Fluoroquinolone and no risk of Achilles-tendinopathy in childhood pneumonia under eight years of age-a nationwide retrospective cohort.

BACKGROUND: The emergence of macrolide-resistant Mycoplasma pneumoniae pneumonia (MRMP) has made its treatment challenging. A few guidelines have recommended fluoroquinolones (FQs) as second-line drugs of choice for treating MRMP in children under the age of eight, but concerns about potential adverse events (i.e., Achilles tendinopathy; AT) have been raised. The aim of this study was to investigate the relationship between the use of FQs and the risk of AT in pneumonia in children under eight years of age. METHODS: Children hospitalized with pneumonia (total of 2,213,807 episodes) from 2002 to 2017 were enrolled utilizing the Korean National Health Insurance Sharing Service (NHISS) database. The independent risk of FQs for AT was analyzed by a generalized estimating equation with adjustment for age, sex, and underlying diseases. RESULTS: Among 2,213,807 episodes of pneumonia hospitalization, children in a total of 6,229 episodes (0.28%) were treated with FQs (levofloxacin 40.9%, ciprofloxacin 36.1%, moxifloxacin 11.6%, and others 11.4%). The FQ-exposure group showed a 0.19% (12/6,229) incidence of AT within 30 days after the first administration of FQ. The use of FQs increased the risk of AT (OR 3.00; 95% CI: 1.71-5.29), but became null after adjusting for age, sex, and underlying diseases (aOR 0.85; 95% CI: 0.48-1.51). All AT related to the use of FQs occurred after the use of ciprofloxacin or levofloxacin, and not in children under eight years of age. CONCLUSIONS: AT was a rare adverse event of FQ use for childhood pneumonia, particularly under eight years of age. Clinicians could consider using FQs as a second-line option in the treatment of childhood pneumonia when there are no alternative therapeutic options.

Lysophosphatidylcholine exerts an anti-skin photoaging effect via heat shock protein 70 induction.

OBJECTIVE: Skin-brightening agents prevent melanogenesis and reduce melanin production. However, a lower melanin content leads to weaker protection against sunlight. In this study, we evaluated the effect of lysophosphatidylcholine (LPC) and its commercial-grade product, Lysofix Dry™ (LD), on heat shock protein 70 (HSP70) expression in epidermal cells and their anti-skin photoaging effect against ultraviolet B (UVB) and blue light. METHODS: The HSP70 induction was detected using ELISA. To confirm the inhibition of melanin synthesis by LPC or LD, the melanin content assay and gene expression were analyzed. Cell viability was assessed to verify whether LPC or LD prevents photo-induced skin damage. The split-face test was performed to confirm skin-brightening effect of LD. Cream formulation with 2% of LD and placebo were used for 8 weeks, and skin brightness (L) was measured with chromameter (CR-400, Konica Minolta). RESULTS: LPC- and LD-induced HSP70 expression in epidermal cells. LPC and LD effectively suppressed melanogenesis provoked by α-MSH in B16 cells. They also inhibited the mRNA transcription of MITF and tyrosinase under blue light irradiation. LD increased the viability of B16 and HaCaT cells after UVB and blue light irradiation in vitro. The cream containing 2% LD increased ΔL by 1.7 after 8 weeks of use, whereas the placebo led to an increase of 0.7. CONCLUSION: LPC and LD were effective in suppressing melanogenesis and enhancing cell viability under UVB and blue light via HSP70 expression. Thus, they can be considered as potent skin-brightening agents with protective effects against skin photoaging.

Topical application of Zanthoxylum piperitum extract improves lateral canthal rhytides by inhibiting muscle contractions.

