Comparison of the influence of postoperative oral nutritional supplementation between octogenarian and non-octogenarian patients undergoing gastrectomy for cancer.

BACKGROUND: Despite recent reports, the effectiveness of postoperative oral nutritional supplementation (ONS) on body weight loss and malnutrition after gastrectomy remains controversial. We aimed to elucidate the effectiveness of ONS especially in octogenarian patients undergoing oncological gastrectomy. METHODS: A total of 286 consecutive patients who underwent gastrectomy for gastric cancer were eligible. Postoperative body weight loss, malnutrition, and sarcopenia were compared between patients with and without postoperative ONS among octogenarian patients aged ≥ 80 years and non-octogenarian patients aged < 80 years. RESULTS: In this study, 36 (62.1%) octogenarian and 121 (53.1%) non-octogenarian patients continued postoperative ONS for three months. The clinicopathologic characteristics were not different between the ONS (-) and ONS (+) groups among the octogenarian and non-octogenarian patients. The changes in body weight and serum albumin levels at postoperative 1 year were different between the ONS (-) and ONS (+) groups (P = 0.03 and P = 0.04, respectively) among the octogenarian patients, but not between the two groups among the non-octogenarian patients (P = 0.99 and P = 0.29, respectively). Also, the decline in psoas muscle mass index at postoperative 6 months and 1 year was significantly lower in the ONS (+) group than in the ONS (-) group (P < 0.01 and P < 0.01, respectively). In addition, similar results were found in octogenarian patients who underwent distal gastrectomy. CONCLUSIONS: Postoperative ONS could prevent body weight loss, malnutrition, and sarcopenia especially in octogenarian patients who underwent gastrectomy for gastric cancer.

Enhancing Preoperative Diagnosis Accuracy of Stage III Gastric Cancer with Circulating circRNAs.

BACKGROUND: The prognosis remains poor for stage III gastric cancer, and neoadjuvant chemotherapy is increasingly used to improve outcomes. Accurate diagnosis prior to treatment is essential to develop appropriate treatment strategies for poor prognosis subgroups. This study aims to enhance the accuracy of pre-treatment gastric cancer diagnosis using a biological approach centered on circulating circular RNA (circRNA). MATERIALS AND METHODS: We conducted a comprehensive analysis of circRNA expression profiles using two Gene Expression Omnibus datasets to identify circRNA candidates associated with stage III gastric cancer. Subsequently, we validated these circRNA biomarkers in two independent clinical cohorts comprising a total of 174 patients with gastric cancer and non-disease controls through real-time polymerase chain reaction (PCR). RESULTS: Genome-wide circRNA analysis identified a panel of four biomarkers capable of diagnosing pathologically confirmed stage III (pStage III) gastric cancer. In a training cohort (n = 83), a clinically applicable panel of four circRNAs was developed (AUC 0.81), which was successfully validated in an independent clinical cohort (n = 82; AUC 0.76). To assess clinical utility, we combined clinical imaging (cStage) with the circRNA panel. Among those initially diagnosed as cStage III but later confirmed as pStage I/II, 86% were accurately diagnosed using the molecular biological approach with circRNAs. CONCLUSIONS: We have developed a circRNA-based non-invasive liquid biopsy that can improve the diagnostic performance of pStage III gastric cancer before treatment. Our circRNA model could provide a sophisticated and personalized approach to assist in treatment planning for patients with advanced gastric cancer.

Molecular mechanisms driving the interactions between platelet and gastric cancer cells during peritoneal dissemination.

