Humanized Mouse Models of Systemic Lupus Erythematosus: Opportunities and Challenges

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.

Life factors acting on systemic lupus erythematosus

“…The exact etiology of SLE remains unclear, but genetic risk loci, such as N-acetyltransferase 2 (NAT2) slow acetylator genotype, and environmental factors are crucial in the development of susceptibility to SLE ( 3 , 4 ). Although many SLE susceptibility genes have been identified recently, gene therapy approaches remain a distant prospect from the point of view of the clinical treatment ( 5 ). Furthermore, the significant side effects of high-dose immunosuppressive therapy for SLE, such as osteoporosis, hypertension and infection, have caused much concern ( 4 , 6 ).…”

Abnormal presentation of pregnancy and postpartum initial-onset systemic lupus erythematosus combined with diffuse alveolar hemorrhage: A case report

“…Clinicians should consider the presence of autoantibodies, such as ANAs, detected in the sera of patients with connective tissue diseases like SLE. 7,8 It is also necessary to combine the specific diagnostic criteria for SLE (see Table 3 for details) based on the patient's clinical manifestations and family history, which can lead to early detection, diagnosis, and treatment of SLE. Hormonal changes due to pregnancy are important in triggering or exacerbating SLE, and its development is a risk factor for adverse pregnancy outcomes.…”

The development and improvement of immunodeficient mice and humanized immune system mouse models

“…Humanized mouse models constructed by engrafting peripheral blood mononuclear cells have mainly revealed the presence of human T cells ( 47 , 48 ). However, in stem cell transplant models, B-cell reconstitution is efficient with T-cell engraftment lagging ( 49 ).…”

“…In this model, human peripheral blood mononuclear cells (PBMCs) or peripheral blood lymphocytes (PBLs) are transplanted into mice via a caudal vein or peritoneal injection ( 48 , 55 , 56 ). In general, 50–80% of human CD45 + cells can be detected in the blood and spleen of mice.…”