Facial wrinkles are the predominant phenotypes of skin aging. To date, one of the most effective ways to improve wrinkles is botulinum toxin type A (BoNT/A) injection, which inhibits muscle contractions by reducing acetylcholine release from neurons. However, since BoNT/A is a hazardous neurotoxin, the injection can only be performed by medical doctors and the procedure is only possible through invasive injection, causing inconveniences such as pain. To overcome these inconveniences, we tried to find a way to reduce wrinkles non-invasively via mechanisms similar to BoNT/A. We first designed in vitro assays to test BoNT/A-like muscle contraction inhibition in two different model systems. By using the assays, we identified Zanthoxylum piperitum (Z. piperitum) fruit extract as a BoNT-like reagent (27.7% decrease of muscle contraction rates by 1000 ppm of Z. piperitum extract treatment). Next, we determined mechanisms of how Z. piperitum extract decreases muscle contraction rates and found that the extract treatment inhibits electrical signal transduction in neurons. We also showed that among known components of Z. piperitum extract, quercitrin is responsible for muscle contraction inhibition. We further identified that Z. piperitum extract has synergistic effects with acetyl hexapeptide-8 and BoNT/A light chain, which are well-known BoNT-like peptides. Finally, we showed that topical treatment of the Z. piperitum extract indeed decreases facial wrinkles and treatment of Z. piperitum extract with acetyl hexapeptide-8 has a tendency to improve wrinkles synergistically (14.5% improvement on average). The synergistic effect of the combination is expected to improve wrinkles effectively by implementing the BoNT/A mechanisms in a non-invasive way.

Inverse association between dietary fiber intake and depression in premenopausal women: a nationwide population-based survey.

OBJECTIVE: Depression is among the most common neuropsychiatric disorders, and its prevalence is twofold higher in women than in men. This study aimed to investigate the relationship between dietary fiber intake and depression in women by menopause status using data from a nationwide population-based survey conducted in Korea. METHODS: We utilized the Korea National Health and Nutritional Examination Survey data for 2014, 2016, and 2018 with a complex sampling design. Dietary fiber intake was calculated according to the 24-hour recall method, and we used Patient Health Questionnaire-9 scores to assess depression. A t test based on the general linear model was used to compare mean dietary fiber intake according to the presence of depression by menopause status. A logistic regression analysis was conducted to compute the odds ratio for depression according to the gradually adjusted model. RESULTS: This study included 5,807 women. Among the premenopausal women, dietary fiber intake was higher in the nondepression group than in the depression group (P < 0.001), while there was no significant difference among postmenopausal women. Accordingly, among the premenopausal women, a significantly inverse relationship was observed between a change in daily dietary fiber intake as 1 g/1,000 kcal and the prevalence of depression in the fully adjusted model with an odds ratio of 0.949 (95% confidence interval, 0.906-0.993; P = 0.03). However, among the postmenopausal women, this significant association was not observed. CONCLUSIONS: Dietary fiber intake was inversely associated with depression in premenopausal but not postmenopausal women.

Annual and seasonal patterns in etiologies of pediatric community-acquired pneumonia due to respiratory viruses and Mycoplasma pneumoniae requiring hospitalization in South Korea.

BACKGROUND: Community-acquired pneumonia (CAP) is one of the leading worldwide causes of childhood morbidity and mortality. Its disease burden varies by age and etiology and is time dependent. We aimed to investigate the annual and seasonal patterns in etiologies of pediatric CAP requiring hospitalization. METHODS: We conducted a retrospective study in 30,994 children (aged 0-18 years) with CAP between 2010 and 2015 at 23 nationwide hospitals in South Korea. Mycoplasma pneumoniae (MP) pneumonia was clinically classified as macrolide-sensitive MP, macrolide-less effective MP (MLEP), and macrolide-refractory MP (MRMP) based on fever duration after initiation of macrolide treatment, regardless of the results of in vitro macrolide sensitivity tests. RESULTS: MP and respiratory syncytial virus (RSV) were the two most commonly identified pathogens of CAP. With the two epidemics of MP pneumonia (2011 and 2015), the rates of clinical MLEP and MRMP pneumonia showed increasing trends of 36.4% of the total MP pneumonia. In children < 2 years of age, RSV (34.0%) was the most common cause of CAP, followed by MP (9.4%); however, MP was the most common cause of CAP in children aged 2-18 years of age (45.3%). Systemic corticosteroid was most commonly administered for MP pneumonia. The rate of hospitalization in intensive care units was the highest for RSV pneumonia, and ventilator care was most commonly needed in cases of adenovirus pneumonia. CONCLUSIONS: The present study provides fundamental data to establish public health policies to decrease the disease burden due to CAP and improve pediatric health.

