Department of Surgery
Osaka University Graduate School of Medicine
Ectopic expression of human CD55 on porcine cells suppresses macrophage-mediated xenogeneic rejection
Akira Maeda1, Pei-Chi Lo1, Rieko Sakai1, Mayumi Asada1, Rei Matsuura1, Kengo Nakahata1, Kazuaki Yamanaka1, Takuji Kawamura1, Hiroshi Eguchi1, Hiroomi Okuyama1, Shuji Miyagawa1.
1Department of Surgery, Division of Organtransplantation, Suita, Japan
Although xenograft is one of most attractive strategy to overcome the shortage of donor, cellular rejection by macrophages is not well defined. Macrophages are well known to mediate robust immune response in xenograft.
Human CD55 is well-known to accelerate the decay of C3bBb and C42a and inactivate complement C3b and C4b. Hence, transgenic expression of human CD55 on porcine cells may be one of very attractive strategies to reduce xenogeneic complementary rejection. Actually, transgenic expression of human complement regulatory proteins reduces the frequency of hyper acute rejection (HAR) in xenotransplantation.
After a strategy to handle HAR was developed, the delayed-type rejection, which is mediated by monocytes, macrophages, and NK cells, became a critical problem. While the main infiltrating cells in allograft rejection are cytotoxic T cells, the infiltration of NK cells and macrophages are mainly induced into the xenografted tissues. Therefore, the developement of strategy to inhibit NK and macrophage-mediated xenorejection is indispensable for the clinical trial of xenograft.
We previously reported that human CD55 does not suppress only complement-mediated rejection but also NK-mediated xenogeneic cytotoxicity. In the present study, we investigate the effect of CD55 in macrophage-mediated xenogeneic cytotoxicity. To evaluate the macrophage-mediated xenocytotoxicity to human complement regulatory protein-expressing swine endothelial cells (SEC), WST-8 assay was employed. 1x104 of naïve SEC, SEC/CD55 was co-cultured with 1x105 of human monocyte-like cells, THP-1 which were differentiated to macrophage with 200nM PMA. 24hours after co-culture, cytotoxicity by THP-1 cells was measured by WST-8 assay. While differentiated THP-1 cells induced significant cytotoxicity against SEC (%cytotoxicity: 40.4±4.8%), human CD55 significantly reduced the THP-1 mediated cytotoxicity (%cytotoxicity: 28.6±11.7% p<0.01 vs SEC).
These findings indicate that CD55 might have a great clinical potential in both HAR and delayed type xenogeneic rejection, including macrophage-mediated rejection.
 MIyagawa S et al. J Immunol. 2004 ;173:3945-52.
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|Inflammation & Coagulation||Ectopic expression of human CD55 on porcine cells suppresses macrophage-mediated xenogeneic rejection||Room 109|