A CCR4 antagonist enhances DC activation and homing to the regional lymph node and shows potent vaccine adjuvant activity through the inhibition of regulatory T-cell recruitment

CCR4 is a major chemokine receptor expressed by Treg cells that downregulate immune responses. Here, we investigated the role of CCR4-mediated Treg cell recruitment in antigen-specific immune responses. CCR4-deficient mice immunized intramuscularly with ovalbumin (OVA) showed enhanced OVA-specific IgG responses. Furthermore, intramuscular administration of OVA induced the expression of MDC/CCL22, a ligand for CCR4, in macrophages of the muscle tissues, and enhanced the recruitment of CCR4+ Treg cells in wild-type mice, whereas this recruitment of Treg cells was severely impaired in CCR4-deficient mice. Furthermore, OVA-loaded dendritic cells (DCs) derived from the muscle injection site of CCR4-deficient mice had an upregulated expression of the DC activation marker CD40 and 86, and the lymphoid organ homing receptor CCR7 resulting in an increased number of migratory DCs in the regional lymph node. Compound 22, a CCR4 antagonist, also inhibited the recruitment of Treg cells to the muscle tissue, and further enhanced DC activation and homing to the regional lymph node. Consequently, Compound 22 enhanced OVA-specific IgG responses, and the expression levels of IL-4 and IFN-γ in CD4+ T cells and the levels of IFN-γ in CD8+ T cells. Finally, intramuscular administration of OVA and Compound 22 significantly inhibited the growth of OVA-expressing tumors. Collectively, CCR4 plays a pivotal role in Treg cell recruitment to the muscle tissue, and intramuscular administration of CCR4 antagonists may be a promising approach for enhancing vaccine efficacy. Keywords: CCR4, CCL22, Treg, Muscle, Vaccine, Adjuvan

Disease Severity in Patients with Simultaneous Influenza and Bacterial Pneumonia

Objective To determine the differences in the clinical features of bacterial pneumonia patients between patients co-infected with influenza virus or not co-infected. Methods Fifteen adult patients with bacterial pneumonia (7 men and 8 women) who also tested positive for influenza virus antigen were compared with those with bacterial pneumonia alone (n=28). Results Complications with chronic lung diseases were more frequently found in bacterial pneumonia patients with influenza virus infection, compared with those who had bacteria pneumonia alone. Statistical differences were also found in body temperature, and heart rates between the two groups. CRP levels, chest X-ray infiltrates and the severity of pneumonia, as determined using the criteria of the Japan Respiratory Society (JRS) and/or the Infectious Diseases Society of America (IDSA), were also significantly worse in patients of bacterial pneumonia infected with influenza virus, than in those who had bacterial pneumonia alone. Conclusions The severity of pneumonia in patients co-infected with influenza virus and bacteria was significantly higher than in those infected with bacteria alone. These data suggested that the influenza virus infection enhanced the bacterial pneumonia. Further study of the pathogenesis of the synergic interaction between influenza virus and bacteria is warranted

A Patient with Fulminant Primary Influenza Pneumonia Which Developed into Secondary Bacterial Pneumonia

An 88-year old man was admitted to our hospital because of severe respiratory disturbance and fever, but no sputum. We found diffuse reticular shadow on chest X-ray, and detected influenza virus antigen from nasopharyngeal swab. Primary influenza pneumonia was suspected and oseltamivir was prescribed. Data were improved after adding steroid; however, hemoptysis appeared on day 9, and the patient died 2 days later. We suspected the recurrence of primary virus pneumonia with alveolar damage, but Staphylococcus aureus was cultured from the hemosputum after his death despite oral administration of antibiotics. Subsequent secondary bacterial pneumonia as well as severe primary influenza virus pneumonia was finally suspected in this case. It was a rare case that not only fulminant primary virus pneumonia but also different type of severe influenza pneumonia were found in one patient. We need to observe influenza patients carefully, even if antibiotics were administered

Severe Japanese Spotted Fever Successfully Treated with Fluoroquinolone

A 77 years old woman who had a bite with eschar on her left arm, was admitted to emergency ward in our hospital, because of high fever, severe malaise, skin eruption, and consciousness disturbance beginning 5 days previously. She was diagnosed as Japanese spotted fever by seropositive of Rickettsia japonica (R. japonica) antibody, and successfully treated with fluoroquinolone, after minocycline hydrochloride had been proven ineffective. R. japonica-specific DNA was detected by PCR from the tick: Haemaphysalis hystricis larvae collected from a mountainous location in Fukuoka, Japan where the patient had been bitten