Platelets (PLTs) facilitate tumor progression and the spread of metastasis. They also interact with cancer cells in various cancer types. Furthermore, PLTs form complexes with gastric cancer (GC) cells via direct contact and promote their malignant behaviors. The objective of the present study was to explore the molecular mechanisms driving these interactions and to evaluate the potential for preventing peritoneal dissemination by inhibiting PLT activation in GC cells. The present study examined the roles of PLT activation pathways in the increased malignancy of GC cells facilitated by PLT-cancer cells. Transforming growth factor-ß receptor kinase inhibitor (TRKI), Src family kinase inhibitor (PP2) and Syk inhibitor (R406) were used to identify the molecules influencing these interactions. Their therapeutic effects were verified via cell experiments and validated using a mouse GC peritoneal dissemination model. Notably, only the PLT activation pathway-related inhibitors TRKI and PP2, but not R406, inhibited the PLT-enhanced migration and invasion of GC cells. In vivo analyses revealed that PLT-enhanced peritoneal dissemination was suppressed by PP2. Overall, the present study revealed the important role of the Srk family in the interactions between PLTs and GC cells, suggesting kinase inhibitors as promising therapeutic agents to mitigate the progression of peritoneal metastasis in patients with GC.

C-C Chemokine 21-Expressing T-cell Zone Fibroblastic Reticular Cells, Abundant in Lymph Nodes, Are Absent in Cancer Lymphoid Stroma.

Cancer tissue generally possesses an immunosuppressive microenvironment. However, some cancers are associated with lymphoid stroma (i.e., a widely developed tertiary lymphoid structure). The T-cell zone (paracortex) of secondary lymphoid organs, particularly lymph nodes, is characterized by an abundance of T-cell zone fibroblastic reticular cells (TCZ-FRCs) that express C-C motif chemokine ligand 21 (CCL21) and smooth muscle actin (SMA). We analyzed the presence of TCZ-FRCs in 30 cases of carcinomas with lymphoid stroma of the breast, stomach, colon, tongue, and skin. Immunohistochemistry corroborated the abundance of CCL21+ SMA+ TCZ-FRCs in the normal lymph nodes. In sharp contrast, all 30 carcinomas with lymphoid stroma displayed no CCL21+ SMA+ TCZ-FRCs despite the affluence of T cells. Real-time reverse transcription polymerase chain reaction confirmed a marked decrease in the messenger ribonucleic acid expression of CCL21 and its receptor C-C motif chemokine receptor 7 in cancer lymphoid stroma compared to that in lymph nodes. Next, we analyzed the T cell phenotypes. The cancer lymphoid stroma demonstrated an abundance of CD3+ CD62L- memory-type T cells, in contrast to the presence of CD3+ CD62L+ naïve- and central memory T cells in the T cell zone of lymphoid tissues. Our data demonstrated the following: 1) Cancer lymphoid stroma lacked TCZ-FRCs with abundance of more activated T cells than in lymph nodes and 2) these were common phenomena in cancer lymphoid stroma irrespective of the histological types and organs involved.

Changes in and clinical utility of maximum phonation time and repetitive saliva swallowing test scores after esophagectomy.

BACKGROUND: Postoperative pneumonia in patients with esophageal cancer occurs due to swallowing dysfunction and aspiration. Recently, maximum phonation time (MPT) assessment and repetitive saliva swallowing test (RSST) have been focused on as swallowing function assessment methods that can identify patients as high risk for pneumonia. We aimed to evaluate the clinical utility of MPT assessment and RSST in patients undergoing oncological esophagectomy. METHODS: In total, 47 consecutive patients who underwent esophagectomy for esophageal cancer between August 2020 and July 2023 were eligible. The perioperative changes in MPTs and RSST scores were examined. In addition, univariate and multivariate analyses were performed to identify the predictive factors of postoperative pneumonia. RESULTS: The median MPTs before surgery and on postoperative days (PODs) 3, 6, and 10 were 18.4, 7.2, 10.6, and 12.4 s, respectively; postoperative MPTs were significantly lower than preoperative MPT. In addition, the MPT of POD 6 was significantly longer than that of POD 3 (P < 0.05). Meanwhile, there were no significant changes in perioperative RSST scores. Overall, 8 of 47 patients (17.0%) developed pneumonia postoperatively. A short MPT on POD 6 was one of the independent predictive factors for the incidence of postoperative pneumonia (odds ratio: 12.6, 95% confidence interval: 1.29-123, P = 0.03) in the multivariate analysis. CONCLUSIONS: The MPT significantly decreased after esophagectomy. However, the RSST score did not. The MPT on POD6 can be a predictor of postoperative pneumonia.

