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dc.description.abstractThe C5a anaphylatoxin protein plays a central role in inflammation associated with complement activation. This protein is commonly regarded as one of the most potent inducers of the inflammatory response; however it has not been tested as a potential immunotherapeutic molecule. In this report we describe the creation of a mini-gene construct that directs C5a expression to any cell of interest. Functional expression could be demonstrated in the murine mammary sarcoma, EMT6. When C5a expressing cells were injected into syngeneic mice, most C5a-expressing clones had significantly reduced tumor growth. Further characterization of a clone expressing low levels of C5a demonstrated that one third of mice injected with this line had complete tumor regression. The mice whose tumors regressed were immune to subsequent challenge with unmodified EMT6 cells, suggesting that a component of the innate immune response can be used to augment adaptive immunity. Cellular analyses demonstrated that a significant difference in actual tumor cell number could be detected as early as day 10 in the mice injected with C5a expressing EMT6 cells. A block in cell cycle progression was evident at all time points and high levels of apoptosis were observed early in the regression event. These data demonstrate that the complement protein C5a can play a significant protective role in tumor immunity.;C5a는 보체계의 활성화시 연쇄 반응으로 생산되는 최종산물의 하나로 강력한 화학주성 단백질이다. 이 단백질은 염증반응의 유발에 중심 역할을 하나 최근까지 유력한 면역 유도 물질로 제시되지는 못하였다. 이에 저자는 특정 종양 세포주에 직접적으로 C5a 발현을 유도하여 항종양 면역효과가 있는지를 알아보고자 하였다. Murine mammary sarcoma EMT6 세포주에 mini-gene construct로 C5a를 발현시켰고 기능적 검사를 시행하여 C5a의 화학주성 능력을 검증하였다. C5a발현 EMT6세포를 주입한 군들의 쥐들은 의미있게 감소된 종양성장 추세를 보였고 장기간 추적 관찰하였을 때 31%의 실험군 쥐들에서 완전한 종양 퇴행이 관찰되었다. 또한 C5a발현 EMT6세포 주입 후 완전 종양퇴행을 관찰할 수 있었던 쥐들에게 EMT6세포를 재주입하였을 때 종양의 형성을 관찰할 수 없었다. 세포 주기 분석에서는 종양세포 주입 10일째 부터 C5a발현 EMT6 세포주를 주입한 쥐에서 apoptosis는 유의하게 증가되고 증식주기는 유의하게 감소되었음을 관찰하였다. 이 연구는 C5a가 종양 면역유도에 의미있는 매개체로 작용할 수 있음을 증명하였다.-
dc.description.tableofcontentsLIST OF FIGURES = ⅴ ACKNOWLEDGMENTS = ⅵ ABSTRACT = ⅶ Ⅰ. INTRODUCTION = 1 Ⅱ. METHODS = 5 2.1 Cells and cellular assays = 5 2.2 Constructs = 6 2.3 Tumor studies = 8 2.4 Tumor harvest = 8 2.5 Cell cycle analysis = 9 Ⅲ. RESULTS = 10 3.1 Construction of a mini-gene coding for secreted C5a = 10 3.2 Functional expression of C5a in the EMT6 mammary sarcoma cell line = 12 3.3 Expression of C5a does not alter logarithmic EMT6 cell growth in vitro = 14 3.4 The C5a mini-gene product reduces tumor incidence and size = 15 3.5 The C5a mini-gene induces immunity to unmodified tumors = 19 3.6 The C5a mini-gene greatly decreases tumor cellularity = 21 3.7 The C5a mini-gene product results in early apoptosis and fewer mitotic cells = 23 Ⅳ. DISCUSSION = 28 Ⅴ. CONCLUSION = 35 REFERENCE = 37 논문개요 = 46-
dc.format.extent1181006 bytes-
dc.publisher이화여자대학교 대학원-
dc.titleTumor regression by expression of complement protein C5a in murine mammary cancer model-
dc.typeDoctoral Thesis-
dc.format.pageviii, 46 leaves-
dc.identifier.major대학원 의학과- 8-
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