Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209(+) dendritic cells for immune T cell areas.

Dendritic cells (DCs), critical antigen-presenting cells for immune control, normally derive from bone marrow precursors distinct from monocytes. It is not yet established if the large reservoir of monocytes can develop into cells with critical features of DCs in vivo. We now show that fully differentiated monocyte-derived DCs (Mo-DCs) develop in mice and DC-SIGN/CD209a marks the cells. Mo-DCs are recruited from blood monocytes into lymph nodes by lipopolysaccharide and live or dead gram-negative bacteria. Mobilization requires TLR4 and its CD14 coreceptor and Trif. When tested for antigen-presenting function, Mo-DCs are as active as classical DCs, including cross-presentation of proteins and live gram-negative bacteria on MHC I in vivo. Fully differentiated Mo-DCs acquire DC morphology and localize to T cell areas via L-selectin and CCR7. Thus the blood monocyte reservoir becomes the dominant presenting cell in response to select microbes, yielding DC-SIGN(+) cells with critical functions of DCs.

Drug persistence and compliance affect patient-reported outcomes in overactive bladder syndrome.

PURPOSE: To evaluate persistence and compliance for patients receiving antimuscarinics for overactive bladder (OAB), and to assess patient-reported outcomes (PROs) according to persistence and compliance. METHODS: This was a 24-week, multicenter, prospective, observational study that included 952 OAB patients who had newly started antimuscarinics. Patients aged ≥18 years with a total OAB Symptom Score (OABSS) ≥3 and an urgency score of OABSS ≥2 were eligible for the study. Drug persistence and compliance were evaluated at 4, 12, and 24 weeks. Changes in scores on PROs were compared between groups (persistence vs. non-persistence and compliance vs. non-compliance) after 24 weeks. Factors contributing to persistence were examined using multivariate logistic regression. RESULTS: After 24 weeks, 56.8 % of patients remained on treatment. The persistence rates were 85.6 and 71.4 % after 4 and 12 weeks, respectively. The compliance rates were 75.6, 53.8, and 34.3 % after 4, 12, and 24 weeks, respectively. Patients who were persistent in taking antimuscarinics resulted in significant improvements in OABSS and OAB questionnaire short form score compared with those who were non-persistent (all p < 0.05). Changes from baseline in OABSS (p = 0.735) and the EuroQoL five-dimensions score (p = 0.384) were not significantly different between compliant and non-compliant groups. Predictors of high persistence included older age (OR 1.017, p = 0.007) and dry OAB (OR 1.422, p = 0.013). CONCLUSIONS: Patients who were persistent with antimuscarinics showed significant improvements in PROs compared to those who were non-persistent.

A nationwide analysis of the treatment patterns, survival, and medical costs in Korean patients with relapsed or refractory diffuse large B-cell lymphoma.

Background: Approximately one-third of patients with diffuse large B-cell lymphoma (DLBCL) are refractory to treatment or experience relapse after initial therapy. Unfortunately, treatment options for older patients and those who experience relapse or become refractory to hematopoietic stem cell transplantation (HSCT) are limited. This nationwide population-based study aimed to identify treatment patterns, survival times, and treatment costs in patients with relapsed/refractory DLBCL (R/R DLBCL). Materials and methods: Between 2011 and 2020, data on patients with R/R DLBCL were retrieved from the Korean Health Insurance Review & Assessment Service, encompassing the entire population. We identified the treatment patterns for each treatment line using a Sankey diagram and calculated the median time to the subsequent treatment in line. Median overall and progression-free survival times were estimated using the Kaplan-Meier survival curves. Finally, the medical costs incurred during DLBCL treatment were calculated for each treatment line and the costs related to HSCT were summarized at the episode level. Results: A total of 864 patients with R/R DLBCL who received second-line treatment were identified, and a regimen of ifosfamide, carboplatin, and etoposide (ICE) was administered the most. Among them, 353 were refractory or relapsed cases that were treated with third-line treatments. The median times for second-line to third-line, third-line to fourth-line, fourth-line to fifth-line, and fifth-line to sixth-line treatment failures gradually decreased (3.93, 2.86, 1.81, and 1.38 months, respectively). The median overall survival time was 8.90 and 4.73 months following the second-line and third-line treatments, respectively. In the third-line treatment setting, the patients did not show a significant difference in survival time after HSCT. The median medical cost was $39,491 across all treatment lines including the cost of HSCT which was $22,054. Conclusion: The treatment patterns in patients with R/R DLBCL, especially at third-line treatments and thereafter, were complicated, and their prognosis was poor despite the high medical costs. Novel and effective treatment options are expected to improve the prognosis and alleviate the economic burden of patients with R/R DLBCL.

Targeting of LcrV virulence protein from Yersinia pestis to dendritic cells protects mice against pneumonic plague.

