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CD28 costimulatory blockade exacerbates disease severity and accelerates epitope spreading in a virus-induced
K L Neville1, M C Dal Canto, J A Bluestone
1Department of Microbiology-Immunology, Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Abstract:
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 autoimmune disease multiple sclerosis (MS), which is thought to be initiated as a secondary consequence of a virus infection. Although TMEV-IDD is initiated 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 regulate this chronic virus-induced immunopathologic process. Contrary to previous studies showing that blockade of B7-CD28 costimulatory interactions inhibit the initiation of experimental autoimmune encephalomyelitis, treatment of SJL mice at the time of TMEV infection with murine CTLA-4 immunoglobulin or a combination of anti-B7-1 and anti-B7-2 antibodies significantly enhanced clinical disease severity. Costimulatory blockade inhibited early TMEV-specific T-cell and antibody responses critical in clearing peripheral virus infection. The inhibition of virus-specific immune responses led to significantly increased CNS viral titers resulting in increased damage to myelin-producing oligodendrocytes. Following clearance of the costimulatory antagonists, epitope spreading to myelin epitopes was accelerated as a result of the increased availability of myelin epitopes leading to a more severe chronic disease course. Our results raise concern about the potential use of B7-CD28 costimulatory blockade to treat human autoimmune diseases potentially associated with acute or persistent virus infections.
Insights
Blocking B7 costimulatory molecules during Theiler's murine encephalomyelitis virus (TMEV) infection worsened disease severity. This approach impaired virus clearance, increased central nervous system viral load, and accelerated autoimmune responses, raising concerns for treating virus-associated autoimmune diseases.
Area of Science:
- Immunology
- Virology
- Neuroscience
Background:
- Theiler's murine encephalomyelitis virus (TMEV) causes persistent central nervous system (CNS) infection and demyelination in mice, modeling human multiple sclerosis (MS).
- TMEV-induced demyelinating disease (TMEV-IDD) involves virus-specific CD4(+) T cells and epitope spreading to self myelin antigens, contributing to chronic pathogenesis.
- B7 costimulatory molecules play a role in T-cell activation and immune responses.
Purpose of the Study:
- To investigate the effect of blocking B7 costimulatory molecules on the chronic immunopathologic process in TMEV-induced demyelinating disease (TMEV-IDD).
- To assess whether targeting B7-CD28 interactions could regulate TMEV-induced autoimmunity.
Main Methods:
- SJL mice were treated with murine CTLA-4 immunoglobulin or anti-B7-1/anti-B7-2 antibodies during TMEV infection.
- Clinical disease severity, T-cell and antibody responses, viral titers in the CNS, and epitope spreading were evaluated.
Main Results:
- B7 costimulatory blockade significantly enhanced clinical disease severity in TMEV-infected mice.
- Blockade inhibited early TMEV-specific T-cell and antibody responses, leading to increased CNS viral titers and oligodendrocyte damage.
- Following blockade withdrawal, accelerated epitope spreading to myelin antigens resulted in a more severe chronic disease course.
Conclusions:
- Contrary to expectations, B7 costimulatory blockade exacerbated TMEV-IDD by impairing viral clearance and promoting autoimmunity.
- These findings raise concerns about using B7-CD28 costimulatory blockade for treating human autoimmune diseases linked to viral infections.