Recognition of CD47 on human hematopoietic stem cells results in improved human chimerism in xenografts and permits investigation of rare human progenitors in vivo. (P4469)

Abstract

Abstract Human immune system (HIS) mice represent an important biotechnology for fundamental human immunology research, disease models and drug development. The NOD mouse strain has been primarily used in the development of HIS mice as they possess several advantageous polymorphisms. NOD, but not Balb/c mice contain a polymorphism in Sirpα (an inhibitory receptor that prevents phagocytosis upon binding CD47) allowing NOD, but not Balb/c Sirpα to recognize human CD47 on engrafted cells. Despite this, Balb/c immunodeficient mice are still permissive to human engraftment and their use in human immune studies becoming more prevalent. To determine the importance of the CD47-Sirpα interactions in human hematopoietic reconstitution, we generated a congenic Balb/c Rag2-/-γC-/- HIS mouse expressing NOD Sirpα. A functional CD47-Sirpα interaction resulted in significantly higher human chimerism, with specific improvements in T cell, NK cell and progenitor reconstitution compared to HIS mice expressing only Balb/c Sirpα. Improved human reconstitution has allowed us to carefully study bone marrow resident human hematopoietic progenitors. We have identified 2 subsets of CD7+CD244.2+CD38+CD45RA+Lin-(CD56-) bone marrow precursors with either high or exclusive restriction to the NK cell lineage. Our results reveals the degree by which phagocytosis restricts xeno-engraftment and demonstrates a novel, highly sensitive xenograft model for human immunology studies.