Role of Human CD200 Overexpression in Pig-to-Human Xenogeneic Immune Response Compared with Human CD47 Overexpression

Ji Jing Yan, Tai Yeon Koo, Han Sin Lee, Wook Bin Lee, Bohae Kang, Jae Ghi Lee, Joon Young Jang, Taishi Fang, Jung Hwa Ryu, Curie Ahn, Sung Joo Kim, Jaeseok Yang

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Background Macrophages play important roles in xenograft rejection. Here, we investigated whether overexpression of human CD200 or CD47 in porcine endothelial cells (PEC) can suppress macrophages activation in xenogeneic immune responses. Methods PECs and human macrophages were incubated together, harvested, and analyzed for in vitro macrophage phagocytic and cytotoxicity activity, and cytokine release. Next, PECs were injected into renal subcapsular space of humanized mice. On day 10 posttransplantation, we analyzed xenograft survival and perigraft inflammatory cell infiltrations in PEC-to-humanized mouse transplantation. Results PECs highly expressing human CD200, CD47, or both CD47/CD200 were established by lentiviral vector transduction. Both CD200 and CD47 suppressed in vitro macrophage phagocytic and cytotoxic activity against PECs; decreased TNF-α, IL-1β, and IL-6 secretion; and increased IL-10 secretion. However, simultaneous overexpression of CD200 and CD47 did not show additive effects. Next, PECs were transplanted into NOD-scid IL-2Rg null mice, and human monocytes and lymphocytes were adoptively transferred 1 day after xenotransplantation. PEC xenograft cell death and apoptosis were decreased in the CD200-PEC and CD47/CD200-PEC groups. Perigraft infiltration of human T cells was suppressed by CD47; CD200 suppressed infiltration of human macrophages to a greater extent than CD47; and the CD47/CD200-PEC group exhibited the lowest level of leukocyte infiltration. In summary, overexpression of CD200 in PECs suppressed xenogeneic activation of human macrophages and improved survival of PEC xenografts in humanized mice; however, coexpression of CD200 and CD47 did not show additive effects. Conclusions Therefore, overexpression of human CD200 in donor pigs could constitute a promising strategy for overcoming xenograft rejection.

Original languageEnglish
Pages (from-to)406-416
Number of pages11
JournalTransplantation
Volume102
Issue number3
DOIs
StatePublished - 1 Mar 2018

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