To help design needed new vaccines for pneumonic plague, we targeted the Yersinia pestis LcrV protein directly to CD8α(+) DEC-205(+) or CD8α(-) DCIR2(+) DC along with a clinically feasible adjuvant, poly IC. By studying Y. pestis in mice, we could evaluate the capacity of this targeting approach to protect against a human pathogen. The DEC-targeted LcrV induced polarized Th1 immunity, whereas DCIR2-targeted LcrV induced fewer CD4(+) T cells secreting IFN-γ, but higher IL-4, IL-5, IL-10, and IL-13 production. DCIR-2 targeting elicited higher anti-LcrV Ab titers than DEC targeting, which were comparable to a protein vaccine given in alhydrogel adjuvant, but the latter did not induce detectable T-cell immunity. When DEC- and DCIR2-targeted and F1-V+ alhydrogel-vaccinated mice were challenged 6 wk after vaccination with the virulent CO92 Y. pestis, the protection level and Ab titers induced by DCIR2 targeting were similar to those induced by F1-V protein with alhydrogel vaccination. Therefore, LcrV targeting to DC elicits combined humoral and cellular immunity, and for the first time with this approach, also induces protection in a mouse model for a human pathogen.

The economic impact of disease progression and death in hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer patients: using Korean nationwide health insurance claims data.

OBJECTIVES: Recognizing the value of anticancer treatments based on progression-free survival and overall survival may help decision making in healthcare policy. We aimed to measure and compare the impact of disease progression and terminal state prior to death on healthcare costs in HR+, HER2- ABC patients. METHODS: We conducted a retrospective study using Korean nationwide health insurance claims database between 1 September 2012 and 31 August 2017. The impact of disease progression was estimated by measuring the average incremental monthly cost per patient during 1 year after progression compared to 1 year before progression. Death-related costs per patient per month (PPPM) were measured for those who died within 1 year after progression. Generalized estimating equation (GEE) was used to estimate the variations in PPPM costs by progression and death with adjustment for clinical factors. RESULTS: After progression, 1,636 patients expensed $2,892 per month more on average than before progression ($3762 vs. $870). The GEE analysis with adjustment for baseline characteristics showed that PPPM costs increased by 3.46 folds (95% CI = 3.06-3.93) after progression. Also, PPPM costs were 1.74 (95%CI = 1.43-2.12) times higher in patients who died within 1 year after progression relative to survived patients. When considering the interaction between progression and death, deceased patients showed higher increased ratio of PPPM costs after progression (4.91; p=value<.0001) than survived patients (2.95; 95% CI = 2.61-3.34). CONCLUSIONS: From the payer's perspective, more healthcare costs incurred during the progression state than terminal state in HR+, HER2- ABC patients. The impact of disease progression emphasizes the importance of effectively treating HR+, HER2- ABC patients.

Familial hypercholesterolemia and atherosclerotic cardiovascular mortality among Korean adults with low levels of serum cholesterol.

BACKGROUND AND AIMS: A few studies examined association between familial hypercholesterolemia (FH) and atherosclerotic cardiovascular disease (ASCVD) in Asians with low levels of serum cholesterol. The objectives of this study were to estimate the prevalence of familial hypercholesterolemia phenotype (FH-P) and examined their associations with cardiovascular mortality among Korean population. METHODS: The Korea National Health and Nutrition Examination Survey (KNHANES) data and data from a cohort study were used to obtain the prevalence estimate of FH-P and the association of FH-P with mortality, respectively. A cohort study included 502,966 individuals who visited health promotion centers and were given a medical examination from 1994 to 2004. FH-P was defined using the Make Early Diagnosis to Prevent Early Death (MEDPED) criteria and the modified MEDPED which substracted 20 mg/dL from original MEDPED. RESULTS: FH-P prevalences defined by MEDPED and modified MEDPED among KNHANES were 0.11% and 0.25%. After 14.6-year follow-up, 23,413 deaths (3888 ASCVD) were observed. Overall, FH-P defined by MEDPED showed weaker associations with mortality compared with modified MEDPED. The hazard ratios (95% confidence intervals) of FH-P defined by modified MEDPED were 1.74 (1.46-2.07) for all-cause death, 2.18 (1.51-3.14) for ASCVD, and 2.06 (1.66-2.56) for non-cancer. Of note, the hazard ratios for all-cause death was 5.27 (2.62-10.57) among women aged less than 50 years. CONCLUSIONS: FH-P increased all-cause and ASCVD mortality. Long-term follow-up studies with detailed information on cause of mortality are necessary to confirm these findings. Subjects with FH are at high risk for death and need appropriate treatment and management.

Factors associated with quality of life and functional disability among rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs for at least 6 months.