Re-consideration of Lymph Node Metastasis in Pancreatic Cancer Patients Following Radical Resection: A Retrospective Study.

BACKGROUND/AIM: Perioperative chemotherapy has become more common in patients with pancreatic cancer (PC), and the significance of lymph node (LN) metastasis and the role of surgical resection in PC have gradually evolved. In the present study, we reconsidered the significance of LN metastasis for patients with PC. PATIENTS AND METHODS: We analyzed 142 PC patients who underwent radical resection at our hospital between September 2012 and December 2021. Patients were divided into three groups based on the performance of preoperative chemotherapy, as follows: up-front surgery (US, n=109), neoadjuvant chemotherapy (NAC, n=22), and conversion surgery (CS, n=11). The characteristics of patients with LN metastasis in the US group were clarified, and a prognostic analysis was performed. The prognostic impact of LN metastasis in the NAC/CS group was examined and compared to that in the US group. RESULTS: Multivariate analysis revealed that high CA19-9 levels, large tumor size, and positive lymphatic invasion were significantly associated with LN metastasis. LN metastasis and portal vein invasion were independent poor prognostic factors in multivariate analysis. Patients without LN metastasis in the NAC group tended to have a better prognosis than those in the US group; however, the prognosis of patients with LN metastasis was similar between the two groups. In the CS and US groups, the prognosis was comparable for patients with and without LN metastasis. CONCLUSION: LN metastasis is a notably poor prognostic factor for PC patients, even after NAC, and more aggressive perioperative treatments may be considered for these patients.

Differences in glycemic trends due to reconstruction methods after proximal gastrectomy from the perspective of continuous glucose-monitoring.

PURPOSE: In recent years, clinicians have focused on the importance of preventing hypoglycemia. We evaluated the impact of different reconstruction procedures after proximal gastrectomy on glycemic variability in non-diabetic patients with gastric cancer. METHODS: This prospective observational study was conducted between April 2020 and March 2023. Flash continuous glucose-monitoring, a novel method for assessing glycemic control, was used to evaluate the glycemic profiles after gastrectomy. A flash continuous glucose-monitoring sensor was placed subcutaneously at the time of discharge, and glucose trends were evaluated for 2 weeks. RESULTS: The anastomotic methods for proximal gastrectomy were esophagogastrostomy in 10 patients and double-tract reconstruction in 10 patients. The time below this range (glucose levels < 70 mg/dL) was significantly higher in the double-tract reconstruction group than in the esophagogastrostomy group (p = 0.049). A higher nocturnal time below this range was significantly correlated with an older age and double-tract reconstruction (p = 0.025 and p = 0.025, respectively). CONCLUSION: These findings provide new insights into reconstruction methods after proximal gastrectomy by assessing postoperative hypoglycemia in non-diabetic patients with gastric cancer.

CCL28: A Promising Biomarker for Assessing Salivary Gland Functionality and Maintaining Healthy Oral Environments.

The oral cavity serves as the primary path through which substances from the outside world enter our body. Therefore, it functions as a critical component of host defense. Saliva is essential for maintaining a stable oral environment by catching harmful agents, including pathogens, allergens, and chemicals, in the air or food. CCL28, highly expressed in mucosal tissues, such as the colon and salivary glands, is a chemokine that attracts CCR10/CCR3 expressing cells. However, the role of CCL28 in salivary gland formation remains unclear. In this study, we investigated the salivary gland structure in CCL28-deficient mice. Histological analysis showed decreased staining intensity of Alcian blue, which detects acidic mucous, reduced expression of MUC2, and higher infiltration of gram-positive bacteria in the salivary glands of CCL28-deficient mice. In addition, CCL28-deficient mice contained ectopically MUC2-expressed cells in the ducts and reduced the expression of cytokeratin 18, a marker for ductal cells, within the submandibular glands, resulting in decreased duct numbers. Additionally, the submandibular glands of CCL28-deficient mice showed reduced expression of several stem cell markers. These results suggest that CCL28 regulates saliva production via proper differentiation of salivary gland stem cells and could be a valuable biomarker of salivary gland function.

