賈景山 教授                                                                 

     Jean-San Chia, Professor                          

 

國立台灣大學 牙醫學士 民國六十九年     

國立台灣大學微生物碩士 民國八十年

國立台灣大學微生物博士 民國八十二年                

BDS National Taiwan University, 1980

M.S. National Taiwan University,1991

Ph.D. National Taiwan University, 1993

專長:口腔微生物學及免疫學

研究領域 細菌與宿主交互作用及口腔癌的免疫抑制機轉

研究主題 目前本實驗室有兩個重點研究,簡述如下

I.人類共生鏈球菌與宿主細胞的交互作用參與在致病的機制

人類的身體內存在著複雜的共生菌族群,主要附著並生存在人體的黏膜表面,而這些共生菌在其常態生存的環境區域內,可適應於宿主環境並與宿主和平共存;但如果經由血液循環散布,將可能引發發炎反應而進一步引起全身性疾病。感染性心內膜炎是一種常由人類口腔共生鏈球菌所引起,且與細菌生物膜形成有關的感染性疾病,而我們的研究目標首先是利用感染性心內膜炎大鼠模型,來探討宿主因子(主要為嗜中性白血球與血小板)是如何幫助細菌在受損的心臟瓣膜上形成細菌生物膜及其相關的免疫致病機制(主要研究抗去氧核醣核酸抗體及其它自體免疫抗體形成的機制);此外,我們實驗室也研究在先天免疫反應中,上皮細胞參與在由病原相關分子型態(PAMPs)所引發抑制發炎反應的角色。本實驗室目前進行的研究的主題分成:

1.    人類共生菌在血液循環系統中逃避宿主免疫攻擊的機制

2.    血小板凝集與血液凝集系統在細菌形成生物膜的角色

3.    正常口腔上皮細胞透過Toll like receptor (TLR)的訊息傳遞對人類共生菌所引發的反應

臨床上治療感染性心內膜炎所遇到的問題,主要是由於細菌生物膜的形成所引起的高抗藥性,而針對細菌與宿主細胞的交互關係,將可對於感染性心內膜炎提供新的預防或治療方向;利用本實驗室已建立好的試管內生物膜模型及大鼠心內膜炎動物模式,加上與臨床病理及心臟外科專科的合作,我們可以將基礎研究的結果連結至轉譯醫學,將來可應用於臨床上感染心內膜炎的治療及預防;此外,透過已成功建立的正常口腔上皮細胞原代培養技術,我們將可研究人類共生菌是如何調控人類免疫的恆定性。

II.口腔癌腫瘤微環境和交互作用

口腔癌是一種在世界各地常見的癌症,特別流行在東南亞和台灣並且有較差的術後恢復。在口腔所生成的癌症大部分為口腔上皮細胞所轉變成的鱗狀上皮細胞癌,而本實驗室先前發現口腔鱗狀上皮細胞癌會造成一個高度發炎的微環境,產生許多造成發炎的細胞激素,並且吸引巨噬細胞、第十七型輔助T細胞和調節性T細胞浸潤,更有趣的是,我們發現癌相關纖維細胞和口腔癌細胞的侵害有關;我們也建立了生物體外共同培養系統來研究不同免疫細胞或是基質細胞和癌細胞的交互作用,更進一步發現在口腔鱗狀上皮細胞癌症微環境能夠誘導出一群具有免疫抑制功能的細胞。而現在實驗室的研究興趣和方向為:

(1)口腔癌中浸潤調節性T細胞的功能分析

在我們之前的研究發現了在腫瘤浸潤免疫細胞中一群特別的調節性T細胞,這群IL-17+FOXP3+T細胞會表現CCR6和抑制性細胞激素介白素10,而這群細胞的穩定性以及抑制細胞的分子機制和訊息調控仍在研究中。

(2)口腔癌細胞與輔助性T細胞及基質細胞的交互作用

口腔癌細胞可以產生一系列能夠促進分化、擴增和抑制輔助性T細胞的細胞激素,相反地,免疫細胞所分泌的細胞激素也可以調節口腔癌細胞的發炎機制;相似的情形也可以在癌症相關纖維母細胞中被發現,在生物體外的實驗中,這些細胞能夠被口腔癌細胞活化並且分泌特定的趨化細胞激素幫助口腔癌細胞的入侵。

這些基礎的研究和台大醫院合作並且與轉譯癌症研究結合,找出跟病人術後回復相關的免疫生物標記。

 


 

 

The current research interests in Dr. Chia’s laboratory:

I. Commensal bacteria-host interaction in the pathogenesis of endocarditis 

The human body is home to a complex microbial community, which adheres to and colonizes mucosal surfaces. Commensal microflora is well adapted and tolerated by the host at their ecological niches, but can cause systemic diseases after disseminating through the circulation inducing inflammatory responses. Infective endocarditis (IE) is a typical biofilm-associated infectious disease frequently caused by oral commensal streptococci. Our reach goals are firstly, to delineate the role of host factors (platelets and neutrophils) contributing to the biofilm formation and immunopathogenesis (anti-DNA and other autoantibodies) in an experimental rat model of endocarditis. Secondly, our laboratory is focused on the role of normal epithelial cells in mediating inflammatory signals triggered by pathogen associated molecular patterns (PAMPs) during innate immune responses. The current research topics are summarized as follows:

1.         Commensal bacterial resistance to immune surveillance in the blood circulation.

2.         Platelet aggregation and coagulation systems in the bacterial biofilm formation.

3.         Normal oral epithelial cells response to commensals through Toll like receptor (TLR) signaling. 

The major clinical problem for IE treatment is the refractory to antibiotics due to bacterial biofilm formation. Targeting at the bacteria-host interaction will provide new strategy for controlling IE. Using well-established in-vitro bacterial biofilm and in-vivo rat IE models, we will link basic research to translational research on IE therapy with the collaboration of clinical pathology and cardiovascular surgery. Through well-established cell culture system for primary normal epithelial cells, we could explore how commensal mciroflora maintain immune homeostasis.