Clinical Manifestations and Risk Factors of Anaphylaxis in Pollen-Food Allergy Syndrome.

PURPOSE: Many studies have reported that pollen-food allergy syndrome (PFAS) can cause anaphylaxis. No comprehensive investigations into anaphylaxis in PFAS have been conducted, however. In this study, we investigated the clinical manifestations and risk factors for anaphylaxis in PFAS in Korean patients with pollinosis. MATERIALS AND METHODS: Data were obtained from a nationwide cross-sectional study that previously reported on PFAS in Korean patients with pollinosis. Data from 273 patients with PFAS were collected, including demographics, list of culprit fruits and vegetables, and clinical manifestations of food allergy. We analyzed 27 anaphylaxis patients and compared them with patients with PFAS with oropharyngeal symptoms only (n=130). RESULTS: The most common cause of anaphylaxis in PFAS was peanut (33.3%), apple (22.2%), walnut (22.2%), pine nut (18.5%), peach (14.8%), and ginseng (14.8%). Anaphylaxis was significantly associated with the strength of sensitization to alder, hazel, willow, poplar, timothy, and ragweed (p<0.05, respectively). Multivariable analysis revealed that the presence of atopic dermatitis [odds ratio (OR), 3.58; 95% confidence interval (CI), 1.25-10.23; p=0.017]; sensitization to hazel (OR, 5.27; 95% CI, 1.79-15.53; p=0.003), timothy (OR, 11.8; 95% CI, 2.70-51.64; p=0.001), or ragweed (OR, 3.18; 95% CI, 1.03-9.87; p=0.045); and the number of culprit foods (OR, 1.25; 95% CI, 1.15-1.37; p<0.001) were related to the development of anaphylaxis in PFAS. CONCLUSION: The most common culprit foods causing anaphylaxis in PFAS were peanut and apple. The presence of atopic dermatitis; sensitization to hazel, timothy, or ragweed; and a greater number of culprit foods were risk factors for anaphylaxis in PFAS.

Erratum: Pollen-Food Allergy Syndrome in Korean Pollinosis Patients: A Nationwide Survey.

This corrects the article on p. 648 in vol. 10, PMID: 30306747.

The changes of prevalence and etiology of pediatric pneumonia from National Emergency Department Information System in Korea, between 2007 and 2014.

PURPOSE: Understanding changes in pathogen and pneumonia prevalence among pediatric pneumonia patients is important for the prevention of infectious diseases. METHODS: We retrospectively analyzed data of children younger than 18 years diagnosed with pneumonia at 117 Emergency Departments in Korea between 2007 and 2014. RESULTS: Over the study period, 329,380 pediatric cases of pneumonia were identified. The most frequent age group was 1-3 years old (48.6%) and the next was less than 12 months of age (17.4%). Based on International Classification of Diseases, 10th revision diagnostic codes, confirmed cases of viral pneumonia comprised 8.4% of all cases, pneumonia due to Mycoplasma pneumoniae comprised 3.8% and confirmed cases of bacterial pneumonia 1.3%. The prevalence of confirmed bacterial pneumonia decreased from 3.07% in 2007 and 4.01% in 2008 to 0.65% in 2014. The yearly rate of pneumococcal pneumonia also decreased from 0.47% in 2007 to 0.08% in 2014. A periodic prevalence of M. pneumoniae pneumonia (MP) was identified. CONCLUSION: The increased number of patients with pneumonia, bacterial pneumonia, pleural effusion, and empyema in 2011 and 2013-2014 resulted from an MP epidemic. We provide evidence that the frequency of confirmed cases of bacterial pneumonia and pneumococcal pneumonia has declined from 2007 to 2014, which can simultaneously reflect the effectiveness of the pneumococcal conjugate vaccine.

Pollen-Food Allergy Syndrome in Korean Pollinosis Patients: A Nationwide Survey.

