| Budget Amount *help |
¥17,130,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2007: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2006: ¥7,900,000 (Direct Cost: ¥7,900,000)
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| Research Abstract |
It has been reported that macrophage-induced cytotoxicity is involved in lon-term xenograft survival, however, the mechanism has remained unknown. A recent report indicates that the signal regulatory protein (SIRP) α is a critical immune inhibitory receptor on macrophages, and its interaction with CD47, a ligand for SIRPα, prevents autologous phagocytosis. We confirmed that interspecies incompatibility of CD47 significantly contributes to the rejection of xenogeneic cells by macrophages. Genetic induction of human CD47 on porcine cells could provide inhibitory signaling to SIRPα on human macrophages, providing a novel approach to preventing macrophage-mediated xenograft rejection. CD47-SIRPα signaling system may also play an important role in adaptive immune response. We have analyzed the frequency and proliferative activity of human T cells responding to either porcine or allogenic PBMCs by using in vitro mixed lymphocyte reaction (MLR) assay with a CFSE-labeling technique. The freque
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ncies of alloreactive and xenoreactive CD4^+ T cell precursors were almost identical, however, the Stimulation Index (SI) of xenoreactive CD4^+ T cells was significantly higher than that of alloreactive, indicating a stronger reaction by a single xenoreactive CD4^+ T cell. Moreover, when CD4^+ T cells were depleted from the responders in the MLR, the proliferation of xenoreactive CD8^+ T cells was significantly less than that of alloreactive CD8^+ T cells, indicating that the human CD4^+ T cells, but not CDS, T cells, are sufficient to induce porcine xenograft rejection. Further, The SI of xenoreactive CDC and Cost T cells was also significantly suppressed in the presence of human CD47-Fc. These results suggest that the human T cell responses to porcine cells are stronger than those to allogeneic cells because of the interspecies incompatibility of CD47. Moreover, genetic manipulation of porcine cells to induce human CD47 expression might attenuate human T cell-mediated xenograft rejection. Less
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