Inhibition of experimental autoimmune encephalomyelitis in SJL mice by oral administration of retro-inverso derivative of encephalitogenic epitope P87 – 99

Abstract

Retro‐inverso modification of peptides preserves parent peptide overall topology and provides at the same time stability to proteolysis, leading to derivatives with prolonged half‐life in vitro and in vivo. In this study the encephalitogenic epitope P87 – 99 of myelin basic protein has been prepared in the retro‐inverso form to examine its biological activity in a murine model of multiple sclerosis. Experiments of in vivo T cell tolerance induction in SJL mice revealed that the retro‐inverso peptide was able to induce a selective T cell hyporesponsiveness, as measured by a reduction in the proliferative response of lymphnode T cells after antigen challenge. Oral administration of retro‐inverso peptide decreased the disease severity significantly and delayed considerably the disease onset in treated mice. Enhancement of resistance to proteolysis by retro‐inverso modification of encephalitogenic epitopes may increase the therapeutic value of oral tolerance induction in the treatment of multiple sclerosis and other Th1‐associated inflammatory disorders.

Contribution of peptides to multiple sclerosis research

“…New evidence indicating that the identified LGRAGLTY motif is preferentially expressed in MBP(83-99)-reactive T cells was provided. 18 A significantly increased CD8þ T-cell response to MBP (111)(112)(113)(114)(115)(116)(117)(118)(119) and MBP(87-95) epitopes with high binding affinity to HLA-A2, in patients with MS compared with healthy individuals, was recently reported. 19 In addition, exploiting the single-cell resolution capability of the enzyme-linked immunospot (ELISPOT) assay, a large set of overlapping peptides of PLP and MBP have been used to perform comprehensive epitope mapping in RR-MS patients in a longitudinal study to define the role of myelin responses in disease progression.…”

“…T cell lines to MOG and MOG(202-218) could also be raised in SJL/J and PL/J mice, respectively. T-cell reactivity to MOG (104)(105)(106)(107)(108)(109)(110)(111)(112)(113)(114)(115)(116)(117) was not observed in other mouse strains. None of the peptides tested induced detectable clinical signs in SJL/J mice.…”

“…23 To understand whether MOG can also play a role in the pathogenicity of MS, the ability of MOG peptides as potential T-cell epitopes inducing neurological disease in mice was tested. Both strains of mice tested (SJL/J and PL/J mice) were able to mount a primary T-cell response to MOG(1-21), MOG , MOG , MOG (104)(105)(106)(107)(108)(109)(110)(111)(112)(113)(114)(115)(116)(117), and MOG(202-218) T cell lines could be raised in both strains to MOG and MOG , but epitope definition revealed that each strain recognized a different minimal epitope within these two peptides. T cell lines to MOG and MOG(202-218) could also be raised in SJL/J and PL/J mice, respectively.…”

“…32 A panel of 20-mer peptides with overlapping by 10-amino acids, representing the sequence of murine OSP, was tested for ability to induce EAE. SJL mice challenged with murine peptides OSP(52-71), OSP(82-101), OSP (102)(103)(104)(105)(106)(107)(108)(109)(110)(111)(112)(113)(114)(115)(116)(117)(118)(119)(120)(121), OSP(142-161), OSP(182-201), and OSP(192-207) exhibited clinical EAE. Moreover, it was demonstrated that OSP(52-71) elicited severe RR-EAE in some individuals.…”

“…Enhancement of resistance to proteolysis by retroinverso modification of encephalitogenic epitopes may increase the therapeutic value of oral tolerance induction. 117 …”