Plasmacytoid dendritic cells stimulated with Lactococcus lactis strain Plasma produce soluble factors to suppress SARS-CoV-2 replication.

Innate immune responses are important in the control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. We have previously found a lactic acid bacteria species, Lactococcus lactis strain Plasma (LC-Plasma), which possesses specific feature to activate plasmacytoid dendritic cells (pDCs) and thus may affect innate immune responses. Here, we investigated the impact of pDC activation by LC-Plasma on SARS-CoV-2 replication in vitro. Addition of the culture supernatant of pDCs stimulated with LC-Plasma resulted in suppression of SARS-CoV-2 replication in Vero and Calu-3 cells. We confirmed interferon-α (IFN-α) secretion in the supernatant of pDCs stimulated with LC-Plasma and induction of IFN-stimulated genes in cells treated with the pDC supernatant. Anti-IFN-α antibody impaired the suppression of SARS-CoV-2 replication by the supernatant of LC-Plasma-stimulated pDCs, suggesting that IFN-α plays an important role in the SARS-CoV-2 suppression. Our results indicate the potential of LC-Plasma to induce inhibitory responses against SARS-CoV-2 replication through pDC stimulation with IFN-α secretion.

[A Recurrent Colon Cancer Successfully Treated by Nivolumab plus Ipilimumab with On and Off for Preventing Exacerbation of Skin Disorders].

Here, we report a case in which nivolumab plus ipilimumab combination therapy was significantly effective for MSI-high recurrent colon cancer with acute exacerbation after 5-FU/L-OHP/CPT-11 treatment. At the end of 4 cycles of combination therapy, clinical CR was obtained on diagnostic imaging. At the end of the 2 cycles of transition from combination therapy to monotherapy, eosinophilia was observed in a quadratic function, and exacerbation of skin disorders was observed. Eosinophil counts normalized promptly after discontinuation of treatment, and skin disorders gradually improved. Two months after the discontinuation of treatment, monotherapy was restarted. After the resumption of treatment, an increase in eosinophils and worsening of skin symptoms were observed again, and stopped treatment. We report an interesting case in which immune checkpoint inhibiter were turned on and off according to eosinophil counts for preventing exacerbation of skin disorders, and for maintaining cancer remission by continuing immune checkpoint inhibitor treatment.

Fecal Microbes Associated with the Outcomes After Esophagectomy in Patients with Esophageal Cancer.

BACKGROUND: Although accumulating evidence suggests that an imbalanced gut microbiota leads to cancer progression, few studies demonstrated the implication in patients who underwent oncologic esophagectomy. This study aimed to elucidate the association between gut microbes and the outcomes after oncologic esophagectomy, as well as the host's inflammatory/nutritional status. METHODS: Overall, 783 consecutive patients who underwent oncologic esophagectomy were eligible. We investigated the microbiota detected by fecal culture tests and then assessed the association between the gut microbiota and patient characteristics, short-term outcomes, and long-term survival. RESULTS: Seventeen different species could be cultivated. We comprehensively examined the impact of each detected microbe on survival. The presence of Bacillus species (Bacillus sp.; 26.8%) was associated with favorable prognosis on overall and cancer-specific survival (p = 0.02 and 0.02, respectively). Conversely, the presence of Proteus mirabilis (P. mirabilis; 3.4%) was associated with unfavorable overall and recurrence-free survivals (p = 0.02 and < 0.01, respectively). Multivariate analysis showed that the presence of P. mirabilis was one of the independent prognostic factors for poor recurrence-free survival (p < 0.01). Patients with Bacillus sp. had lower modified Glasgow prognostic score and better response to preoperative treatment than those without (p = 0.01 and 0.03, respectively). Meanwhile, patients with P. mirabilis were significantly associated with higher systemic inflammation scores and increased postoperative pneumonia incidence than those without (p = 0.01 and 0.02, respectively). CONCLUSIONS: Preoperative fecal microbiota was associated with the host's inflammatory and nutritional status and may influence the outcomes after oncologic esophagectomy.

