 0.15) for abstracts reporting the funding source and CoI versus the funding source only. CONCLUSIONS: We found no evidence of a large impact of trial report abstracts mentioning funding sources or CoI on GPs' confidence in the conclusions of the abstracts. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01679873.

In vivo manipulation of dendritic cell migration and activation to elicit antitumour immunity.

Two approaches have been pursued to elicit antitumour immunity: (i) induce recruitment of immature dendritic cells or their precursors at a site of antigen delivery, and (ii) induce activation of tumour-infiltrating dendritic cells (DCs). The recruitment of selected DC subtype conditions the class of the immune response. Each immature DC population displays a unique spectrum of chemokine responsiveness. For examples, Langerhans cells (LCs) migrate selectively in response to CCL20/MIP-3alpha (through CCR6), blood CD11c+ DC to MCP chemokines (through CCR2). All these chemokines are inducible in response to inflammatory stimuli. CCL20/MIP-3alpha in particular is only detected within inflamed epithelium, at the site of antigen entry, which is infiltrated by immature DCs. Furthermore, to reach the site of injury, sequential responsiveness might operate, blood DC precursors are recruited by a set of chemokines (MIP, MCP) while within the tissue other chemokines will direct their navigation (CCL20/MIP-3alpha). Of interest, when injected in vivo together with antigen, MCP-4/CCL13, but not CCL20/MIP-3alpha, recruits blood monocytes or blood DC precursors that promptly differentiate into typical DCs and that improve antitumour immune responses. After antigen uptake, DCs acquire, upon maturation, responsiveness to CCR7 ligands (CCL21/SLC/6Ckine, CCL19/ELC/MIP-3beta) due to receptor up-regulation. In particular, in the periphery, CCL21/SLC/6Ckine expressed by lymphatic vessels may direct into the lymph stream, antigen-loaded maturing DCs leaving the site of infection; while within lymph-node, CCL21/SLC/6Ckine plays a critical role in the entry of naïve T cells from the blood through HEV. In regard to its central role, we decided to investigate whether the expression of CCL21/SLC/6Ckine in tumour may lead to antitumour immune responses. C26 colon carcinoma tumour cell line transduced with CCL21/SLC/6Ckine showed reduced tumorigenicity when injected in vivo into immunocompetent mice. The protection was CD8 dependent and associated with an important intratumoral infiltration of DCs. Most tumour infiltrating DCs (TIDCs) had an immature phenotype, were able to present TAA in the context of MHC class I, but were refractory to stimulation with the combination of LPS, IFNgamma and anti-CD40 antibody. TIDC paralysis could be reverted, however, by in vitro or in vivo stimulation with the combination of a CpG immunostimulatory sequence and an anti-interleukin 10 receptor (IL10R) antibody. CpG or anti-IL10R alone were inactive in TIDC, while CpG triggered activation in normal DC. In particular, CpG plus anti-IL10R enhanced the TAA-specific immune response and triggered de novo IL-12 production. Subsequently, CpG plus anti-IL10R treatment showed robust antitumour therapeutic activity exceeding by far that of CpG alone, and elicited antitumour immune memory.

Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody.

Progressing tumors in man and mouse are often infiltrated by dendritic cells (DCs). Deficient antitumor immunity could be related to a lack of tumor-associated antigen (TAA) presentation by tumor-infiltrating DCs (TIDCs) or to a functional defect of TIDCs. Here we investigated the phenotype and function of TIDCs in transplantable and transgenic mouse tumor models. Although TIDCs could encompass various known DC subsets, most had an immature phenotype. We observed that TIDCs were able to present TAA in the context of major histocompatibility complex class I but that they were refractory to stimulation with the combination of lipopolysaccharide, interferon gamma, and anti-CD40 antibody. We could revert TIDC paralysis, however, by in vitro or in vivo stimulation with the combination of a CpG immunostimulatory sequence and an anti-interleukin 10 receptor (IL-10R) antibody. CpG or anti-IL-10R alone were inactive in TIDCs, whereas CpG triggered activation in normal DCs. In particular, CpG plus anti-IL-10R enhanced the TAA-specific immune response and triggered de novo IL-12 production. Subsequently, CpG plus anti-IL-10R treatment showed robust antitumor therapeutic activity exceeding by far that of CpG alone, and elicited antitumor immune memory.

Regulation of dendritic cell recruitment by chemokines.

Dendritic cells (DC) are a heterogeneous family of cells that function as sentinels of the immune system. This article summarizes observations suggesting that inflammatory chemokines secreted at the site of pathogen invasion determine the DC subset recruited and influence the class of the immune response initiated. Langerhans cells are selectively recruited by MIP-3alpha/CCL20. In contrast, CCR7 ligands have a key role in the accumulation of antigen-loaded mature DC in T cell-rich areas of the draining lymph node. Improved understanding of the regulation of DC trafficking might offer new opportunities for therapeutic interventions to control immune responses.