CD28 costimulatory blockade exacerbates disease severity and accelerates epitope spreading in a virus-induced autoimmune disease

Theiler's murine encephalomyelitis virus (TMEV) is a natural mouse pathogen which causes a lifelong persistent infection of the central nervous system (CNS) accompanied by T-cell-mediated myelin destruction leading to chronic , progressive hind limb paralysis. TMEV-induced demyelinating disease (TMEV -IDD) is considered to be a highly relevant animal model for the human auto immune disease multiple sclerosis (MS), which is thought to be initiated as a secondary consequence of a virus infection. Although TMEV-IDD is initiat ed by virus-specific CD4(+) T cells targeting CNS-persistent virus, CD4(+) T-cell responses against self myelin protein epitopes activated via epitope spreading contribute to chronic disease pathogenesis. We thus examined the ability of antibodies directed against B7 costimulatory molecules to regul ate this chronic virus-induced immunopathologic process. Contrary to previo us studies shelving that blockade of B7-CD28 costimulatory interactions inh ibit the initiation of experimental autoimmune encephalomyelitis, treatment of SJL mice at the time of TMEV infection with murine CTLA-4 immunoglobuli n or a combination of anti-B7-1 and anti-B7-2 antibodies significantly enha nced clinical disease severity. Costimulatory blockade inhibited early TMEV -specific T-cell and antibody responses critical in clearing peripheral vir us infection. The inhibition of virus-specific immune responses led to sign ificantly increased CNS viral titers resulting in increased damage to myeli n-producing oligodendrocytes. Following clearance of the costimulatory anta gonists, epitope spreading to myelin epitopes was accelerated as a result o f the increased availability of myelin epitopes leading to a more severe ch ronic disease course. Our results raise concern about the potential use of B7-CD28 costimulatory blockade to treat human autoimmune diseases potential ly associated with acute or persistent virus infections.