Establishment of a double humanized lupus mouse model with human immune system and SLE patient microbiota 2284

Abstract Description Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease influenced by complex interactions between the immune system and microbiota. To investigate these interactions, we established a Double humanized SLE (DhuSLE) mouse model by engrafting NSG mice with human CD34+ hematopoietic stem and progenitor cells (NSG-hu mice) and fecal microbiota transplantation from SLE patients (SLE-FMT). FMT transiently suppressed the development of human T cells in NSG-hu mice, indicating a modulatory effect of the transplanted microbiota on immune reconstitution. SLE-FMT alone did not induce most lupus clinical signs but promoted skin lesions, highlighting a microbiota-driven cutaneous response. Contrary to a previous report, pristane injection alone failed to drive lupus-like disease in NSG-hu mice. However, the combination of SLE-FMT and pristane induced lupus nephritis in DhuSLE mice. Interestingly, however, clinical signs observed in DhuSLE mice did not fully reflect those of the microbiota donors. Together, these results suggest that the combination of SLE-FMT and pristane induces lupus nephritis in NSG-hu mice. This indicates the successful establishment of a DhuSLE humanized lupus mouse model. However, limitations exist, and the model may benefit from estrogen conditioning and a different immunodeficient background, as shown in the recently published THX mouse. Upon further development, the DhuSLE mouse can be used to elucidate the pathogenetic mechanisms of human SLE. Funding Sources Supported by United States Department of Defense CDMRP program award number: HT9425-23-1-0343 Topic Categories Basic Autoimmunity (BA)