Double humanised lupus mouse model with human immune system and faecal microbiota from patients with SLE.

Abstract

OBJECTIVE: We aimed to create a double humanised lupus mouse model with a human immune system and faecal microbiota from patients with SLE. METHODS: We established the Double humanised SLE (DhuSLE) mouse by engrafting NSG immunodeficient mice with human CD34haematopoietic stem and progenitor cells (NSG-hu mice) and performing faecal microbiota transplantation from patients with SLE (SLE-FMT). RESULTS: While FMT in general transiently suppressed the development of human T cells in NSG-hu mice, SLE-FMT but not FMT from non-SLE donors promoted superficial skin lesions. Importantly, the combination of SLE-FMT and pristane in NSG-hu, now called the DhuSLE-P mouse, induced proteinuria although this clinical sign observed in mice did not reflect that of the microbiota donors. DhuSLE-P mice exhibited a higher level of human IgM in the circulation than NSG-hu mice, which was positively correlated with the frequency of plasma cells in the spleen. In the splenic sections of DhuSLE-P mice, nuclear BCL6 was minimally detected but CD138 expression was evident, suggesting that most plasma cells generated were not class switched and produced IgM. Some human IgG was detected in the kidney of DhuSLE-P mice with a trend towards increased total IgG in the serum. Analysis of the faecal microbiota revealed that the gut microbiota compositions were different between DhuSLE-P mice and NSG-hu mice due to SLE-FMT but not the injection of pristane. CONCLUSION: Together, these results introduced the first humanised lupus mouse model combining the human immune system and gut microbiota from patients with SLE. However, limitations exist and the model may benefit from methods that promote antibody class switching. On further development, the DhuSLE model can be useful for elucidating mechanisms and/or evaluating SLE treatments.