Is Prophylactic Cervical Drainage Effective in Patients Undergoing McKeown Esophagectomy Reconstructed Through the Retrosternal Route with Two-Field Lymphadenectomy?

BACKGROUND: McKeown esophagectomy with two-field lymphadenectomy is the treatment of choice for oncologic esophagectomy. A cervical drain is placed in cases after modern two-field lymph node dissection (M2FD) to provide information on anastomotic leakage. However, the necessity of prophylactic cervical drainage during surgery remains unknown. This study aimed to clarify the clinical significance of cervical drainage in patients who underwent McKeown esophagectomy with M2FD. METHODS: A total of 293 patients underwent McKeown surgery with two-field lymphadenectomy at our institute between January 2013 and December 2019. We compared the day of drain removal, amount of drainage volume, and the appearance of drainage fluid between patients with and without anastomotic leakage. RESULTS: McKeown esophagectomy reconstructed through the retrosternal route is 203 patients (69.3%) of all. Nineteen patients (6.5%) experienced anastomotic leakage. The amount of cervical drain discharge was comparable between patients with and without anastomotic leakage. In addition, no purulent or salivary discharge was observed in patients with anastomotic leakage. There was no difference in the median day of drain removal between the groups. The initial clinical findings for the diagnosis of anastomotic leakage were surgical site infection in 10 (52.6%), fever in 5 (26.3%), prolonged inflammation in a blood test in 3 (15.8%), and bloody discharge from the chest tube in 1 (5.3%). There was no mortality due to any cause. CONCLUSION: A prophylactic cervical drain may not be mandatory in patients with esophageal cancer undergoing McKeown esophagectomy reconstructed through the retrosternal route with two-field lymphadenectomy.

C-reactive protein to prealbumin ratio: a useful inflammatory and nutritional index for predicting prognosis after curative resection in esophageal squamous cell carcinoma patients.

PURPOSE: Although C-reactive protein to prealbumin ratio (CPR) can predict the outcomes of several types of cancer surgeries, little is known about the implication of CPR in patients undergoing esophagectomy for esophageal squamous cell carcinoma (ESCC). METHODS: Between 2009 and 2018, 682 consecutive ESCC patients who underwent curative esophagectomy were enrolled. The clinicopathological factors and prognoses were compared between the groups stratified by preoperative CPR levels. A logistic regression model was used to determine the risk factors of postoperative pneumonia. Survival curves were constructed using the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards model was used to elucidate prognostic factors. RESULTS: There were more elderly patients, more males, and more advanced clinical T and N categories in the high CPR group than in the low CPR group. Also, the incidence of postoperative pneumonia was significantly higher in the high CPR group than in the low CPR group (32.4% vs. 20.3%, p < 0.01). In multivariate analyses, high CPR was one of the independent predictive factors for postoperative pneumonia (OR, 1.71; 95% CI, 1.15-2.54; p < 0.03). Moreover, high CPR was an independent prognostic factor for overall, cancer-specific, and recurrence-free survivals (HR 1.62; 95% CI 1.18-2.23; p < 0.01, HR 1.57; 95% CI 1.08-2.32; p = 0.02, HR 1.42; 95% CI 1.06-1.90; p = 0.02). CONCLUSION: Preoperative CPR was found to be a useful inflammatory and nutritional indicator for predicting the occurrence of pneumonia and prognosis in patients with ESCC undergoing esophagectomy.

Long-Term Insufficiency of Oral Intake after Esophagectomy: Who Needs Intense Nutritional Support after Esophagectomy?

