Early exposure of NOD/ShiLtJ mice to Freund's adjuvant prompts delayed, spontaneous progressive encephalomyelitis

Abstract

Drugs able to efficiently counteract primary progressive MS (PP-MS) remain an unmet need. The availability of reliable animal models of PP-MS might boost the identification of treatments capable of counteracting disease evolution. Recently, we characterized primary progressive EAE (PP-EAE) in NOD/ShiLtJ mice, showing that it recapitulates several key features of PPMS. However, a fundamental difference between PPMS and PPEAE is that the latter is triggered by loss of tolerance deliberately induced via peripheral expansion of myelin-specific effector T cells (Teff). In the present study, we report that NOD/ShiLtJ mice challenged with complete Freund's adjuvant (CFA) to prevent diabetes onset, developed spontaneous PP-EAE (SPP-EAE). Specifically, we report that the sole CFA challenge induced encephalomyelitis with a similar pattern of that prompted by the complete immunization protocol including CFA, pertussis toxin and MOG_35–55. Mice with SPP-EAE show primary progressive disease evolution, widespread neurodegeneration, and insensitivity to dexamethasone-dependent immunosuppression. Remarkably, however, at variance with the rapid onset of PP-EAE, SPP-EAE manifested after a latency of approximately 4.5 months following CFA injection. This model may represent a valuable experimental tool to study mechanisms underlying spontaneous loss of self-tolerance toward CNS antigens and MS progression, as well as to identify therapies of relevance to treatment of PMS patients.