Expression of recipient CD47 on rat insulinoma cell xenografts prevents macrophage-mediated rejection through SIRPα inhibitory signaling in mice

異種移植におけるマクロファージ性拒絶抑制効果に対するレシピエント種CD47遺伝子導入の有用性

Teraoka Yoshifumi

We have previously proven that the interspecies incompatibility of CD47 is responsible for in vitro phagocytosis of xenogeneic cells by host macrophages. Utilizing an in vivo model in the present study, we investigated whether genetically engineered expression of mouse CD47 in rat insulinoma cells (INS-1E) could inhibit macrophage-mediated xenograft rejection. INS-1E cells transfected with the pRc/CMV-mouse CD47 vector (mCD47-INS-1E) induced SIRPa-tyrosine phosphorylation in mouse macrophages in vitro, whereas cells transfected with the control vector (cont-INS-1E) did not. When these cells were injected into the peritoneal cavity of streptozotocin-induced diabetic Rag2-/-γ chain -/- mice, which lack T, B, and NK cells, the expression of mouse CD47 on the INS-1E cells markedly reduced the susceptibility of these cells to phagocytosis by macrophages. Moreover, these mice became normoglycemic after receiving mCD47-INS-1E, whereas the mice that received cont-INS-1E failed to achieve normoglycemia. Furthermore, injection of an anti-mouse SIRPa blocking monoclonal antibody into the mouse recipients of mCD47-INS-1E cells prevented achievement of normoglycemia. These results demonstrate that interspecies incompatibility of CD47 significantly contributes to in vivo rejection of xenogeneic cells by macrophages. Thus, genetic induction of the expression of recipient CD47 on xenogeneic donor cells could provide inhibitory signals to recipient macrophages via SIPRa; this constitutes a novel approach for preventing macrophage-mediated xenograft rejection.

Medical sciences [ 490 ]

eng

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[Created] 2014-11-21

Yoshifumi Teraoka, Kentaro Ide, Hiroshi Morimoto, Hiroyuki Tahara, Hideki Ohdan; Expression of Recipient CD47 on Rat Insulinoma Cell Xenografts Prevents Macrophage-Mediated Rejection through SIRPα Inhibitory Signaling in Mice; PLoS ONE; March 2013, Volume 8 Issue 3, e58359 (doi: 10.1371/journal.pone.0058359) references

[DOI] http://dx.doi.org/10.1371/journal.pone.0058359 references

広島大学