BACKGROUND: Patients with esophageal cancer are at a high risk of malnutrition after esophagectomy, and nutritional support may at times be required for several months following surgery. In this study, we aimed to clarify the clinical features and preoperative risk factors of patients with long-term insufficiency of oral intake after esophagectomy by evaluating the duration of feeding enterostomy placement. METHODS: A total of 306 patients who underwent esophagectomy, reconstruction with gastric conduit, and feeding enterostomy creation were retrospectively reviewed. We analyzed the clinical features and preoperative risk factors for long-term placement of feeding enterostomy. RESULTS: The feeding enterostomy tube was removed less than 90 days after esophagectomy in 234 patients (76.5%) (short group), whereas 72 patients still needed enteral nutrition after 90 days (23.5%; long group). Although severe malnutrition was observed more frequently in the long group compared with the short group (p = 0.021), overall survival time was comparable between the groups (p = 0.239). Multivariate analysis revealed that higher age (odds ratio [OR] 1.04; 95% confidence interval [CI], 1.01-1.07; p = 0.021), poor performance status (OR 2.94; 95% CI, 1.10-7.87; p = 0.032), and lower preoperative body weight (BW) (OR 0.96; 95% CI, 0.94-0.99; p = 0.009) were the independent variables predicting the long-time placement of feeding enterostomy. CONCLUSION: Nutritional support via feeding enterostomy for more than 90 days after esophagectomy was required in 23.5% of patients. The elderly, poor performance status, and lower BW were the independent preoperative factors for predicting the long-term placement of feeding enterostomy.

Current status of robot-assisted minimally invasive esophagectomy: what is the real benefit?

Robot-assisted minimally invasive esophagectomy (RAMIE) for esophageal cancer has been performed increasingly frequently over the last few years. Robotic systems with articulated devices and tremor filtration allow surgeons to perform such procedures more meticulously than by hand. The feasibility of RAMIE has been demonstrated in several retrospective comparative studies, which showed similar short-term outcomes to conventional minimally invasive esophagectomy (cMIE). Considering the number of harvested lymph nodes, RAMIE may be superior to cMIE in terms of left upper mediastinal lymph node dissection. However, whether or not the addition of a robotic system to cMIE can help improve perioperative and oncological outcomes remains unclear. Given the lack of established evidence from randomized controlled trials, we must await the results of ongoing studies to reach any meaningful conclusions. Further advancements in robotic platforms, as well as the reduction in medical expenses, will be essential to demonstrate the real benefit of RAMIE.

Outcomes of esophagectomy for patients with esophageal squamous cell carcinoma accompanied by recurrent laryngeal nerve palsy at diagnosis.

BACKGROUND: Hoarseness is one of the classical symptoms in patients with locally advanced thoracic esophageal squamous cell carcinoma (ESCC), and it results from recurrent laryngeal nerve palsy, which is caused by nodal metastasis along the recurrent laryngeal nerve or by main tumors. We reviewed the short-term and long-term results of esophagectomy for patients with locally advanced ESCC and hoarseness at diagnosis. PATIENTS: Patients who initially presented with hoarseness from recurrent laryngeal nerve palsy between 2009 and 2018 and underwent esophagectomy for thoracic ESCC were eligible for this study. Pharyngolaryngectomy or cervical ESCC were exclusionary. RESULTS: A total of 15 patients were eligible, and 14 underwent resection of the recurrent laryngeal nerves. The remaining patient had nerve-sparing surgery. Nine patients (60%) had post-operative complications ≥ Clavien-Dindo class II and, pulmonary complications were most common. Two patients (13%) died in the hospital. The 5-year overall survival rate for all patients was 16%. Age (≤ 65 years), cT1/T2 tumor, and remarkably good response to neoadjuvant treatment were likely related to longer survival; however, these relationships were not statistically significant. CONCLUSIONS: Esophagectomy for ESCC patients who are diagnosed with recurrent laryngeal nerve paralysis at initial presentation could be a treatment option if the patient is relatively young, has a cT1/T2 tumor, or shows a remarkably good response to neoadjuvant treatment. However, clinicians should be aware of the possibility of postoperative pulmonary complications, which were frequently observed with the procedure.

Chemical Modification of Phage-Displayed Helix-Loop-Helix Peptides to Construct Kinase-Focused Libraries.