Intratumoral delivery of a highly active form of XCL1 enhances antitumor CTL responses through recruitment of CXCL9-expressing conventional type-1 dendritic cells.

Conventional type 1 dendritic cells (cDC1s) play a crucial role in antitumor immunity through the induction and activation of tumor-specific CD8+ cytotoxic T cells (CTLs). The chemokine XCL1 is a major chemotactic factor for cDC1s and its receptor XCR1 is selectively expressed on cDC1s. Here, we investigated the effect of intratumoral delivery of a highly active form of murine XCL1 (mXCL1-V21C/A59C) on cDC1-mediated antitumor immunity using a hydrophilic gel patch. The hydrophilic gel patch containing mXCL1-V21C/A59C increased cDC1 accumulation in the tumor masses and promoted their migration to the regional lymph nodes, resulting in enhanced induction of tumor-specific CTLs. Tumor-infiltrating cDC1s not only expressed XCR1 but also produced CXCL9, a ligand for CXCR3 which is highly expressed on CTLs and NK cells. Consequently, CTLs and NK cells were increased in the tumor masses of mice treated with mXCL1-V21C/A59C, while immunosuppressive cells such as monocyte-derived suppressive cells and regulatory T cells were decreased. We also confirmed that anti-CXCL9 treatment decreased the tumor infiltration of CTLs. The intratumoral delivery of mXCL1-V21C/A59C significantly decreased tumor growth and prolonged survival in E.G7-OVA and B16-F10 tumor-bearing mice. Furthermore, the antitumor effect of mXCL1-V21CA59C was enhanced in combination with anti-programmed cell death protein 1 treatment. Finally, using The Cancer Genome Atlas database, we found that XCL1 expression was positively correlated with tumor-infiltrating cDC1s and a better prognosis in melanoma patients. Collectively, our findings provide a novel therapeutic approach to enhance tumor-specific CTL responses through the selective recruitment of CXCL9-expressing cDC1s into the tumor masses.

Investigating Cytoglobin Expression in Colon Cancer: Clinicopathological Insights from Immunohistochemical Analysis.

BACKGROUND/AIM: Cytoglobin (Cygb), a protein involved in cellular oxygen metabolism and protection, has garnered attention owing to its potential role in the initiation and progression of cancer, particularly colon cancer (CC). This study investigated the expression and significance of Cygb in CC. PATIENTS AND METHODS: This study included 145 patients who underwent R0 surgery for CC (clinical stage II/III) at our institution between January 2007 and December 2014. Immunohistochemical analysis was performed to evaluate the Cygb expression patterns in CC tissues. Additionally, the correlation between Cygb expression levels and the clinicopathological characteristics of patients with CC was investigated. RESULTS: Colon cancer tissues were categorized into high-expression (95 cases) and low-expression (50 cases) groups. Cygb was highly expressed in well-differentiated cases, whereas its expression decreased in poorly differentiated cases. No significant differences in other clinicopathological factors were observed between the two groups. Cygb expression had no significant effect on recurrence-free survival or overall survival. CONCLUSION: This study contributes to the growing understanding of Cygb expression and its significance in CC. The expression of Cygb in CC was found to be unrelated to the recurrence rate and prognosis, but showed a correlation with differentiation status.

Dynamics of perioperative pancreatic exocrine function in patients undergoing reconstruction after gastrectomy for gastric cancer.