AIM: To determine characteristics of rheumatoid arthritis (RA) patients in Korea using disease-modifying anti-rheumatic drugs (DMARDs) for at least 6 months, and to identify factors associated with poor health-related outcomes. METHOD: A total of 2000 RA patients aged > 20 years, treated with DMARDs for at least 6 months, and signed informed consent, were enrolled in this non-interventional, multicenter, cross-sectional observational study from December 2012 to June 2013. Health-related quality of life (HRQoL) was measured using EuroQuol 5D (EQ-5D) and functional disability was measured using the Korean Health Assessment Questionnaire (KHAQ). Univariate and multivariate linear regression analyses were used to determine the association between patient characteristics and patient-reported outcomes (PROs). RESULTS: Of all RA patients, 84% were female, patients with low Disease Activity Score of 28 joints erythrocyte sedimentation rate (DAS-28-ESR < 3.2) was 54%, while moderate (DAS-28-ESR 3.2-5.1) and high disease activity score (DAS-28-ESR > 5.1) were 38% and 7.6%, respectively. Mean EQ-5D index score and KHAQ score were 0.6 ± 0.28 and 0.7 ± 0.67, respectively. In multivariate analysis with both PROs, average HRQoL and functional disability score appeared to be worse in persons with older age compared to younger age (P < 0.001), and worse in females compared to males (P < 0.001). Compared to patients having lower DAS (< 3.2), those with moderate and highest DAS (3.2-5.1 and > 5.1) had worse outcome measures (P < 0.001). CONCLUSION: In this study, higher DAS was one of the most influential factors for poor PROs among all other factors. Therefore, we could suggest appropriate treatment approaches according to DAS along with other significantly associated factors with PROs in the early stage of RA.

CD8α(-) Dendritic Cells Induce Antigen-Specific T Follicular Helper Cells Generating Efficient Humoral Immune Responses.

Recent studies on T follicular helper (Tfh) cells have significantly advanced our understanding of T cell-dependent B cell responses. However, little is known about the early stage of Tfh cell commitment by dendritic cells (DCs), particularly by the conventional CD8α(+) and CD8α(-) DC subsets. We show that CD8α(-) DCs localized at the interfollicular zone play a pivotal role in the induction of antigen-specific Tfh cells by upregulating the expression of Icosl and Ox40l through the non-canonical NF-κB signaling pathway. Tfh cells induced by CD8α(-) DCs function as true B cell helpers, resulting in significantly increased humoral immune responses against various human pathogenic antigens, including Yersinia pestis LcrV, HIV Gag, and hepatitis B surface antigen. Our findings uncover a mechanistic role of CD8α(-) DCs in the initiation of Tfh cell differentiation and thereby provide a rationale for investigating CD8α(-) DCs in enhancing antigen-specific humoral immune responses for improving vaccines and therapeutics.

Induction of pulmonary mucosal immune responses with a protein vaccine targeted to the DEC-205/CD205 receptor.

It is of great interest to develop a pneumonic plague vaccine that would induce combined humoral and cellular immunity in the lung. Here we investigate a novel approach based on targeting of dendritic cells using the DEC-205/CD205 receptor (DEC) via the intranasal route as way to improve mucosal cellular immunity to the vaccine. Intranasal administration of Yersinia pestis LcrV (V) protein fused to anti-DEC antibody together with poly IC as an adjuvant induced high frequencies of IFN-γ secreting CD4(+) T cells in the airway and lung as well as pulmonary IgG and IgA antibodies. Anti-DEC:LcrV was more efficient to induce IFN-γ/TNF-α/IL-2 secreting polyfunctional CD4(+) T cells when compared to non-targeted soluble protein vaccine. In addition, the intranasal route of immunization with anti-DEC:LcrV was associated with improved survival upon pulmonary challenge with the virulent CO92 Y. pestis. Taken together, these data indicate that targeting dendritic cells via the mucosal route is a potential new avenue for the development of a mucosal vaccine against pneumonic plague.

Identification of antigen-presenting dendritic cells in mouse aorta and cardiac valves.

Presumptive dendritic cells (DCs) bearing the CD11c integrin and other markers have previously been identified in normal mouse and human aorta. We used CD11c promoter-enhanced yellow fluorescent protein (EYFP) transgenic mice to visualize aortic DCs and study their antigen-presenting capacity. Stellate EYFP(+) cells were readily identified in the aorta and could be double labeled with antibodies to CD11c and antigen-presenting major histocompatability complex (MHC) II products. The DCs proved to be particularly abundant in the cardiac valves and aortic sinus. In all aortic locations, the CD11c(+) cells localized to the subintimal space with occasional processes probing the vascular lumen. Aortic DCs expressed little CD40 but expressed low levels of CD1d, CD80, and CD86. In studies of antigen presentation, DCs selected on the basis of EYFP expression or binding of anti-CD11c antibody were as effective as DCs similarly selected from the spleen. In particular, the aortic DCs could cross-present two different protein antigens on MHC class I to CD8(+) TCR transgenic T cells. In addition, after intravenous injection, aortic DCs could capture anti-CD11c antibody and cross-present ovalbumin to T cells. These results indicate that bona fide DCs are a constituent of the normal aorta and cardiac valves.