GENETIC-ANALYSIS OF INFLAMMATION, CYTOKINE MESSENGER-RNA EXPRESSION AND DISEASE COURSE OF RELAPSING EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS IN DA RATS

Genetic analysis of experimental autoimmune encephalomyelitis (EAE) ca n provide clues to the etiology of multiple sclerosis (MS). Identifyin g the susceptibility genes of DA rats may be particularly rewarding si nce they are prone to develop a remarkably MS-like chronic and demyeli nating disease. As a first step in this direction, we investigated the role of DA genes within and outside the major histocompatibility comp lex (MHC) for susceptibility to severe protracted and relapsing EAE (S PR-EAE). This form of EAE developed in DA rats but not in LEW, ACI and BN rats after immunization with syngeneic spinal cord and complete Fr eund's adjuvant. Studies of crosses between DA and BN rats revealed th at non-MHC genes determine susceptibility to SPR-EAE. A role for MHC-g enes was also established using MHC-congenic rat strains, in which the DA MHC haplotype (av1) associated with relapsing EAE. Again, non-MHC genes were decisive since a high incidence of SPR-EAE only occurred in rats with DA non-MHC genes. Analysis of cytokine mRNA expression and infiltrating cells in the spinal cords of congenic strains revealed th at the av1 haplotype associated with a high CD4/CD8 ratio and expressi on of mRNA for interferon-gamma (IFN-gamma), but not for transforming growth factor-beta (TGF-beta) or interleukin-10 (IL-10). In contrast, the other MHC haplotypes (h, l, u) associated with low CD4/CD8 ratios and mRNA expression for TGF-beta and IL-10, but not for IFN-gamma. DA non-MHC genes determined the intensity of inflammation since the numbe r of cells expressing MHC class II, CD4 and interleukin-2 receptor (IL -2R) was higher in DA rats than in LEW.1AVl and PVG.1AVl rats which al so carry the av1 haplotype. We conclude that the MHC haplotype of DA r ats favors a prolonged proinflammatory autoimmune response associated with relapses, while the DA background intensifies inflammation correl ating with a high incidence of relapsing disease. (C) 1997 Elsevier Sc ience B.V.