Conformationally constrained peptides hold promise as molecular tools in chemical biology and as a new modality in drug discovery. The construction and screening of a target-focused library could be a promising approach for the generation of de novo ligands or inhibitors against target proteins. Here, we have prepared a protein kinase-focused library by chemically modifying helix-loop-helix (HLH) peptides displayed on phage and subsequently tethered to adenosine. The library was screened against aurora kinase A (AurA). The selected HLH peptide Bip-3 retained the α-helical structure and bound to AurA with a KD value of 13.7 µM. Bip-3 and the adenosine-tethered peptide Bip-3-Adc provided IC50 values of 103 µM and 7.7 µM, respectively, suggesting that Bip-3-Adc bivalently inhibited AurA. In addition, the selectivity of Bip-3-Adc to several protein kinases was tested, and was highest against AurA. These results demonstrate that chemical modification can enable the construction of a kinase-focused library of phage-displayed HLH peptides.

Comparison of Outcomes Between Additional Esophagectomy After Noncurative Endoscopic Resection and Upfront Esophagectomy for T1N0 Esophageal Squamous Cell Carcinoma.

BACKGROUND: Esophagectomy with lymph node dissection is a choice of additional treatment after noncurative endoscopic resection (ER) of T1N0 esophageal squamous cell carcinoma (ESCC). The efficacy and safety of esophagectomy in this situation remain unclear when compared with upfront esophagectomy. METHODS: We investigated the short- and long-term outcomes of 321 patients with clinical T1N0M0 ESCC who underwent curative esophagectomy, and compared the status of lymph node metastasis, surgical results, and the prognosis between the ER and non-ER groups. RESULTS: The ER group consisted of 57 patients (17.8%), while the non-ER group consisted of 264 patients (82.2%). The incidence of lymph node metastasis was not significantly different between the ER (24.6%) and non-ER groups (30.7%), and there was no significant difference in surgical outcomes between the groups. The distribution of metastatic lymph nodes was very similar between the groups. However, 13 of 14 patients (93%) with lymph node metastasis in the ER group and 63 of 82 patients (77%) with lymph node metastasis in the non-ER group had pN1 disease, while the remaining 18 patients (23%) with lymph node metastasis in the non-ER group had pN2 or N3 disease. Overall and relapse-free survival rates were significantly better in the ER group than in the non-ER group (p < 0.05 and p < 0.01, respectively). To date, no patients in the ER group experienced disease recurrence. CONCLUSIONS: Additional esophagectomy is a safe and effective treatment modality for patients after noncurative ER.

Clinical Significance of Serum Squamous Cell Carcinoma Antigen for Patients with Recurrent Esophageal Squamous Cell Carcinoma.

BACKGROUND: Squamous cell carcinoma antigen (SCC-Ag) is a widely used tumor marker of SCC. However, the clinical significance of serum SCC-Ag levels in recurrent esophageal SCC (ESCC) remains unclear. This study aimed to investigate the clinical relevance of serum SCC-Ag levels in patients with recurrent ESCC after surgery. METHODS: This study retrospectively analyzed 208 patients who experienced recurrence after curative resection for ESCC. Serum SCC-Ag levels at the time of recurrence were collected from the patients' records. The patients were classified into tertiles based on the serum SCC-Ag values (low, middle, and high), and the clinical characteristics and outcomes were compared among the groups. RESULTS: Significant differences in sex (p = 0.001), pathologic T (p = 0.034), and N stages of primary cancer (p = 0.015) were observed among the groups. Although the recurrence patterns did not differ significantly, a high SCC-Ag was significantly associated with multiple recurrences (p = 0.019). The high-SCC-Ag group patients demonstrated a shorter time to recurrence than the other groups (p = 0.044). The SCC-Ag levels were significantly associated with overall survival after recurrence (p = 0.036). Multivariate analysis showed that serum SCC-Ag value at recurrence was an independent poor prognosticator (p = 0.031). CONCLUSION: Elevated serum SCC-Ag levels at recurrence were significantly associated with a reduced time to recurrence, multiple recurrences, and a poor prognosis after recurrence. An alternative to the current standard treatment is required to improve the outcome for patients with high serum SCC-Ag levels at recurrence.

Influence of Damaged Stomach on Anastomotic Leakage following Cervical Esophagogastrostomy in Patients with Esophageal Cancer.

