OBSERVATIONS ON ATTEMPTS TO PRODUCE ACUTE DISSEMINATED ENCEPHALOMYELITIS IN MONKEYS.
The Pasteur rabies vaccine, developed in the late 19th century, was produced by intracranial inoculation of rabbits with rabies virus, then treating dried infected spinal cord with potassium hydroxide to kill the virus. Shortly after introduction of the vaccine, it was noted that some recipients developed an acute paralytic illness with a characteristic pathological picture of perivascular inflammation and demyelination in the central nervous system (CNS). This disorder, termed acute disseminated encephalomyelitis (ADEM), was recognized as having some pathologic similarities to multiple sclerosis (MS). Through studies in monkeys, Dr. Rivers and colleagues sought to determine whether ADEM was caused by rabies virus escaping inactivation or by exposure to normal brain constituents in the vaccine. In their 1933 paper, Rivers et al. reported that there was no evidence of transmission of rabies infection. Rather, after repeated intramuscular injection of rabbit CNS-derived extract alone, 2 of 8 monkeys developed clinical and pathologic manifestations similar to those described in humans with ADEM and MS.
This paper represents the first description of experimental autoimmune encephalitis (EAE), which has been extensively studied up to the present as an inducible animal model of MS. The voluminous literature on EAE includes studies of immunologic, pathologic, and physiologic assessments in a wide range of variations of the model in different animal species, strains, and genetic backgrounds; with a large number of different CNS-derived immunogens; and utilizing a variety of induction protocols. Concepts derived from studies of EAE have dominated thinking over the last century about the pathogenesis and therapy of MS as an autoimmune disease. Virtually every potential MS therapy has been tested in EAE. Nevertheless, it also has become evident that EAE is an inexact model of MS and that no individual EAE version fully recapitulates all the features of the human disease.