PURPOSE: Pollen-food allergy syndrome (PFAS) is an immunoglobulin E (IgE)-mediated allergy in pollinosis patients caused by raw fruits and vegetables and is the most common food allergy in adults. However, there has been no nationwide study on PFAS in Korea. In this study, we investigated the prevalence and clinical characteristics of PFAS in Korea. METHODS: Twenty-two investigators participated in this study, in which patients with allergic rhinoconjunctivitis and/or bronchial asthma with pollen allergy were enrolled. The questionnaires included demographic characteristics, a list of fruits and vegetables, and clinical manifestations of food allergy. Pollen allergy was diagnosed by skin prick test and/or measurement of the serum level of specific IgE. RESULTS: A total of 648 pollinosis patients were enrolled. The prevalence of PFAS was 41.7% (n = 270). PFAS patients exhibited cutaneous (43.0%), respiratory (20.0%), cardiovascular (3.7%) or neurologic symptoms (4.8%) in addition to oropharyngeal symptoms. Anaphylaxis was noted in 8.9% of the PFAS patients. Seventy types of foods were linked to PFAS; e.g., peach (48.5%), apple (46.7%), kiwi (30.4%), peanut (17.4%), plum (16.3%), chestnut (14.8%), pineapple (13.7%), walnut (14.1%), Korean melon (12.6%), tomato (11.9%), melon (11.5%) and apricot (10.7%). Korean foods such as taro/taro stem (8.9%), ginseong (8.2%), perilla leaf (4.4%), bellflower root (4.4%), crown daisy (3.0%), deodeok (3.3%), kudzu root (3.0%) and lotus root (2.6%) were also linked to PFAS. CONCLUSIONS: This was the first nationwide study of PFAS in Korea. The prevalence of PFAS was 41.7%, and 8.9% of the PFAS patients had anaphylaxis. These results will provide clinically useful information to physicians.

Effect of Pregnancy on Quantitative Medication Use and Relation to Exacerbations in Asthma.

BACKGROUND: The quantification of asthma medication reduction and its relation to an aggravation of asthma during pregnancy at an individual level are unclear. METHODS: We conducted a nationwide retrospective cohort study of asthmatic pregnant women in South Korea. All of the asthma medications were ranked from 1 to 4 according to the guideline-based stepwise approach. We assessed the daily sums of the ranks of the asthma medications and their association with exacerbations during three phases based on the individual's delivery date: before, during, and after pregnancy. RESULTS: The study cohort included 115,169 asthmatic pregnant women who gave birth between 2011 and 2013. The subjects were clustered into four groups according to the daily rank sums of their asthma medication. Asthma medications were rapidly reduced at the beginning of the pregnancy and then slowly increased after delivery. Exacerbations were more frequent in the group with higher rank-sum values than in the group with lower values. Overall exacerbations were reduced during pregnancy compared to before or after delivery. CONCLUSIONS: Asthmatic pregnant women tended to reduce their asthma medication use during pregnancy. This led to a greater number of exacerbations in a small part of the study population.

Serum amyloid A3 exacerbates cancer by enhancing the suppressive capacity of myeloid-derived suppressor cells via TLR2-dependent STAT3 activation.

Myeloid-derived suppressor cells (MDSCs), which suppress diverse innate and adaptive immune responses and thereby provide an evasion mechanism for tumors, are emerging as a key population linking inflammation to cancer. Although many inflammatory factors that induce MDSCs in the tumor microenvironment are known, the crucial components and the underlying mechanisms remain elusive. In this study, we proposed a novel mechanism by which serum amyloid A3 (SAA3), a well-known inflammatory factor, connects MDSCs with cancer progression. We found that SAA3 expression in BALB/c mice increased in monocytic MDSCs (Mo MDSCs) with tumor growth. The induction of SAA3 by apo-SAA treatment in Mo MDSCs enhanced their survival and suppressive activity, while it inhibited GM-CSF-induced differentiation. Endogenous SAA3 itself contributed to the increase in the survival and suppressive activity of Mo MDSCs. We demonstrated that SAA3 induced TLR2 signaling, in turn increasing the autocrine secretion of TNF-α, that led to STAT3 activation. In addition, activated STAT3 enhanced the suppressive activity of Mo MDSCs. Furthermore, SAA3 induction in Mo MDSCs contributed to accelerating tumor progression in vivo. Collectively, these data suggest a novel mechanism by which Mo MDSCs mediate inflammation through SAA3-TLR2 signaling and thus exacerbate cancer progression by a STAT3-dependent mechanism.

