Inhibition Of Graft-Versus-Host Disease By Indoleamine-gene Modified Dendritic Cells

Allogeneic hematopoetic stem cell transplantation (allo-HSCT) is an important therapy to cure malignant/ nonmalignant hematopathy, genetic disease and auto-immune disorder. Graft-versus-host disease(GVHD) remains a significant complication in allo-HSCT. We propose a novel strategy to selectively deplete a donor stem cell graft of only those T cells that mediate GVHD , while leaving T cells with other antigen specificities intact. In the eventual application, host dendritic cells genetically engineered to express IDO(indoelamine 2,3-dioxygenase) would be co-cultured with allogeneic donor stem cell graft. This interaction with IDO expressing DCs(DC-IDO) will cause selective activation of alloreactive donor T cells in the graft and subsequently initiate apoptosiss only in these activated T cells. It is experimentally demonstrated that BALB/C mouse DC-IDO reduced proliferation of C57BL/6 mouse T cells responding to C3H mouse spleenocytes. Donor spleenocytes transplanted into irradiated host mice caused rapid, acute GVHD and death of host mice. When the same cells were pre-treated ex vivo with host DC-IDO, acute GVHD did not occur in host mice. Taken together, these experiments show that ex vivo treatment with DC-IDO only induced apoptosis of the specific alloreactive T cells, preserving T cells with other antigen specificityes. This suggests that ex vivo DC-IDO treatment ofdonor stem cell graft might be usefull for reducing GVHD without ablating the anti-tumor effect.