BACKGROUND: Anastomotic leakage (AL) is one of the most common complications after esophagectomy. Although some patients have a history of peptic ulcers or other prior stomach diseases, the influence of a damaged stomach (DS) on AL incidence remains unclear. Therefore, we investigated the association between DS and incidence of AL in patients who underwent esophagectomy. PATIENTS AND METHODS: Between 2015 and 2019, a total of 447 consecutive patients who underwent cervical esophagogastrostomy using gastric tube following esophagectomy were enrolled. DS was defined on the basis of endoscopic findings of ulcers or scars due to medical history or prior treatment. We compared the incidence of AL between patients with DS and those with a healthy stomach (HS). Univariate and multivariate logistic regression analyses were used to identify factors that could predict AL incidence. RESULTS: Fifty-one patients (11.4%) had DS. Causes of DS included peptic ulcer (n = 36), endoscopic resection for early gastric cancer (n = 9), percutaneous endoscopic gastrostomies (n = 5), and post-chemotherapy scar for gastric malignant lymphoma (n = 1). Overall, AL occurred in 35 patients (7.8%). The incidence of AL in the DS group was significantly higher than in the HS group (15.7 vs. 6.8%, p = 0.03). DS was one of the independent predictive factors for AL (odds ratio, 2.75; 95% confidence interval, 1.10-6.92; p = 0.03) on multivariate analysis. Further, the diseases in the lower third of the conduit were associated with AL. CONCLUSIONS: Presence of DS can predict AL in patients who underwent cervical esophagogastrostomy after esophagectomy.

Additional Treatment Following Noncurative Endoscopic Resection for Esophageal Squamous Cell Carcinoma: A Comparison of Outcomes between Esophagectomy and Chemoradiotherapy.

BACKGROUND: Endoscopic resection (ER) has been widely implemented for cT1N0 esophageal squamous cell carcinoma (ESCC). Additional therapy, including esophagectomy and chemoradiotherapy (CRT), is sometimes required after noncurative ER. METHODS: We retrospectively reviewed 108 patients who received any additional treatment following noncurative ER (positive vertical margins, lymphovascular invasion, or invasion depth of submucosa or more), and compared the short- and long-term outcomes between the two treatment modalities. RESULTS: Of 108 patients, 56 underwent esophagectomy (E group), and 52 received CRT (CRT group). A positive vertical margin was observed in 17 (14.8%) patients and high risks of occult lymph node metastasis were observed in 91 (85.2%) patients, as well as lymphovascular invasion in 35 (32.4%) patients, invasion depth of the submucosa or more in 27 (25.0%) patients, and both in 29 (26.9%) patients. The E group patients were significantly younger (p = 0.046) and tended to present with larger tumors than those in the CRT group (p = 0.057). Lymphatic invasion was more frequent in the E group (p = 0.019), and, furthermore, one treatment-related death was observed in the E group. There were no significant differences between the groups in overall and disease-specific survival (p = 0.406 and 0.151, respectively), however, recurrence was only observed in the CRT group. CONCLUSION: Both esophagectomy and CRT are safe and effective as additional treatments after noncurative ER in patients with ESCC. Esophagectomy is oncologically safe, whereas a risk of postoperative morbidity and mortality remains. Although the adverse events are acceptable, CRT has a certain degree of risk of disease recurrence.

Macropinocytosis-Inducible Extracellular Vesicles Modified with Antimicrobial Protein CAP18-Derived Cell-Penetrating Peptides for Efficient Intracellular Delivery.

The antimicrobial protein CAP18 (approximate molecular weight: 18 000), which was first isolated from rabbit granulocytes, comprises a C-terminal fragment that has negatively charged lipopolysaccharide binding activity. In this study, we found that CAP18 (106-121)-derived (sC18)2 peptides have macropinocytosis-inducible biological functions. In addition, we found that these peptides are highly applicable for use as extracellular vesicle (exosomes, EV)-based intracellular delivery, which is expected to be a next-generation drug delivery carrier. Here, we demonstrate that dimerized (sC18)2 peptides can be easily introduced on EV membranes when modified with a hydrophobic moiety, and that they show high potential for enhanced cellular uptake of EVs. By glycosaminoglycan-dependent induction of macropinocytosis, cellular EV uptake in targeted cells was strongly increased by the peptide modification made to EVs, and intriguingly, our herein presented technique is efficiently applicable for the cytosolic delivery of the biologically cell-killing functional toxin protein, saporin, which was artificially encapsulated in the EVs by electroporation, suggesting a useful technique for EV-based intracellular delivery of biofunctional molecules.

