Construction of humanized mice, kinetics of human immune system development and induction of matured and specific T-dependent and T-independent antibody responses

Abstract

Abstract Inbred mice, the most widely used surrogates for human biology, recapitulate many features of the human immune system and immune response. They, however, diverge from humans in important immune elements and functions, such as differential TLR expression, certain antibody and T cell responses, species-specific viral and/or bacterial infections and drug interactions, thereby underscoring the need for a human model that mimics the in vivo human immune response. Humanized mice have recently provided some data on human infections, autoimmunity and cancer, with limited results. We have undertaken a systematic approach to the generation of humanized mice by grafting NOD.Cg-KitW-41J Prkdcscid Il2rgtm1Wjl/WaskJ (NSGW41) mice within 48 hours of birth, devoid of prior irradiation, with human hematopoietic (CD34+) stem cells. Human umbilical cord hematopoietic stem cells were collected within 30 minutes post-partum and injected intracardially, consistently yielding up to 95% human cell peripheral reconstitution. Human leukocyte development, differentiation and long-term persistence in our CD34+ cell-grafted NSGW41 mice revealed B and T cell maturation as part of a full immune system development, which led to emergence of IgM, IgG, IgA and IgE antibody titers comparable to wild type mice. CD34+ cell-grafted NSGW41 mice supported specific T-dependent and T-independent antibody responses that include human B cell class switch DNA recombination, plasma cell and memory B cell differentiation. They also supported a hydrocarbon-induced autoantibody response leading to symptoms mimicking systemic lupus. Thus, we have devised a robust in vivo platform allowing for generation and maturation of human antibody and autoantibody responses.