Triple knockout mice do not express the recombination activating gene 2 (Rag2), the CD47 antigen (CD47) gene, or the X-linked interleukin 2 receptor, gamma chain (Il2rg) gene. These mice are viable and fertile. These mice contain no T cells, B cell, or Natural Killer (NK) cells. The disruption of the Il2rg gene (γc) prevents the development of thymomas and delays the onset of graft versus host disease (GVHD). Recognition of human CD47 by the murine signal-regulatory protein alpha (SIRPα) is required to suppress macrophage-mediated phagocytosis of transplanted human hematopoietic stem cells (HSCs). C57BL/6 mice express a form of the SIRPα receptor that does not recognize human CD47, leading to a lack of tolerization of xenotransplantation. Since phagocytes developed in a CD47-negative environment are tolerized to cells that do not express CD47, disruption of murine CD47 in this C57BL/6 model negates the requirement for CD47-SIRPα signaling and induces tolerance to transplanted human cells.
After transplantation of human bone marrow, liver, and thymus into a similar model, mice develop organized lymphoid tissues and have an intact complement system. Transplantation results in a majority of leukocytes in the peripheral circulation being from human origin. These mice may be good in applications associated with graft versus host disease (GVHD) and virus-specific immune responses.
