2 MODELS OF MULTIPLE-SCLEROSIS - EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS (EAE) AND THEILERS MURINE ENCEPHALOMYELITIS VIRUS (TMEV) INFECTION- A PATHOLOGICAL AND IMMUNOLOGICAL COMPARISON

Theiler's murine encephalomyelitis virus (TMEV) infection and experime ntal allergic encephalomyelitis (EAE) are considered among the best mo dels of human multiple sclerosis (MS) In both models, clinical disease is characterized by paralysis, while pathological changes consist of inflammatory demyelination. In both models there is a genetic influenc e on susceptibility/resistance to the development of disease. This has been thoroughly studied in TMEV infection, and it has been found to d epend on both major histocompatibility complex (MHC) and non-MHC genes . At least four genes have been so far identified. Because of this gen etic influence, some strains of mice are more susceptible to both clin ical and pathological changes than others, and susceptibility appears to best correlate with the ability of a certain murine strain to devel op a delayed-type hypersensitivity (DTH) response to viral antigens. W e have also observed that even among mice which are equally susceptibl e clinically, striking differences may be seen under pathological exam ination. These consist of different gradients of severity of inflammat ion, particularly in regards to the macrophage component. There is an inverse relationship between the number of macrophages, and their leng th of stay in the CNS, and the ability of mice to remyelinate their le sions. The most severe lesions are in SJL/J mice, and remyelination in this strain is extremely poor. The least severe lesions in terms of m acrophage invasion are in strains such as NZW and RIIIS/J, and these a re able to remyelinate lesions very successfully. Murine chronic relap sing EAE (CR-EAE) shows pathological changes in many ways similar to t hose in TMEV-infected SJL/J mice, although less severe in terms of deg rees of macrophage infiltration and tissue destruction. Mice with CR-E AE have a correspondingly limited ability to remyelinate their lesions . In both models the pathology appears to be mediated through a DTH re sponse. However, while in EAE the DTH response is clearly against neur oantigens, the response in TMEV infection is against the virus itself The end result in both models would be that of myelin destruction thro ugh a lymphotoxin-cytokine-mediated mechanism. The importance of the D TH response in both models is well illustrated by the effects of toler ance induction in EAE and TMEV infection to neuroantigens and virus, r espectively. These are important models of human MS, since the current hypothesis is that a viral infection early in life, on the appropriat e genetic background, may trigger a secondary misdirected immune respo nse which could be directed either against myelin antigens and/or poss ible persistent virus(es). (C) 1995 Wiley-Liss, Inc.