Airflow Limitation Predicts Postoperative Pneumonia after Esophagectomy.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is known to be a risk factor of pneumonia after esophagectomy. In this study, we investigated the relationship of airflow limitation with the occurrence and the severity of pneumonia in esophageal cancer patients who underwent esophagectomy. METHODS: We enrolled 844 patients who underwent curative esophagectomy between 2009 and 2018. The airflow limitation was evaluated using the percent-predicted forced expiratory volume at 1 s (%FEV1) with spirometry. RESULTS: There were 597 (70.7%), 141 (16.7%), 68 (8.1%), and 38 patients (4.5%) with %FEV1 of ≥ 90%, 80-90%, 70-80%, and < 70% categories, respectively. One hundred and ninety-one patients (22.6%) occurred pneumonia, and the incidences of pneumonia in each category of patients were 18.8%, 28.4%, 29.4%, and 50.0%, respectively. In multivariate analysis, the categories of 80%-90%, 70-80%, and < 70% were significantly associated with a higher incidence of postoperative pneumonia (OR 1.57; 95% CI 1.02-2.43, OR 1.87; 95% CI 1.04-3.36, OR 3.34; 95% CI 1.66-6.71, respectively), with the %FEV1 category of ≥ 90% as reference. The incidence of severe pneumonia of Clavien-Dindo grade III or higher was also significantly associated with the %FEV1. In patients without COPD, the incidence of pneumonia was significantly higher in those with %FEV1 < 90% than in those with %FEV1 ≥ 90% (32.2% versus 17.5%, p < 0.001). CONCLUSIONS: The airflow limitation can help predict the occurrence of pneumonia after esophagectomy in patients with and without COPD. Exclusive preventive measures should be considered in patients with reduced %FEV1 undergoing esophagectomy.

Measuring the Normal Stress Distribution Acting on a Locked-Wheel of Push-Pull Locomotion Rovers via a Wheel Sensor System.

The resistance force generated when the locked-wheel acts on the soil is critical for deciding the traveling performance of push-pull locomotion. The resistance force depends on the tangential force of the sliding soil wedge beneath the wheel, and the tangential force depends on the forces of the soil and the wheel perpendicular to the tangential direction. Hence, the normal stress distribution of the locked-wheel can affect the resistance force. Previous studies indicated different insights that describe either a uniform or non-uniform shape of the normal stress distribution. The distribution of the locked-wheel still needs to be examined experimentally. This study measured the normal stress distribution using the wheel sensor system, and the variation of the contact area and slip surface beneath the wheel were also observed in PIV analysis. Those results showed that the normal stress distribution was non-uniform along the wheel contact area, and the change of the distribution was confirmed with the change of the contact area and slip surface. Then, the resistance force calculated by a preliminary model based on the measured data was compared with the total resistance force of the wheel measured by a separate sensor. This comparison provided a theoretical consideration for the measured data.

Characterization of genomic DNA of lactic acid bacteria for activation of plasmacytoid dendritic cells.

