Improvement of preclinical animal models for autoimmune-mediated disorders via reverse translation of failed therapies

•The high attrition of new therapies for AIMID calls for action.•The cause is the poor translation from inbred/SPF mice models to the patient.•Microbially clean mice lack an inward-directed adaptive immune compartment.•The inward compartment of primates is a reservoir of pathogenic T cells.•Analysis of failed treatments in primates guides improvement of mice models. The poor translational validity of autoimmune-mediated inflammatory disease (AIMID) models in inbred and specific pathogen-free (SPF) rodents underlies the high attrition of new treatments for the corresponding human disease. Experimental autoimmune encephalomyelitis (EAE) is a frequently used preclinical AIMID model. We discuss here how crucial information needed for the innovation of current preclinical models can be obtained from postclinical analysis of the nonhuman primate EAE model, highlighting the mechanistic reasons why some therapies fail and others succeed. These new insights can also help identify new targets for treatment.