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The Study of B7-H1/PD-1 Inhibitory Pathway and Relationship to Regulatory T Cells in Human Colon Carcinoma

Author: MaJingWei
Tutor: LuXiaoMing
School: Huazhong University of Science and Technology
Course: Surgery
Keywords: Colon cancer B7-H1 PD-1 Regulatory T cells IL-10
CLC: R392
Type: Master's thesis
Year: 2011
Downloads: 39
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Abstract


Objective: To analyze the expression levels of B7-H1 and PD-1 molecule in colon carcinoma, and analysis of the abnormal increase in colon cancer microenvironment T Reg and B7-H1. Methods: Western Blot and flow cytometry studies of patients with colon cancer surgery removal of the cancerous tissue and adjacent normal tissue expression of B7-H1 and PD-1; using flow cytometry colon cancer tissue and adjacent normal tissue the difference in the amount of infiltrating T Reg ; Western Blot Detection of colon cancer tissue extracted T Reg the CD4 CD25 - / sup> T cells express IL-10 level difference; immunomagnetic bead separation processes that separate human peripheral blood the CD4 the CD25 and CD4 CD25 - cells in vitro cultured and stimulated with anti-CD3 and anti-CD28, IL-10 expression the ELISA detected in the culture system; immunomagnetic beads sorting human colon infiltrating T < sub> Reg cell separation from human peripheral blood mononuclear cells co-cultured, level of the flow detection monocyte expression of B7-H1; induce high expression after T Reg B7-H1, monocytes and selected separately from the colon tissue macrophages and healthy human peripheral sorting Na (I | ¨) ve T cell co-culture, the CFSE-Determination of T cell proliferation, to determine by T Reg -induced high expression of B7-H1 mononuclear cells on T cell immune suppression capability. Results: (1) Western Blot results show that colon cancer tissue in patients with cancer and adjacent normal tissue expression of B7-H1 molecules and cancer tissue than in adjacent normal tissue, high levels of B7-H1 expression; 2. Flow cytometry showed that B7 -H1 expression in macrophages, high levels of B7-H1 expression and macrophage infiltration of cancer tissue than in adjacent normal tissue, 38 ± 4% and 5 ± 2%; mean fluorescence intensity (MFI) 1900 ± 20 and 250 ± 100; 3. flow cytometry showed that PD-1 is mainly expressed the CD8 T cells, CD8 infiltration of cancer tissue than in adjacent normal tissue T cells, 51 ± 6% and 6 ± 2%; election separate from colon cancer tissue macrophages with human peripheral blood by sorting CFSE stained Na (i | ¨) VE T cell co-culture, the flow detected by inducing high expression of B7-H1 of monocytes or colon sources macrophages group T-cell proliferation (CFSE dim : 30 ± 5%) than the control group (Na (i | ¨) ve T cells were cultured alone group of CFSE dim : 63 ± 7%, adjacent normal tissue Na (i | ¨) ve T cells co-cultured group of CFSE dim : 55 ± 8%) was significantly inhibited, blocking B7-H1 pathway the inhibition state can be restored (joined B7-H1 blocking antibody group of CFSE < sup> dim : 51 ± 10%, adding PD-1 blocking antibody the groups of CFSE dim : 54 ± 11%); Flow cytometry showed that colon cancer tissue infiltrating T Reg increase than in adjacent normal tissues, Foxp3 T Reg accounting the CD3 CD4 in the proportion of cells were 18 ± 5% and ± 3%; Western Blot election separate from the colon cancer tissue CD4 CD25 cells than CD4 CD25 - cell expression of IL-10 high; the peripheral blood of healthy people carve election CD4 CD25 and CD4 CD25 - cells were cultured in vitro and stimulate 48 hours with CD3, CD28 ELISA detected CD4 CD25 cell group to express IL-10 concentration was significantly higher than the CD4 CD25 - cells group concentrations were 180 ± 27pg/ml, 52 ± 9pg/ml; sorting T Reg in the tumor tissue and healthy human peripheral blood mononuclear cells were cultured streaming detected T Reg and mononuclear cells co-cultured group B7-H1 expression level (ratio : 28 ± 3%; MFI: 1200 ± 80) was significantly higher (scale: 5 ± 1%; MFI: 150 ± 20) and added IL-10 antagonist antibody group (ratio: 6 ± 2% of; MFI: 350 ± 50); 8. by T Reg induces high expression of B7-H1 mononuclear cells and peripheral blood of healthy people sorting by CFSE staining Na (i | ¨) VE T cells Total culture, the flow detected by inducing high expression of B7-H1 the monocytes group T cell proliferation (CFSE dim : 32 ± 8%) than the control group (Na (i | ¨) VE T- The cells were cultured alone group of CFSE dim : 60 ± 7%, co-cultured peripheral blood mononuclear cells uninduced Na (i | ¨) ve T the Group of CFSE dim : 64 ± 11%) was significantly inhibited, blocking B7-H1 pathway inhibition state can be restored (B7-H1 blocking antibody the groups of CFSE dim : 52 ± 8% joined the PD- 1 blocking antibody the groups of CFSE dim : 55 ± 5%) after T Reg induced high expression of B7-H1 by B7-H1/PD-1 way to inhibit T cell proliferation. Conclusion: 1. Macrophages in colon cancer microenvironment high expression of B7-H1; colon tissue infiltrating CD8 T cells high expression of PD-1; colon cancer microenvironment of T in Reg abnormally high levels and high expression of IL-10, colon cancer microenvironment T Reg by high expression of IL-10 to promote macrophage expression of B7-H1; 3 colon cancer micro- environment B7-H1/PD-1 pathway can inhibit T cell proliferation and promote colon tumor immune escape; 4. blocking B7-H1/PD-1 pathway restores the proliferative capacity of T cells in the colon microenvironment , the intervention B7-H1/PD-1 pathway may in the future immune adjuvant treatment of colon cancer one of the methods.

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