BACKGROUND: Each method of reconstruction after gastrectomy results in a change in the digestive and absorptive status. However, there are few reports on the changes in pancreatic exocrine function after gastrectomy. We conducted this study to investigate the dynamics of pancreatic exocrine function after gastrectomy according to the method of reconstruction performed. METHODS: The subjects of this study were 45 patients who underwent pancreatic exocrine function tests preoperatively and postoperatively, from among all patients who underwent gastrectomy for gastric cancer at our hospital between September, 2020 and March, 2022. We assessed pancreatic exocrine function using the Pancreatic Function Diagnostant (PFD) test. RESULT: The mean preoperative PFD test result values for the distal gastrectomy (DG) Billroth I reconstruction (B-I) group and the DG Roux-en-Y reconstruction (R-Y) group were 62.6 and 67.3 (p = 0.36), respectively, and the mean postoperative PFD test result values for each group were 65.8 and 46.9 (p = 0.0094), respectively. A significant decrease in postoperative pancreatic function was observed in the DG R-Y group but not in the DG B-I group. The logistic regression analysis identified that age and the R-Y group were significantly correlated with a 10% decrease in the PFD value after gastrectomy. CONCLUSIONS: Our study suggests that R-Y reconstruction may result in more impaired pancreatic exocrine function than B-I reconstruction.

Prognostic Impact of Stromal Profiles Educated by Gastric Cancer.

BACKGROUND: Cancer-associated fibroblasts exhibit diversity and have several subtypes. The underlying relationship between the diversity of cancer-associated fibroblasts and their effect on gastric cancer progression remains unclear. In this study, mesenchymal stem cells were differentiated into cancer-associated fibroblasts with gastric cancer cell lines; clinical specimens were used to further investigate the impact of cancer-associated fibroblast diversity on cancer progression. METHODS: Nine gastric cancer cell lines (NUGC3, NUGC4, MKN7, MKN45, MKN74, FU97, OCUM1, NCI-N87, and KATOIII) were used to induce mesenchymal stem cell differentiation into cancer-associated fibroblasts. The cancer-associated fibroblasts were classified based on ACTA2 and PDPN expression. Cell function analysis was used to examine the impact of cancer-associated fibroblast subtypes on cancer cell phenotype. Tissue samples from 97gastric patients who underwent gastrectomy were used to examine the clinical significance of each subtype classified according to cancer-associated fibroblast expression. RESULTS: Co-culture of mesenchymal stem cells with nine gastric cancer cell lines revealed different subtypes of ACTA2 and PDPN expression in differentiated cancer-associated fibroblasts. Cancer-associated fibroblast subtypes with high ACTA2 plus PDPN expression levels significantly increased gastric cancer cell migration, invasion, and proliferation. The cancer-associated fibroblast subtype with ACTA2 plus PDPN expression was an independent prognostic factor along with lymph node metastasis for patients who had gastric cancer and were undergoing surgery. CONCLUSIONS: Cancer-associated fibroblasts are educated by gastric cancer cells during the development of cancer-associated fibroblast diversity. Differentiated cancer-associated fibroblasts with distinct expression patterns could affect gastric cancer progression and enable prognostic stratification for gastric cancer.

Biomarkers for Risk Stratification in Patients With Type A Acute Aortic Dissection.

Type A acute aortic dissection (AAD) is a fatal disease and thus, accurate and objective risk stratification is essential. In this study, we evaluated the prognostic value of readily available and assessable biomarkers in patients with type A AAD. This was a retrospective, multicenter, observational study. A total of 703 patients with type A AAD diagnosed using contrast-enhanced computed tomography were included. Therapeutic strategies were left to the physician's discretion in a real-world clinical setting. The prognostic value for in-hospital mortality was examined in 15 circulating biomarkers on admission, which are routinely available in clinical practice. Of the 703 patients, 126 (17.9%) died during the hospitalization. Of the 15 biomarkers, the multivariable analysis identified positive cardiac troponin, a low total bilirubin (T-Bil) level, and increased levels of brain natriuretic peptide (BNP) and lactate dehydrogenase (LDH) as significant predictors of in-hospital death. The receiver operating characteristics curve analysis showed that these 4 biomarkers had an independent additive prognostic value. With the cut-off values of T-Bil, BNP, and LDH, in combination with positive troponin, the increase in the number of positive biomarkers was progressively associated with higher in-hospital mortality from 1.3% to 9.8%, 20.5%, 36.4%, and 75.0% (p <0.001). In conclusion, in patients with type A AAD, positive cardiac troponin, a low T-Bil level, and increased levels of BNP and LDH on admission were related to higher in-hospital mortality, with an incremental prognostic value, suggesting that the readily available and assessable biomarkers can aid in decision-making in therapeutic strategies.