Tumor microenvironmental conversion of natural killer cells into myeloid-derived suppressor cells.

How myeloid-derived suppressor cells (MDSC) emerge in the tumor environment remains unclear. Here, we report that GM-CSF can convert natural killer (NK) cells into MDSCs. When transferred into tumor-bearing mice, adoptively transferred NK cells lost their NK phenotype and were converted into Ly6C(high)Ly6G(high) MDSC. This conversion was abolished by exposure to IL-2 either in vitro or in vivo. Notably, we found that of the 4 maturation stages based on CD11b/CD27 expression levels, only the CD11b(high)CD27(high) NK cells could be converted into CD11b(+)Gr1(+) MDSC ex vivo. Transfer of CD27(high) NK cells from tumor-bearing mice into tumor-bearing recipients was associated with conversion to MDSC in a manner associated with reduced numbers of CD11b(high)CD27(high) and CD11b(high)CD27(low) NK cell populations in the recipients. Our results identify a pathway of MDSC development from immature NK cells in tumor-bearing hosts, providing new insights into how tumor cells modulate their host immune microenvironment to escape immune surveillance.

Blockade of Myd88 signaling induces antitumor effects by skewing the immunosuppressive function of myeloid-derived suppressor cells.

Myd88 is an important adaptor molecule for the activation of NADPH oxidase and arginase-1, which are responsible for the suppressive function of myeloid-derived suppressor cells (MDSCs). When wild-type and Myd88(-/-) mice were subcutaneously injected with CT26 colon cancer cells expressing human Her-2/neu, tumor growth was retarded in Myd88(-/-) mice than in wild-type mice. Although the generation of CD11b(+) Gr-1(+) MDSCs was less in Myd88(-/-) mice than in wild-type mice, Myd88(-/-) mice having tumor masses still had significant quantities of MDSCs, suggesting that MDSC generation might be independent of Myd88 signaling. However, MDSCs obtained from tumor-bearing Myd88(-/-) mice failed to suppress antigen-specific proliferation of CD8(+) T cells and CD4(+) T cells, whereas MDSCs from wild-type mice significantly suppressed both types of T cells. Consistent with this, we found that the levels of costimulatory molecules and MHC class II were significantly increased in MDSCs obtained from Myd88(-/-) mice compared with wild-type mice after tumor challenge. Furthermore, CD4(+) T cells residing in tumor-draining lymph nodes of Myd88(-/-) mice secreted more TNF-α than those of wild-type mice. Finally, the blockade of Myd88 signaling by treatment with Myd88 inhibitory peptide, during later tumor stages, significantly inhibited the growth of immunogenic tumors. Overall, these data suggest that signaling through the Myd88 adaptor molecule is critical for the direct suppressive function of MDSCs and approaches to block Myd88-mediated signaling in MDSCs might be effective to inhibit the immunosuppressive function of MDSCs.

Functional changes in myeloid-derived suppressor cells (MDSCs) during tumor growth: FKBP51 contributes to the regulation of the immunosuppressive function of MDSCs.

Myeloid-derived suppressor cells (MDSCs) are increased by tumor-derived factors and suppress anti-tumor immunity. MDSCs obtained at a late time point after tumor injection had stronger suppressive activity than MDSCs obtained at an early time point, as measured by T cell proliferation assays. To find factors in MDSCs that change during tumor growth, we analyzed gene expression profiles from MDSCs at different time points after tumor injection. We found that immune response-related genes were downregulated but protumor function-related genes were upregulated in both monocytic MDSCs (Mo-MDSCs) and polymorphonuclear granulocytic MDSCs (PMN-MDSCs) at the late time point. Among differentially expressed genes, FK506 binding protein 51 (FKBP51), which is a member of the immunophilin protein family and plays a role in immunoregulation, was increased in the Mo-MDSCs and PMN-MDSCs isolated from the late time points. Experiments using small interfering RNA and a chemical inhibitor of FKBP51 revealed that FKBP51 contributes to the regulation of the suppressive function of MDSCs by increasing inducible NO synthase, arginase-1, and reactive oxygen species levels and enhancing NF-κB activity. Collectively, our data suggest that FKBP51 is a novel molecule that can be targeted to regulate the immunosuppressive function of MDSCs.

