Homo-β-amino acid containing MBP(85-99) analogs alleviate experimental autoimmune encephalomyelitis
Ravi Kant1, Shweta Pasi1, Avadhesha Surolia1
1Molecular Science Laboratory, National Institute of Immunology, New Delhi-110067, India.
Abstract:
MBP(85-99), an immuno-dominant epitope of myelin basic protein which binds to the major histocompatibility complex haplotype HLA-DR2 is widely implicated in the pathogenesis of multiple sclerosis. J5, an antagonist of MBP(85-99), that blocks the binding of MBP(85-99) to soluble HLA-DR2b much more efficiently than glatiramer acetate (a random copolymer comprising major MHC and T-cell receptor contact residues), was transformed into analogs with superior biological half-lives and antagonistic-activities by substitution of some of its residues with homo-β-amino acids. S18, the best analog obtained ameliorated symptoms of experimental autoimmune encephalomyelitis at least twice more effectively than glatiramer acetate or J5. S18 displayed marked resistance to proteolysis in-vitro; biological impact of which was evident in the form of delayed clinical onset of disease and prolonged therapeutic-benefits. Besides active suppression of MBP(85-99)-reactive CD4(+) T-cells in-vitro and in-vivo S18 treatment also generated IL-4 producing CD4(+) T-cell clones, through which protective effect could be transferred passively.
Insights
A novel analog, S18, targeting myelin basic protein (MBP) epitope (85-99) effectively treats experimental autoimmune encephalomyelitis. S18 demonstrates enhanced stability and therapeutic benefits for multiple sclerosis research.
Area of Science:
- Immunology
- Neuroscience
- Pharmacology
Background:
- Myelin basic protein (MBP) (85-99) is a key epitope in multiple sclerosis (MS) pathogenesis, binding to HLA-DR2.
- Current treatments like glatiramer acetate have limitations.
Purpose of the Study:
- To develop novel antagonists of MBP (85-99) with improved biological properties.
- To evaluate the efficacy of these analogs in ameliorating experimental autoimmune encephalomyelitis (EAE).
Main Methods:
- MBP (85-99) antagonist J5 was modified using homo-β-amino acids to create analogs.
- The best analog, S18, was tested for its ability to block MBP (85-99) binding to HLA-DR2b.
- Efficacy was assessed in an EAE model, comparing S18 to glatiramer acetate and J5.
- In vitro and in vivo studies evaluated T-cell responses and proteolysis resistance.
Main Results:
- S18 exhibited superior blockade of MBP (85-99) binding to HLA-DR2b compared to glatiramer acetate.
- S18 significantly ameliorated EAE symptoms, showing at least twice the efficacy of glatiramer acetate or J5.
- S18 demonstrated enhanced resistance to proteolysis, leading to delayed disease onset and prolonged therapeutic effects.
- S18 suppressed MBP (85-99)-reactive CD4(+) T-cells and induced protective IL-4 producing CD4(+) T-cell clones.
Conclusions:
- S18 represents a promising therapeutic candidate for multiple sclerosis with enhanced stability and efficacy.
- The mechanism involves suppression of pathogenic T-cells and induction of regulatory T-cell populations.
- S18 offers potential for passive immunotherapy through generated IL-4 producing T-cell clones.
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