Inhibition of cancer cell­platelet adhesion as a promising therapeutic target for preventing peritoneal dissemination of gastric cancer.

Platelets form complexes with gastric cancer (GC) cells via direct contact, enhancing their malignant behavior. In the present study, the molecules responsible for GC cell-platelet interactions were examined and their therapeutic application in inhibiting the peritoneal dissemination of GC was investigated. First, the inhibitory effects of various candidate surface molecules were investigated on platelets and GC cells, such as C-type lectin-like receptor 2 (CLEC-2), glycoprotein VI (GPVI) and integrin αIIbß3, in the platelet-induced enhancement of GC cell malignant potential. Second, the therapeutic effects of molecules responsible for the development and progression of GC were investigated in a mouse model of peritoneal dissemination. Platelet-induced enhancement of the migratory ability of GC cells was markedly inhibited by an anti-GPVI antibody and inhibitor of galectin-3, a GPVI ligand. However, neither the CLEC-2 inhibitor nor the integrin-blocking peptide significantly suppressed this enhanced migratory ability. In experiments using mouse GC cells and platelets, the migratory and invasive abilities enhanced by platelets were significantly suppressed by the anti-GPVI antibody and galectin-3 inhibitor. Furthermore, in vivo analyses demonstrated that the platelet-induced enhancement of peritoneal dissemination was significantly suppressed by the coadministration of anti-GPVI antibody and galectin-3 inhibitor, and was nearly eliminated by the combined treatment. The inhibition of adhesion resulting from GPVI-galectin-3 interaction may be a promising therapeutic strategy for preventing peritoneal dissemination in patients with GC.

Aggravation of lipopolysaccharide-induced depressive-like behavior in CCR4-deficient mice.

Increasing evidence indicates that immune abnormalities are associated with the pathogenesis of depression. CCR4 is a chemokine receptor that regulates regulatory T cell (Treg) and Th17 cell migration. Here, using a lipopolysaccharide (LPS)-induced depression mouse model, we demonstrated that CCR4 deficiency exacerbated depressive-like behavior. Tregs and M2 macrophages, but not Th17 cells, were decreased in the brain of CCR4-deficient mice. Consistently, treatment with a CCR4 inhibitor reduced Tregs and M2 macrophages in the brain and exacerbated depressive-like behavior. Thus, CCR4 may contribute to the reduction of depressive symptoms by promoting Treg recruitment to the brain and subsequent M2 macrophage polarization.

Clinical characteristics and outcomes in patients with acute type A aortic intramural hematoma.

BACKGROUND: Although type A acute aortic dissection (AAD) including classic double-channel aorta and intramural hematoma (IMH) is a life-threatening condition, the prognostic impact and predictors of IMH remain to be established. The present study evaluated the prevalence, baseline characteristics, and outcomes of IMH as compared with classic non-thrombosed type A AAD. METHODS: This multicenter registry in Japan retrospectively included 703 patients with type A AAD. IMH was defined as a crescentic or circular area along the ascending aortic wall without contrast enhancement on computed tomography (CT). Non-thrombosed type A AAD was defined as the classic double-channel ascending aorta on contrast-enhanced CT. The primary endpoint was in-hospital mortality. RESULTS: Of the 703 patients with type A AAD, 312 (44.3%) had IMH. Older age was an only baseline patient factor significantly associated with the presence of IMH in the multivariable analysis. The longitudinal extent of dissection was greater in patients with classic non-thrombosed AAD than those with IMH, resulting in an increased risk of end-organ malperfusion in the classic AAD group. During the hospitalization, 41 (13.1%) and 85 (21.7%) patients with and without IMH died (p < 0.001). IMH was associated with lower in-hospital mortality in a multivariable model, irrespective of age and the implementation of surgery. CONCLUSIONS: The present study showed that IMH on CT was frequent among patients with type A AAD. Although IMH was more likely to be present in the elderly, its effect on the better survival was independent of age and surgical treatment.

