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.

Central human B cell tolerance manifests with a distinctive cell phenotype and is enforced via CXCR4 signaling in hu-mice

“…72 and 73). The reconstituted HIS in HIS hu-mice cannot recapitulate fullfledged autoimmune diseases (73), but these animal models could be used to dissect immunological processes that underlie the development of autoimmunity, including defects in B cell tolerance (74)(75)(76). Here, we used our HIS hu-mouse Hck model to determine whether HSCs isolated from umbilical cord blood of infants born from T1D, SLE, or RA autoimmune mothers developed into B cells with altered modulation of central tolerance markers.…”

B‐cell intrinsic and extrinsic signals that regulate central tolerance of mouse and human B cells*

“…52 HIS hu-mice are immunodeficient mice transplanted with human hematopoietic stem cells that facilitate the development of functional human B cells and T cells in the mouse host. 53,54 Our hu-mouse model of B cell tolerance, developed based on Igκ-specific macroself transgenic mice, 26 relies on a ubiquitously expressed membrane superantigen (Hcκ; anti-human Igκ) that binds the human Igκ light chain constant region. In Hcκ hu-mice, all developing human κ + B cells (about half of all B cells) undergo central tolerance to the Hcκ self-antigen (mainly in the form of receptor editing) at the immature cell stage in the host bone marrow tissue.…”

The Challenging Melanoma Landscape: From Early Drug Discovery to Clinical Approval

“…Severe Combined Immunodeficiency (SCID) mice have a mutation in the protein kinase DNA-activated catalytic polypeptide (Prkdc) gene, leading to a defective DNA double-strand break repair during V(D)J recombination and, consequently, absence of mature B and T lymphocytes [206][207][208]. Depending on genetic background, pathogen exposure and age, functional B-and T-cells may accumulate due to a 'leaky' phenotype [206].…”

“…This condition may, in turn, lead to the development of spontaneous lymphomas, reducing mice life span and limiting their use in prolonged experiments [209]. Although SCID mice have a functional innate immunity and remnant natural killer (NK) cells may limit the success of primary tumor engraftment, this strain is able to host a larger range of primary human tumors compared to nude mice [207,208]. In the context of melanoma research, SCID mice continue to be used as models for studying signaling pathways associated with disease development and progression, as well as for assessing the biodistribution profiles of nanoparticles and therapeutic compounds (Table 4).…”