The HIP mouse and all of its organs are completely invisible to allogeneic immune cells.

Hypoimmune (HIP) allogeneic cell therapeutics hold the promise to allow off-the-shelf treatments for a broad patient population. Our HIP approach includes the depletion of major histocompatibility complex (MHC) class I and II molecules and the overexpression of Cd47. Here, we report the engineering of HIP mice that stably exhibit the HIP phenotype in all cell types. Parabiosis experiments were designed to broadly assess immune evasiveness of all HIP blood cells in fully allogeneic BALB/c mice. HIP blood cells did not induce any immune response and achieved stable engraftment in BALB/c mice. Parabiosis experiments with irradiated HIP mice served as a model for full-body transplantation. There was no measurable cellular or antibody response in immunocompetent, allogeneic BALB/c parabionts. Transplantation of HIP islets into diabetic, allogeneic BALB/c mice reliably treated diabetes in all animals. Together, these data suggest that all allogeneic tissues can be HIP engineered and HIP cell therapy may be envisioned for many more indications.