Advances in Human Immune System Mouse Models for Personalized Treg-Based Immunotherapies

Abstract

Immunodeficient mice engrafted with a functional human immune system [Human immune system (HIS) mice] have paved the way to major advances for personalized medicine and translation of immune-based therapies. One prerequisite for advancing personalized medicine is modeling the immune system of individuals or disease groups in a preclinical setting. HIS mice engrafted with peripheral blood mononuclear cells have provided fundamental insights in underlying mechanisms guiding immune activation vs. regulation in several diseases including cancer. However, the development of Graft-vs.-host disease restrains relevant long-term studies in HIS mice. Alternatively, engraftment with hematopoietic stem cells (HSCs) enables mimicking different disease stages, however, low frequencies of HSCs in peripheral blood of adults impede engraftment efficacy. One possibility to overcome those limitations is the use of patient-derived induced pluripotent stem cells (iPSCs) reprogrammed into HSCs, a challenging process which has recently seen major advances. Personalized HIS mice bridge research in mice and human diseases thereby facilitating the translation of immunomodulatory therapies. Regulatory T cells (Tregs) are important mediators of immune suppression and thereby contribute to tumor immune evasion, which has made them a central target for cancer immunotherapies. Importantly, studying Tregs in the human immune system in vivo in HIS mice will help to determine requirements for efficient Treg-targeting. In this review article, we discuss advances on personalized HIS models using reprogrammed iPSCs and review the use of HIS mice to study requirements for efficient targeting of human Tregs for personalized cancer immunotherapies.

Preclinical models and evaluation criteria of prostatitis

“…While rodent models of prostatitis may not consistently reflect human immune system responses, they remain valuable tools for investigating the pathogenesis and treatment of the disease. Immunodeficient mice, in particular, have proven useful in a variety of medical research areas, including preclinical trials, regenerative medicine, transplant rejection studies, and immunotherapy ( 15 ).…”

Antigen-Specific Treg Therapy in Type 1 Diabetes – Challenges and Opportunities

“…We used immunodeficient HLA-DQ8transgenic NOD-Scid-IL2Rg knockout (NSG) mice reconstituted with human hematopoietic stem cells to study requirements for human Treg induction in vivo. Importantly, these humanized mice develop a functional human immune system, including the positive selection of autoreactive insulinspecific CD4 + T cells in the thymus (17,21). Using this system under steady state conditions in the absence of autoimmune activation, we were able to demonstrate that, similar to the murine setting, subimmunogenic doses of strong-agonistic insulin variants are able to induce human Tregs in vivo (17).…”

Managing the immune microenvironment of osteosarcoma: the outlook for osteosarcoma treatment

“…[300][301][302] Hence, decreasing the quantity of Tregs is one of the main goals for Treg-based antitumor immunotherapy. 303 For instance, anti-CD25 monoclonal antibodies have been used to reduce the number of CD4 + and CD25 + Tregs to promote specific CD8 + T lymphocyte-mediated cytotoxicity in breast cancer. 304,305 In addition, blocking Tregs to modulate their immunosuppressive functions is also considered another effective strategy.…”