EXPRESSION OF THE HUMAN HISTOCOMPATIBILITY LEUKOCYTE ANTIGEN DR3 TRANSGENE REDUCES THE SEVERITY OF DEMYELINATION IN A MURINE MODEL OF MULTIPLE-SCLEROSIS

The role of various MHC genes in determining the progression of multip le sclerosis (MS) remains controversial. The HLA-DR3 gene has been ass ociated with benign relapsing MS in some genetic epidemiologic studies , but with disease progression in others. We induced demyelination in highly susceptible B10.M and B10.Q mice expressing the DR3 (HLA-DRB10 301) transgene to determine directly the effects of a human transgene by infecting them with Theiler's murine encephalomyelitis virus (TMEV) , DR3 + mice experienced a dramatic reduction in the extent and severi ty of demyelination compared with DR3 - littermate controls, whereas a nti-TMEV antibody titers, delayed-type hypersensitivity responses, and levels of infectious virus, virus antigen, and virus RNA were similar in both groups, To address a possible mechanism of how the human tran sgene is reducing virus-induced demyelination, we analyzed cytokine ex pression in the lesions and also determined whether B10.M mice can res pond to peptides derived from the DR3 molecule. Intense staining for I FN-gamma and IL-4, T helper (TH) 1 and TH2 cytokines, respectively, wa s found in the lesions of TMEV-infected DR3- mice but not in the DR3transgenic mice at day 21 after infection. DR3 peptides elicited stron g proliferative responses in B10.M mice but not in B10.M (DR3+) mice. These experiments are the first to demonstrate that a human class II D R gene can alter the severity of demyelination in an animal model of M S without influencing viral load. These experiments are consistent wit h a mechanism by which DR3 reduces demyelination by altering the cytok ine expression in the lesions, possibly by deleting T cells involved i n virus-induced pathology.