The restoration of myeloid-derived suppressor cells as functional antigen-presenting cells by NKT cell help and all-trans-retinoic acid treatment.

Myeloid-derived suppressor cells (MDSCs), which accumulate during tumor progression, have been shown to function as important suppressor cells. In a previous study, we showed that immunosuppressive MDSCs could function as immunogenic antigen-presenting cells (APCs) with the help of activated natural killer T (NKT) cells. In the current study, however, we found that MDSCs harvested at a late time point after tumor injection (late MDSCs) were poorly immunogenic even when stimulated with activated NKT cells. As tumor growth progressed, the expression of MHC and costimulatory molecules on MDSCs was gradually down-regulated. Late MDSCs also had innate defects in activation and differentiation mediated by cytokine stimuli. Although late MDSCs treated only with all-trans-retinoic acid (ATRA), a stimulating agent for MDSC differentiation, could not become immunogenic, NKT ligand-loaded, ATRA-treated late MDSCs could be converted into immunogenic APCs to induce incremental immune responses. Furthermore, these effects were mediated by NKT cells secreting IFNγ, and ATRA-mediated increases in glutathione (GSH) levels. Thus, combined treatment with differentiating and activating agents is a prerequisite for the conversion of late MDSCs into immunogenic APCs. Collectively, these results suggest that combined treatments are required for the differentiation and activation of late MDSCs in late stage cancer.

NKT ligand-loaded, antigen-expressing B cells function as long-lasting antigen presenting cells in vivo.

We had previously shown that activated NKT cells licensed B cells to be immunogenic antigen-presenting cells and helped to elicit a wide spectrum of cancer targeted immune responses. In the current study, we sought to verify the safety of αGalCer-loaded, and adenovirus-transduced B cell-based vaccines, together with mechanism of action. Intravenously injected αGalCer-loaded, antigen-expressing B cells rapidly localized in the spleen and directly primed CD8(+) T cells in an antigen-specific manner. The transferred antigen was sustained for at least 30 days. While some injected B cells produced nonspecific IgG, the antigen-specific IgG response was completely dependent on endogenous B cells. The liver was one of the main tissues where injected B cells were retained; however, we could not find the signs of liver toxicity. Our results demonstrate that αGalCer-loaded, antigen-expressing B cells behave as "antigen-presenting" cells that stimulate endogenous antigen-specific T cells and B cells in vivo without significant toxicity.

Expression of interferon regulatory factor-1 in the mouse cumulus-oocyte complex is negatively related with oocyte maturation.

OBJECTIVE: We found previously that interferon regulatory factor (Irf)-1 is a germinal vesicle (GV)-selective gene that highly expressed in GV as compared to metaphase II oocytes. To our knowledge, the function of Irf-1 in oocytes has yet to be examined. The present study was conducted to determine the relationship between retinoic acid (RA) and RA-mediated expression of Irf-1 and the mouse oocyte maturation. METHODS: Immature cumulus-oocyte-complexes (COCs) were collected from 17-day-old female mice and cultured in vitro for 16 hours in the presence of varying concentrations of RA (0-10 µM). Rate of oocyte maturation and activation was measured. Gene expression was measured by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) and cytokine secretion in the medium was measured by Bio-Plex analysis. Apoptosis was analyzed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. RESULTS: The rates of oocyte maturation to metaphase II and oocyte activation increased significantly with RA treatment (10 nM-1 µM). With 100 nM RA treatment, lowest level of Irf-1 mRNA and cumulus cell's apoptosis was found. Among 23 cytokines measured by Bio-Plex system, the substantial changes in secretion of tumor necrosis factor-α, macrophage inflammatory protein-1ß, eotaxin and interleukin-12 (p40) from COCs in response to RA were detected. CONCLUSION: We concluded that the maturation of oocytes and Irf-1 expression are negatively correlated, and RA enhances the developmental competence of mouse immature oocytes in vitro by suppressing apoptosis of cumulus cells. Using a mouse model, results of the present study provide insights into improved culture conditions for in vitro oocyte maturation and relevant cytokine production and secretion in assisted reproductive technology.

