Humanized Mouse Models of Systemic Lupus Erythematosus: Opportunities and Challenges.

Jiaxuan Chen,Lawei Yang,Shuxian Chen,Chen Yang,Aifen Li,Shuzhen Liao,Qingjun Pan,Fengbiao Guo,Quanren Pan,Hua-Feng Liu,Huimin Zhou

doi:10.3389/fimmu.2021.816956

Abstract

Animal models have played a crucial role in the understanding of the mechanisms and treatments of human diseases; however, owing to the large differences in genetic background and disease-specific characteristics, animal models cannot fully simulate the occurrence and progression of human diseases. Recently, humanized immune system mice, based on immunodeficient mice, have been developed that allow for the partial reconstruction of the human immune system and mimic the human in vivo microenvironment. Systemic lupus erythematosus (SLE) is a complex disease characterized by the loss of tolerance to autoantigens, overproduction of autoantibodies, and inflammation in multiple organ systems. The detailed immunological events that trigger the onset of clinical manifestations in patients with SLE are still not well known. Two methods have been adopted for the development of humanized SLE mice. They include transferring peripheral blood mononuclear cells from patients with SLE to immunodeficient mice or transferring human hematopoietic stem cells to immunodeficient mice followed by intraperitoneal injection with pristane to induce lupus. However, there are still several challenges to be overcome, such as how to improve the efficiency of reconstruction of the human B cell immune response, how to extend the lifespan and improve the survival rate of mice to extend the observation period, and how to improve the development of standardized commercialized models and use them. In summary, there are opportunities and challenges for the development of humanized mouse models of SLE, which will provide novel strategies for understanding the mechanisms and treatments of SLE.

Highlights

Systemic lupus erythematosus (SLE) is a typical autoimmune disease characterized by excessive activation of T and B cells, producing a large number of autoantibodies and pro-inflammatory cytokines that result in tissue and organ damage [1]
There are two main methods of constructing humanized mouse models of SLE, including transferring human peripheral blood mononuclear cells (PBMCs) or peripheral blood lymphocytes (PBLs) from patients with SLE to immunodeficient mice [18, 19], or transferring human hematopoietic stem cells (HSCs) to immunodeficient mice and injecting intraperitoneally (i. p.) with pristane to induce lupus [20] (Figure 1). For these two humanized SLE mouse models, the PBLs/PBMCs humanized mouse model is widely used, but individual differences in SLE patients often lead to inconsistent model parameters and poor uniformity; the HSCs-pristane humanized mouse model can better reproduce the clinical features of human SLE, but there are very few such studies
A previous study showed that higher levels of human IgG I and IgG II anti-dsDNA autoantibodies were detected in the serum of humanized SLE mice (10–12 weeks old), after the establishment of this model with i.p. injection of PBMCs (3×107 cells/mouse) from patients with SLE (SLEDAI score 5.88 ± 4.18) into SCID mice (8–10 weeks) [28]

Summary

Introduction

Systemic lupus erythematosus (SLE) is a typical autoimmune disease characterized by excessive activation of T and B cells, producing a large number of autoantibodies and pro-inflammatory cytokines that result in tissue and organ damage [1]. A similar study showed that approximately 500 μg/mL of human IgG in the serum of SCID mice (9–13 weeks old) engrafted with PBMCs (3×107 cells/mouse) from patients with SLE could be detected [29].

Results

Conclusion