Early islet xenograft dysfunction in humanized mice

Allogeneic transplantation of human islets improves metabolic control in patients that suffer from type 1 diabetes but is limited by the supply of sufficient numbers of human donor islets. Therefore, the xenogenic transplantation of porcine islets potentially represents an attractive alternative. The immediate blood‐mediated inflammatory reaction (IBMIR) that results in early graft rejection is one of the major hurdles preventing xenotransplantation from clinical applications. Thus, characterizing and modulating IBMIR could be the key to realize clinical porcine islet transplantation. IBMIR is mediated by multiple components of the innate immune system and in order to assess composition and function of distinct myeloid cell types involved in the rejection process, we established a humanized mouse model to study IBMIR in vivo. We combined immune deficient mice that lack T, B, and NK cells with a mutant Kit receptor affecting the function of HSCs allowing for robust engraftment of HSCs and mature myeloid cells types over long periods of time. We could show that human myeloid cells repopulate peripheral organs such as spleen and liver – a prerequisite for the study of IBMIR in a humanized mouse model. We will now engage these mice to transplant porcine islets into the liver via the portal vein to induce immediate rejection of the graft. In this scenario presence of human myeloid cells in the liver of our new mouse model will facilitate a detailed characterization of the human IBMIR against pig islets and will also allow attempts to suppress this immune reaction by specific targeting of human leukocytes.