PATTERNS OF ENGRAFTMENT IN DIFFERENT STRAINS OF IMMUNODEFICIENT MICE RECONSTITUTED WITH HUMAN PERIPHERAL BLOOD LYMPHOCYTES1

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Abstract
Models of immunodeficient mice reconstituted with a competent human immune system would represent an invaluable tool for the study of transplantation immunobiology allergy, autoimmunity, and infectious diseases. Severe combined immune deficiency (scid) mice can be successfully reconstituted with human peripheral blood lymphocytes (PBLs), but rates and levels of engraftment are poor. New strains of mice with diverse immunodeficiencies have been recently characterized or developed, which might prove to be advantageous for in vivo studies of human immune reactivity. We have compared rates and patterns of human PBL engraftment in four available immunodeficient murine strains; scid-beige, nonobese diabetic (NOD)-scid, NOD-scid-β2 m− and rag−. T- and B-lymphocyte engraftment, phenotype of engrafted cells, and occurrence of graft-versus-host disease (GVHD) were studied and compared. Successful engraftment of human PBL was readily obtained in the majority of scid-beige, NOD-scid, and NOD-scid-β2 m− with a single i.p. administration of human PBLs, whereas it was seldom achieved in rag− animals. Human Ig levels were accordingly remarkably low in rag− recipients but, interestingly also in NOD-scid-β2 m− mice. Engraftment was readily observed not only in peripheral blood but also in spleen and bone marrow of successfully reconstituted animals. Phenotypic analysis of engrafted human cells showed preserved CD4/CD8 ratios and a clear skewing toward an activated phenotype. GVHD was invariably observed in successfully reconstituted animals. Our data indicate that a high rate of reconstitution with human lymphocytes can be achieved in scid-beige, NOD-scid, and NOD-scid-β2 m− mice. Human Ig are produced at high levels, except in NOD-scid-β2 m−, including xenoreactive natural antibodies. Scid-beige and NOD-scid appear therefore better suited than NOD-scid-β2 m− or rag− for analysis of human immunoreactivity in vivo. An important caveat is the invariable occurrence of GVHD that precludes long-term studies in this model system.