A Model for Personalized in Vivo Analysis of Human Immune Responsiveness

Personalized humanized mice can model intrinsic defects in human immune disease. Personalized Research From monogrammed towels to engraved wedding memorabilia, personalized gifts offer a way to give that special someone something truly unique. However, for all the talk of personalized medicine, translational research doesn’t always live up to this standard. For example, biomedical research is often performed in animal models that don’t recapitulate disease mechanisms as they manifest in any given human patient. Now, Kalscheuer et al. describe the development of what might be the perfect gift for some patients: “personalized immune” (PI) mice that allow individualized analysis of human immune responses. To generate these PI mice, the authors isolated hematopoietic stem cells (HSCs) from the bone marrow of human adults and injected them along with matched fetal thymic tissue (depleted of T cells to prevent graft rejection) into immunodeficient mice. The resulting T cells in these mice were functional, displayed a diverse repertoire, and didn’t attack healthy tissues in the recipient mouse. Kalscheuer et al. then examined PI mice derived with HSCs from both healthy and type 1 diabetic individuals. The researchers found that T cells that arose from HSCs donated by subjects with type 1 diabetes were more likely to have an activated and memory phenotype than were T cells from healthy subject–derived HSCs, even though the T cells developed in a similar environment. These data suggest that there are intrinsic differences in HSCs from type 1 diabetic patients that contribute to the autoimmune pathology. Extending these studies to other diseases should provide new insights into pathogenesis and suggest new treatment strategies. Studies of human immune diseases are generally limited to the analysis of peripheral blood lymphocytes of heterogeneous patient populations. Improved models are needed to allow analysis of fundamental immunologic abnormalities predisposing to disease and in which to assess immunotherapies. Immunodeficient mice receiving human fetal thymus grafts and fetal CD34+ cells intravenously produce robust human immune systems, allowing analysis of human T cell development and function. However, to use humanized mice to study human immune-mediated disorders, immune systems must be generated from adult hematopoietic cells. Here, we demonstrated robust immune reconstitution in mice with hematopoietic stem cells (HSCs) aspirated from bone marrow of adults with type 1 diabetes (T1D) and healthy control volunteers. In these humanized mice, cryopreservation of human leukocyte antigen allele–matched fetal thymic tissue prevented allogeneic adult HSC rejection. Newly generated T cells, which included regulatory T cells (Tregs), were functional and self-tolerant and had a diverse repertoire. The immune recognition of these mice mimicked that of the adult CD34+ cell donor, but the T cell phenotypes were more predominantly “naïve” than those of the adult donors. HSCs from T1D and control donors generated similar numbers of natural Tregs intrathymically; however, peripheral T cells from T1D subjects showed increased proportions of activated or memory cells compared to controls, suggesting possible HSC-intrinsic differences in T cell homeostasis that might underlie immune pathology in T1D. This “personalized immune” mouse provides a new model for individualized analysis of human immune responses that may provide new insights into not only T1D but also other forms of immune function and dysfunction as well.