Characterization and Optimization of SLE Mouse Models for the Evaluation of Immunomodulation Therapeutics

Abstract Systemic Lupus Erythematosus is a chronic autoimmune disease that causes systemic damage throughout the body and is characterized by a broad spectrum of clinical manifestations. The pathogenic mechanisms underlying the disease remain unclear, but are thought to be the result of gene-by-environment interactions that lead to the breakdown of self-tolerance in susceptible individuals. Mouse models of SLE have been instrumental in our understanding of the genetic and cellular requirements for SLE induction, and represent a valuable resource for testing SLE therapies and drug candidates in vivo. No one mouse model completely recapitulates the complexity of the human disease, thus it is crucial to evaluate the mode of action and therapeutic efficacy of targeted therapeutics in multiple SLE mouse models. Here we demonstrate an effective program for screening therapeutic candidates using two well-established SLE mouse models, NZBWF1/J mice and MRL/MpJ-Faslpr/J mice, which mimic the genetic and pathophysiological aspects of the human disease. We characterize the disease course in each model in order to optimize the treatment schedule for either prophylactic or therapeutics drug efficacy studies. Using the immunosuppressant drug cyclophosphamide, we longitudinally compare the clinical measures of the disease to immune cell profiles during both in-life and at study terminus. This program provides a valuable resource for the investigation into the specific effects novel therapeutics have on immune homeostasis.