A CCR4 antagonist attenuates atopic dermatitis-like skin inflammation by inhibiting the recruitment and expansion of Th2 cells and Th17 cells.

CCR4 is a major trafficking receptor for T-helper (Th) 2 cells and Th17 cells and is considered as a potential therapeutic target for atopic dermatitis (AD). The CCR4 ligands CCL17 and CCL22 have been reported to be upregulated in the skin lesions of AD patients. Of note, thymic stromal lymphopoietin (TSLP), a master regulator of the Th2 immune response, promotes the expression of CCL17 and CCL22 in AD skin lesions. Here, we investigated the role of CCR4 in an AD mouse model induced by MC903, a TSLP inducer. Topical application of MC903 to ear skin increased the expression of not only TSLP but also CCL17, CCL22, the Th2 cytokine IL-4, and the Th17 cytokine IL-17A. Consistently, MC903 induced AD-like skin lesions as shown by increased epidermal thickness; increased infiltration of eosinophils, mast cells, type 2 innate lymphoid cells, Th2 cells, and Th17 cells; and elevated serum levels of total IgE. We also found increased expansion of Th2 cells and Th17 cells in the regional lymph nodes (LNs) of AD mice. Compound 22, a CCR4 inhibitor, ameliorated AD-like skin lesions with reduction of Th2 cells and Th17 cells in the skin lesions and regional LNs. We further confirmed that compound 22 diminished the expansion of Th2 cells and Th17 cells in the coculture of CD11c+ dendritic cells (DCs) and CD4+ T cells derived from the regional LNs of AD mice. Collectively, CCR4 antagonists may exhibit anti-allergic effects by inhibiting both the recruitment and expansion of Th2 cells and Th17 cells in AD.

Mucosal CCL28 Chemokine Improves Protection against Genital Herpes through Mobilization of Antiviral Effector Memory CCR10+CD44+ CD62L-CD8+ T Cells and Memory CCR10+B220+CD27+ B Cells into the Infected Vaginal Mucosa.

Four major mucosal-associated chemokines, CCL25, CCL28, CXCL14, and CXCL17, play an important role in protecting mucosal surfaces from infectious pathogens. However, their role in protection against genital herpes remains to be fully explored. The CCL28 is a chemoattractant for the CCR10 receptor-expressing immune cells and is produced homeostatically in the human vaginal mucosa (VM). In this study, we investigated the role of the CCL28/CCR10 chemokine axis in mobilizing protective antiviral B and T cell subsets into the VM site of herpes infection. We report a significant increase in the frequencies of HSV-specific memory CCR10+CD44+CD8+ T cells, expressing high levels of CCR10, in herpes-infected asymptomatic (ASYMP) women compared with symptomatic women. Similarly, a significant increase in the CCL28 chemokine (a ligand of CCR10), was detected in the VM of herpes-infected ASYMP C57BL/6 mice, associated with the mobilization of high frequencies of HSV-specific effector memory CCR10+CD44+CD62L-CD8+ TEM cells and memory CCR10+B220+CD27+ B cells in the VM of HSV-infected ASYMP mice. Inversely, compared with wild-type C57BL/6 mice, the CCL28 knockout (CCL28-/-) mice (1) appeared to be more susceptible to intravaginal infection and reinfection with HSV type 2, and (2) exhibited a significant decrease in the frequencies of HSV-specific effector memory CCR10+CD44+CD62L-CD8+ TEM cells and of memory CD27+B220+ B cells in the infected VM. These findings suggest a critical role of the CCL28/CCR10 chemokine axis in the mobilization of antiviral memory B and T cells within the VM to protect against genital herpes infection and disease.