BACKGROUND: Lactococcus lactis strain Plasma (LC-Plasma) possesses strong stimulatory activity for plasmacytoid dendritic cells (pDCs) via the TLR9-Myd88 pathway. To reveal the effective lactic acid bacteria (LAB) genome structure for pDCs stimulatory activity, we performed in vitro screening, using randomly selected 200 bp DNA fragments from the LC-Plasma genome. RESULTS: We found that the CpG motif copy number in the fragments was positively and significantly correlated with pDCs stimulatory activity (R = 0.491, p < 0.01). However, the determination coefficient (R2) was 0.24, which means other factors affecte activity. We found that the G + C contents of the fragment showed a significant negative correlation with activity (R = - 0.474, p < 0.01). The correlation between pDCs stimulatory activity and the copy number of CpG motifs was greatly increased when DNA fragments were stratified by G + C contents. We also performed bioinformatics analysis and a screening of LAB strains with high pDCs stimulatory activity. Species with a high copy number of CpG motifs in the low-G + C region of their genomes had higher probability of inducing high-pDCs stimulatory activity. L. lactis subsp. lactis, Leuconostoc mesenteroides, and Pediococcus pentosaceus were three typical examples of LAB that had high pDCs stimulatory activity. CONCLUSIONS: Our data suggested that the G + C content of DNA is one of the critical factors for pDCs stimulatory activity by DNA fragments. Furthermore, we found that the copy number in the low-G + C regions strongly affected the pDCs stimulatory activity of whole cells of LAB strains. These results should be useful for the design of new DNA fragments containing CpG motifs. This study also demonstrated an in silico screening method for identifying bacterial species that are able to activate pDCs.

Plasmacytoid dendritic cell dysfunction caused by heat stress is improved by administration of Lactococcus lactis strain plasma in mice.

Plasmacytoid dendritic cells (pDCs) are crucial in anti-viral immunity, acting as regulators in both adaptive and innate immunity. In this study, brief heat stress caused a decrease in splenic pDC activity in mice. Administration of Lactococcus lactis strain Plasma (LC-Plasma) significantly suppressed the decrease in pDC activity and IFN-α production. Abbreviations: LC-Plasma: Lactococcus lactis strain Plasma; LAB: lactic acid bacteria; pDC: plasmacytoid dendritic cell; IFN: interferons; mDC: myeloid dendritic cells.

The Effects of Plasmacytoid Dendritic Cell-Stimulative Lactic Acid Bacteria, Lactococcus lactis Strain Plasma, on Exercise-Induced Fatigue and Recovery via Immunomodulatory Action.

The unique lactic acid bacteria, Lactococcus lactis strain plasma (LC-Plasma), stimulates plasmacytoid dendritic cells, which play an important role in viral infection. The authors previously reported that LC-Plasma reduced the number of days athletes experienced cold-like symptoms and fatigue feelings after high-intensity exercise training; however, the mechanism was unclear. In this study, the authors investigated the effect of LC-Plasma on recovery from physical damage after single exercise on a treadmill in BALB/c mice model. Oral administration of LC-Plasma (AIN-93G + 0.029% LC-Plasma) for 4 weeks significantly improved the locomotor reduction after treadmill exercise. This effect was not detected in mice receiving Lactobacillus rhamnosus GG, representative probiotics strain. LC-Plasma also improved voluntary locomotor activity after exercise. Blood and muscle sample analysis indicated that LC-Plasma affects plasmacytoid dendritic cell activation, which, in turn, attenuates muscle degenerative genes and the concentration of fatigue-controlled cytokine transforming growth factor-ß.

Administration of plasmacytoid dendritic cell-stimulative lactic acid bacteria enhances antigen-specific immune responses.

Lactic acid bacteria (LAB) have been reported to have beneficial effects on protective immunity against viruses and pathogenic bacteria by activating innate immune cells such as dendritic cells (DC) or macrophages. However, little is known about whether LAB contributes to antigen-specific immune responses. Because plasmacytoid DC (pDC) links innate and acquired immunity, here we investigated whether the pDC-stimulative LAB, Lactococcus lactis strain Plasma (LC-Plasma), influences antigen-specific immune responses. In in vitro co-culture experiments, LC-Plasma enhanced the expression of MHC class I and II, and CD80 and CD86 on both pDC and conventional DC, and this enhancement was abolished by treatment with a Toll-like receptor 9 antagonist. A subsequent in vitro study showed that LC-Plasma increased antigen-specific T cell responses via DC activation. In mice, oral administration of LC-Plasma in combination with intraperitoneal antigen administration enhanced the percentage of antigen-specific CD8+ T cells and the amount of antigen-specific IgG. Furthermore, continuous intake of LC-Plasma increased T helper 1 responses, which contribute to antigen-specific cellular and humoral immune responses. Taken together, these results reveal that the oral intake of pDC-stimulative LAB enhances antigen-specific immune responses.