Changwen Deng

Allergic asthma is a common airway inflammatory disease in which B cells play important roles through IgE production and antigen presentation. SNP (single nucleotide polymorphism) analysis showed that Atg (autophagy-related) allele mutations are involved in asthma. It has been demonstrated that macroautophagy/autophagy is essential for B cell survival, plasma cell differentiation and immunological memory maintenance. However, whether B cell autophagy participates in asthma pathogenesis remains to be investigated. In this report, we found that autophagy was enhanced in pulmonary B cells from asthma-prone mice. Autophagy deficiency in B cells led to attenuated immunopathological symptoms in asthma-prone mice. Further investigation showed that IL4 (interleukin 4), a key effector Th2 cytokine in allergic asthma, was critical for autophagy induction in B cells both in vivo and in vitro, which further sustained B cell survival and enhanced antigen presentation by B cells. Moreover, IL4-induced autophagy depended on JAK signaling via an MTOR-independent, PtdIns3K-dependent pathway. Together, our data indicate that B cell autophagy aggravates experimental asthma through multiple mechanisms.

BACKGROUND: Asthma is a worldwide common chronic airway disease that cannot be cured and results in the huge burden in public health. Oxidative stress was considered an important mechanism in the pathogenesis of asthma. Hydrogen gas been demonstrated to function as a novel antioxidant and exert therapeutic antioxidant activity in a number of diseases and the function of this nontoxic gas in asthma was unclear. The purpose of the study aims to examine the effect of inhalation hydrogen gas on the pathophysiology of a mouse model of asthma. METHODS: A murine model of ovalbumin (OVA)-induced allergic airway inflammation was used in this study. Briefly, Mice were sensitized to ovalbumin and received inhalation of 67% high concentration of hydrogen gas for 60 min once a day for 7 consecutive days after OVA or PBS challenge respectively. Lung function was assessed in the apparatus with 4 channels of biological signal system. Morphology and goblet cell hyperplasia were stained by H/E and Periodic acid-Schiff staining. Cytologic classification in the bronchial alveolar lavage fluid (BALF) was analyzed by Wright Giemsa staining. Serum, BALF and lung tissue were collected for biochemical assay. One-way analysis of variance (ANOVA) was used to determine statistical significance between groups. Multiple comparisons were made by Bonferroni's Multiple Comparison Test by using GraphPad Prism 5 software. RESULTS: Inhalation of hydrogen gas abrogated ovalbumin-induced the increase in lung resistance. Concomitantly, the asthmatic mice showed severe inflammatory infiltration and goblet cell hyperplasia which were reversed by hydrogen gas inhalation. Hydrogen gas inhalation reduced significantly the number of total cells, eosinophils and lymphocytes in BALF. Increased level of IL-4, IL-13, TNF-α and CXCL15 in the BALF and IL-4 in the serum were decreased significantly after inhalation. Hydrogen gas inhalation markedly upregulated the activity of decreased superoxide dismutase and significantly attenuated the increased level of malondialdehyde and myeloperoxidase. CONCLUSIONS: Hydrogen gas inhalation improves lung function and protects established airway inflammation in the allergic asthmatic mice model which may be associated with the inhibition of oxidative stress process. This study provides a potential alternative therapeutic opportunity for the clinical management of asthma.

// Qiang Sun 1 , Shixin Zhou 1 , Jingjing Zhao 1 , Changwen Deng 1 , Ruidi Teng 1 , Yiding Zhao 1 , Jiajia Chen 1 , Jiebin Dong 1 , Ming Yin 2 , Yun Bai 1 , Hongkui Deng 1, 3, 4 and Jinhua Wen 1 1 Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China 2 Beijing Vitalstar Biotechnology Co., Ltd., Beijing, China 3 The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China 4 Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China Correspondence to: Jinhua Wen, email: jhwen@bjmu.edu.cn Hongkui Deng, email: hongkui_deng@pku.edu.cn Yun Bai, email: baiyun@bjmu.edu.cn Keywords: adoptive cell therapy; mesothelin; CAR; lung metastasis Received: May 16, 2017      Accepted: November 13, 2017      Published: January 10, 2018 ABSTRACT Pancreatic cancer is known as one of the most lethal cancers in the world. A majority of advanced stage pancreatic cancer patients are diagnosed with distant metastasis and given poor prognoses, calling for a better therapeutic option. Mesothelin, which is overexpressed in pancreatic cancer and other solid tumors, is a potential target for pancreatic cancer immunotherapy. Adoptive transfer of T cells engineered with chimeric antigen receptors (CART cells) was effective for treating CD19-positive leukemia, but it is more difficult for CART cells to eliminate solid tumors. Because distal metastasis is an important malignant behavior of solid tumors, we investigated whether meso-CART cells exert anti-tumor effects against distant metastases. After expressing meso-CAR in human primary T lymphocytes, the resultant meso-CART cells released cytokines in response to and exhibited cytolytic effects on mesothelin-positive tumor cells in vitro . Injection of meso-CART cells into tumor-bearing mice moderately delayed subcutaneous tumor growth and eliminated lung metastases. This is the first study to show that meso-CART cells are effective against lung metastases induced by intravenous injection of pancreatic tumor cells. Our results suggest that meso-CART cells may be an effective clinical treatment for mesothelin-positive primary and metastatic tumors in pancreatic cancer patients.