Abstract
Genetically modified mice carrying engrafted human tissues provide useful models to study human cell biology in physiologically relevant contexts. However, there remain several obstacles limiting the compatibility of human cells within their mouse hosts. Among these is inadequate cross-reactvitiy between certain mouse cytokines and human cellular receptors, depriving the graft of important survival and growth signals. To circumvent this problem, we utilized a lentivirus-based delivery system to express physiologically relevant levels of human interleukin-7 (hIL-7) in Rag2-/-γc-/- mice following a single intravenous injection. hIL-7 promoted homeostatic proliferation of both adoptively transferred and endogenously generated T-cells in Rag2-/-γc-/- Human Immune System (HIS) mice. Interestingly, we found that hIL-7 increased T lymphocyte numbers in the spleens of HIV infected HIS mice without affecting viral load. Taken together, our study unveils a versatile approach to deliver human cytokines to HIS mice, to both improve engraftment and determine the impact of cytokines on human diseases.
Highlights
The development of effective therapies against many of the most widespread human diseases is hampered by a lack of adequate model systems
We first tested whether T cells that develop in Human Immune System (HIS) mice express the receptor for IL-7 by flow cytometry and observed expression levels similar to those found on normal human T cells in the peripheral blood (Figure 1b). We treated both splenocytes (16106 RBC-depleted) and lymph node cells (56105) from HIS mice with increasing amounts of recombinant human interleukin-7 (hIL-7) and observed a dose dependent increase in the survival of both CD4+ and CD8+ T cells in vitro by day 7 based on 7-AAD staining (Figure 1c). This demonstrates that human T cells maturing in HIS mice are responsive to hIL-7
This approach enabled hIL-7 to be expressed at consistent levels long-term, and improved human T lymphocyte numbers in the HIS model
Summary
The development of effective therapies against many of the most widespread human diseases is hampered by a lack of adequate model systems. Further work has demonstrated that these models are susceptible to infection by human immunodeficiency virus (HIV), and can be used for the study of this human pathogen[8,9] Despite this progress, HIS mice have significant limitations with respect to longevity of engraftment, production of myeloid cell populations, and the consistency of immune cell function in experimental replicates within a group[10]. T cell populations in this model are slow to appear and are greatly outnumbered by B lymphocytes until the mice are greater than 6 months of age These limitations necessitate the improvement of the HIS mouse model if it is to become a practical means of studying human immune responses or the pathology of human diseases
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