Agonistic Anti-CD137 Monoclonal Antibody Treatment Induces CD11bGr-1 Myeloid-derived Suppressor Cells.

CD137 (4-1BB/tnfrsf9) has been shown to co-stimulate T cells. However, agonistic anti-CD137 monoclonal antibody (mAb) treatment can suppress CD4(+) T cells, ameliorating autoimmune diseases, whereas it induces activation of CD8(+) T cells, resulting in diverse therapeutic activity in cancer, viral infection. To investigate the CD137-mediated T cell suppression mechanism, we examined whether anti-CD137 mAb treatment could affect CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs). Intriguingly, anti-CD137 mAb injection significantly increased CD11b(+)Gr-1(+) cells, peaking at days 5 to 10 and continuing for at least 25 days. Furthermore, this cell population could suppress both CD8(+) T cells and CD4(+) T cells. Thus, this study demonstrated that, for the first time, anti-CD137 mAb treatment could induce CD11b(+)Gr-1(+) MDSCs under normal conditions, suggesting a possible relationship between myeloid cell induction and CD137-mediated immune suppression.

CD40-targeted recombinant adenovirus significantly enhances the efficacy of antitumor vaccines based on dendritic cells and B cells.

Despite the advantages of using adenoviral vectors for specific antigenic gene delivery in the development of antigen-presenting cell (APC)-based vaccines, the lack of the coxsackievirus-adenovirus receptor (CAR) on APCs limits the use of adenoviral vectors for in vitro gene delivery. In this study, we used a recombinant adapter protein, CFm40L, which consists of the ectodomain of CAR genetically fused to the ectodomain of CD40 ligand (CD40L) via a trimerization motif, to target Her-2/neu- or human papillomavirus 16 (HPV16) E6/E7-encoding adenoviruses to CD40 on dendritic cells (DCs) and B cells. Targeting CD40 enabled the enhancement of tumor antigen delivery and simultaneous activation of APCs via the CD40-CD40L interaction. We found that these transduced DCs and B cells substantially enhanced the CTL response against human Her-2/neu- and HPV16 E6/E7-expressing tumors, resulting in significant inhibition of tumor growth in a murine tumor model. In addition, the use of the CFm40L adapter protein in combination with gemcitabine treatment allowed for a successful immune response against a self-tumor antigen, murine Her-2/neu. Our results suggest that targeting adenovirus to APCs via CD40, using CFm40L, represents a great improvement in anticancer cellular vaccines.

Conversion of Th2 memory cells into Foxp3+ regulatory T cells suppressing Th2-mediated allergic asthma.

Genetic and epigenetic programming of T helper (Th) cell subsets during their polarization from naive Th cells establishes long-lived memory Th cells that stably maintain their lineage signatures. However, whether memory Th cells can be redifferentiated into another Th lineage is unclear. In this study, we show that Ag-specific memory Th cells were redifferentiated into Foxp3(+) T cells by TGF-beta when stimulated in the presence of all-trans retinoic acid and rapamycin. The "converted" Foxp3(+) T cells that were derived from Th2 memory cells down-regulated GATA-3 and IRF4 and produced little IL-4, IL-5, and IL-13. Instead, the converted Foxp3(+) T cells suppressed the proliferation and cytokine production of Th2 memory cells. More importantly, the converted Foxp3(+) T cells efficiently accumulated in the airways and significantly suppressed Th2 memory cell-mediated airway hyperreactivity, eosinophilia, and allergen-specific IgE production. Our findings reveal the plasticity of Th2 memory cells and provide a strategy for adoptive immunotherapy for the treatment of allergic diseases.