The development of human immune system mice and their use to study tolerance and autoimmunity

Abstract

Autoimmune diseases evolve from complex interactions between the immune system and self-antigens and involve several genetic attributes, environmental triggers and diverse cell types. Research using experimental mouse models has contributed key knowledge on the mechanisms that underlie these diseases in humans, but differences between the mouse and human immune systems can and, at times, do undermine the translational significance of these findings. The use of human immune system (HIS) mice enables the utility of mouse models with greater relevance for human diseases. As the name conveys, these mice are reconstituted with mature human immune cells transferred directly from peripheral blood or via transplantation of human hematopoietic stem cells that nucleate the generation of a complex human immune system. The function of the human immune system in HIS mice has improved over the years with the stepwise development of better models. HIS mice exhibit key benefits of the murine animal model, such as small size, robust and rapid reproduction and ease of experimental manipulation. Importantly, HIS mice also provide an applicable in vivo setting that permit the investigation of the physiological and pathological functions of the human immune system and its response to novel treatments. With the gaining popularity of HIS mice in the last decade, the potential of this model has been exploited for research in basic science, infectious diseases, cancer, and autoimmunity. In this review we focus on the use of HIS mice in autoimmune studies to stimulate further development of these valuable models.

Keywords: Autoimmunity; Human immune system mice; Humanized mice; SCID mice; Tolerance.

Fig. 1

Human immune system mice development and use for autoimmune studies. Human hematopoietic cells used as source for the generation of HIS mice vary according to the model. In the hu-HSC model, human hematopoietic stem cells (HSCs) usually in the form of CD34⁺ cells, are enriched from either umbilical cord blood (CB) obtained after live births or from fetal livers (FT) that are collected subsequent elective and voluntary abortion procedures. These HSCs are then transplanted into either newborn or adult immunodeficient mice that have been preconditioned with a sub-lethal irradiation dose. HSCs are generally injected intra-venously, but they can also be injected intra-hepatically in newborn mice. To setup the hu-BLT model, adult immunodeficient mice are transplanted with thymus fragments obtained either from human fetal tissue or from infants undergoing heart surgery. The thymic fragments are engrafted under the kidney capsule of recipient mice. In addition, these mice are sublethally irradiated and injected with human HSCs isolated from the liver of the same thymus donor fetal tissue (to achieve complete HLA match), or from CB or adult bone marrow (BM) samples that have partial HLA match to the fetal thymus. Injection of the HSCs can occur at the same time of the thymus engraftment or few days after this surgery. In addition to the hu-HSC and hu-BLT models, HIS mice can be generated in a less sophisticated way by injecting immunodeficient mice with total human PBMCs (hu-PBL mice), or with T cells isolated from the blood or other tissues (e.g., the skin). These T cells can be injected as naïve or after culture with APCs (e.g., from the related blood) and specific antigens to enrich for antigen-reactive T cell clones. The figure depicts autoimmune diseases that have been investigated so far using HIS mice: type 1 diabetes (T1D) which manifests in the pancreas, rheumatoid arthritis (RA) which exhibits joint inflammation, experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS) which manifests in the central nervous system, Sjogren’s syndrome (SjS) which displays dryness of eyes, mouth and tongue, alopecia areata which leads to partial or complete hair loss, and systemic lupus erythematosus (SLE) which has multiple manifestations, skin rash and kidney disease being some of these. Alopecia, SjS, and EAE have only been investigated in HIS mice transplanted with human PBMCs or T cells. In addition to the studies of these autoimmune diseases, HIS mice are also starting to be utilized to study the autoimmune manifestations, or immune-related adverse events (irAEs), that arise following cancer immunotherapies with anti-PD1 and anti-CTLA4 antibodies.