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Blockade of CD28/B7-1 interaction prevents epitope spreading and clinical relapses of murine EAE
S D Miller1, C L Vanderlugt, D J Lenschow
1Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Abstract:
Relapsing experimental autoimmune encephalomyelitis (R-EAE) induced with the immunodominant epitope from proteolipid protein, PLP139-151, is characterized by the development of recurrent relapses with recruitment of T cells reactive to additional myelin peptides, including PLP178-191 (epitope spreading). In this study, we have determined that the CD28/B7 costimulatory pathway is involved in this process. We found preferential up-regulation of B7-1 during the course of R-EAE and a selective increase in its functional costimulatory activity, relative to B7-2. Anti B7-1 F(ab) fragment therapy, but not anti B7-2 MAb therapy, blocked clinical relapses, ameliorated CNS pathology, and blocked epitope spreading. These results suggest that the maintenance of autoimmune reactivity in EAE depends on CD28/B7-1-dependent costimulation of newly recruited T cells responsible for epitope spreading. These studies have important implications for the role of epitope spreading in disease progression and the clinical application of costimulatory antagonists in autoimmune diseases.
Insights
Targeting the CD28/B7-1 pathway can block relapses in experimental autoimmune encephalomyelitis (EAE). This approach inhibits T cell costimulation, crucial for epitope spreading and disease progression in autoimmune conditions.
Area of Science:
- Immunology
- Neuroimmunology
- Autoimmunity
Background:
- Relapsing experimental autoimmune encephalomyelitis (R-EAE) involves recurrent relapses and T cell responses to new myelin peptides, a process known as epitope spreading.
- The CD28/B7 costimulatory pathway is a critical regulator of T cell activation and immune responses.
Purpose of the Study:
- To investigate the role of the CD28/B7 costimulatory pathway in R-EAE pathogenesis.
- To determine the specific contribution of B7-1 and B7-2 costimulatory molecules in disease relapses and epitope spreading.
Main Methods:
- Induction of R-EAE in a mouse model using the PLP139-151 epitope.
- Analysis of B7-1 and B7-2 expression and costimulatory activity during R-EAE.
- Therapeutic intervention using anti-B7-1 and anti-B7-2 antibodies to assess their impact on clinical relapses, central nervous system (CNS) pathology, and epitope spreading.
Main Results:
- Preferential upregulation and increased functional activity of B7-1 were observed during R-EAE.
- Anti-B7-1 therapy, but not anti-B7-2 therapy, effectively blocked clinical relapses, reduced CNS pathology, and prevented epitope spreading.
- These findings highlight the critical role of B7-1 in sustaining autoimmune reactivity.
Conclusions:
- The CD28/B7-1 costimulatory pathway is essential for the maintenance of autoimmune reactivity in R-EAE, particularly for T cell recruitment driving epitope spreading.
- Targeting the CD28/B7-1 interaction offers a potential therapeutic strategy for autoimmune diseases characterized by epitope spreading and recurrent relapses.