The suppression of inflammatory macrophage-mediated cytotoxicity and proinflammatory cytokine production by transgenic expression of HLA-E
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- 作者：Akira Maeda ; Takuji Kawamura ; Takehisa Ueno ; Noriaki Usui ; Hiroshi Eguchi ; Shuji Miyagawa
- 关键词：Inflammatory macrophage ; Xenocytotoxicity ; HLA-E ; Immunoreceptor tyrosine-based inhibition motif (ITIM) ; Pro-inflammatory cytokine
- 刊名：Transplant Immunology
- 出版年：December, 2013
- 年：2013
- 卷：29
- 期：1-4
- 页码：76-81
- 全文大小：515 K
文摘
Background
Macrophages participate in xenogenic rejection and represent a major biological obstacle to successful xenotransplantation. The signal inhibitory regulatory protein 伪 (SIRP伪) receptor was reported to be a negative regulator of macrophage phagocytic activity via interaction with CD47, its ligand. Because a majority of human macrophages express the inhibitory receptor CD94/NKG2A, which binds specifically to the human leukocyte antigen (HLA)-E and contains immunoreceptor tyrosine-based inhibition motifs (ITIMs), the inhibitory function of HLA class I molecules, HLA-E, on macrophage-mediated cytolysis was examined. The suppressive effect against proinflammatory cytokine production by macrophages was also examined.Methods
Complementary DNA (cDNA) of HLA-E, and CD47 were prepared and transfected into swine endothelial cells (SEC). The expression of the modified genes was evaluated by flow cytometry and macrophage-mediated cytolysis was assessed using in vitro generated macrophages.
Results
Transgenic expression of HLA-E significantly suppressed the macrophage-mediated cytotoxicity. HLA-E transgenic expression demonstrated a significant suppression equivalent to CD47 transgenic expression. Furthermore, transgenic HLA-E suppressed the production of pro-inflammatory cytokines by inflammatory macrophages.
Conclusions
These results indicate that generating transgenic HLA-E pigs might protect porcine grafts from, not only NK cytotoxicity, but also macrophage-mediated cytotoxicity.