Establishment of a humanized lupus model

Abstract

Abstract Systemic lupus erythematosus (SLE), a systemic autoimmune disease, involves mild to severe manifestations in multiple organs. Currently, lupus-prone mouse models are used to understand the mechanisms of SLE development and discover new therapies. However, due to differences between rodents and humans, such as physiological development, disease progression, and response to therapies and drugs, many mechanisms and therapies discovered in mice may not be efficiently transferred from murine lupus models to SLE patients. Here we present a humanized mouse model of lupus as a new technology to bridge the gap between rodent models and patients. In our model, which involves vigorous selection of donors, we engraft peripheral blood mononuclear cells (PBMCs) from SLE patients into NOD/SCID/IL2Rgnull (NSG) mice to build a human-specific disease-based immune system in the mice. To avoid graft versus host disease, we stimulate PBMCs before transferring them into either female or male NSG mice. This method enhances the survival and maintenance of the engrafted cells. Human T cells and B cells that are critical to lupus development can be detected in the peripheral blood and spleen of humanized mice with no sex preference two weeks after engraftment. The model responds well to dexamethasone treatment with reduced proteinuria and decrease of spleen weight, indicating that our model could be used for preclinical studies for SLE. The therapeutic window can be as long as 3 weeks. This model allows for mechanistic studies and testing of potential therapies of SLE directly on human immune system in vivo without putting human life at risk.