 

II. Tumor microenvironment and crosstalk in oral cancer

Oral cancer is one of the most common cancers worldwide, and particularly prevalent in Southeast Asia and Taiwan, with increasing incidence and poor prognosis. Most of cancers in the oral cavity are squamous cell carcinoma (SCC) originating from the oral keratinocytes. Our previous studies indicate that OSCC constitutes an inflammatory microenvironment characterized by pro-inflammatory cytokine expression, and predominant infiltration of macrophages, T helper 17 (Th17) or FOXP3+ regulatory T (Treg) cells. Most interestingly, we have also found that cancer associated fibroblasts may contribute to the invasion of oral cancer cells. We have established in vitro co-culture systems to investigate the interaction of different immune or stroma cells with cancer cells and their roles in inducing immune suppression in the OSCC microenvironment. Our current research interests are:

(1)  Functional characterization of Treg cells in oral cancer microenvironment

Our previous studies identified heterogeneous subsets of Treg cells in tumor infiltrating lymphocytes (TILs). One unique IL-17+FOXP3+ T cells express CCR6 and inhibitory cytokine IL-10. Their lineage stability and molecular mechanisms or signaling involved in suppression is being investigated.

(2)  Crosstalk between oral cancer cells with CD4+ T cells and stroma cells

Oral cancer cells can produce a panel of cytokines which can induce the differentiation, expansion or suppression of CD4+ T cells. Reciprocally, the cytokines from T cells could further modulate the expression of inflammatory mediators in oral cancer cells. Similar situations are also found with oral cancer associated fibroblasts which could be activated by oral cancer cells in vitro to promote cancer invasion through specific chemokines.

Basic researches are linked to translational cancer research to identify potential immunological biomarkers associated with patient prognosis by collaboration with surgeons and pathologists in NTUH.

 

 

 

 

研究成員

博士後研究員:葉秋月、鍾筱菁

碩士班研究生:陳學儒、李泱、陳鏡文、胡渝翔、黃英哲、林芷穎、
 
陳宜婷、杜茂寬、楊佳儒、林昱璇

研究助理:連惠婷

 

研究團隊照片

 

  

 

五年內研究著作

Selected publications (2005-2010)

1.     Lee JJ, Chang YL, Lai WL, Ko ZY, Kuo YP, Chiang CB, Azuma M, Chen CW, Chia JS*. Increased prevalence of IL-17-producing CD4+ tumor infiltrating lymphocytes in human oral squamous cell carcinoma. 2010. Head and Neck. In press.

2.     Chia JS*, Du JL, Hsu WB, Sun A, Chiang CP, Wang WB. Inhibition of metastasis, angiogenesis, and tumor growth by Chinese herbal cocktail Tien-Hsien Liquid. BMC Cancer. 2010. 10:175.

3.     Chen PM, Chen YY, Yu SL, Sher S, Lai CH, Chia JS*. Role of GlnR in acid-mediated repression of genes encoding proteins involved in glutamine and glutamate metabolism in Streptococcus mutans. Appl Environ Microbiol. 2010. 76(8):2478-2486.

4.     Jung CJ, Zheng QH, Shieh YH, Lin CS, Chia JS*. Streptococcus mutans autolysin AtlA is a fibronectin-binding protein and contributes to bacterial survival in the bloodstream and virulence for infective endocarditis. Mol Microbiol. 2009 . 74(4):888-902.

5.     Shun CT, Yeh CY, Chang CJ, Wu SH, Lien HT, Chen JY, Wang SS, Chia JS*. Activation of human valve interstitial cells by a viridians streptococci modulin induces chemotaxis of mononuclear cells. J Infect Dis. 2009. 199(10):1488-1496.

6.     Chen PM, Chen HC, Ho CT, Jung CJ, Lien HT, Chen JY, Chia JS*. The two-component system ScnRK of Streptococcus mutans affects hydrogen peroxide resistance and murine macrophage killing. Microbes Infect. 2008. 10(3):293-301.

7.     Yeh CY, Lin CN, Chang CF, Lin CH, Lien HT, Chen JY, Chia JS*. C-terminal repeats of Clostridium difficile toxin A induce production of chemokine and adhesion molecules in endothelial cells and promote migration of leukocytes. Infect Immun. 2008. 76(3):1170-1178.

8.     Yeh CY, Chen JY, Chia JS*. Glucosyltransferases of viridans group streptococci modulate interleukin-6 and adhesion molecule expression in endothelial cells and augment monocytic cell adherence. Infect Immun. 2006. 74(2):1273-1283.

9.     Shun CT, Lu SY, Yeh CY, Chiang CP, Chia JS*, Chen JY. Glucosyltransferases of viridans streptococci are modulins of interleukin-6 induction in infective endocarditis. Infect Immun. 2005. 73(6):3261-3270.