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.

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“…Brain-mediated physiological activity of d-amino acid retro-inverso transformed, naturally occurring peptides have been demonstrated following parenteral (subcutaneous or intraperitoneal) administration (Goodman et al, 1992;Lapchak et al, 2000;Lu et al, 2000;Marino et al, 1999;Murphy et al, 1985;Yan et al, 2000). We and others have conjectured that the d-amino acid peptide bonds of the receptor hydrophobic eigenmode matched, retro-inverso peptides, being resistant to proteolytic digestion, permit the peptide to remain in the extracellular fluid in sufficient concentration and over sufficient time to diffuse into the brain, without the necessity of a membrane transporter.…”

Emerging Peptide Therapeutics for Inflammatory Autoimmune Diseases

“…In addition, depending on where the modification is located in the sequence, certain pseudopeptide analogues can be efficiently presented by MHC class I and class II molecules and are recognized in this context by T cell clones and T hybridomas specific for the parent peptide [84][85][86][87][88]. Oral administration of a retro-inverso analogue of encephalitogenic MBP peptide 87-99 was found to significantly decrease severity and delay the onset of autoimmune encephalomyelitis in treated mice [89]. This family of peptide mimetics has thus a considerable potential as synthetic, therapeutic vaccines, since their increased resistance to proteases may overcome one of the major drawbacks of classical peptide vaccines.…”

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“…Loss of both the ability to bind to MHC class II molecules and to elicit specific T cells was observed for retro-inverse analogues of Toxin α 24-36 , HEL 103-121 , rep [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] and OVA 323-339 [101]. In contrast, the retro-inverso analogue of the poliovirus peptide, PV1 [103][104][105][106][107][108][109][110][111][112][113][114][115] and the mouse IgG2a allopeptide, γ 2a b 435-446 induced T cell proliferation and IL-2 secretion to the same extent as the parent peptides despite reduced binding affinity to MHC class II molecules [102]. Similarly, partially retro-inverso analogue of the antigenic peptide M 58-66 derived from the influenza matrix protein, modified between P1-P2, showed increased stability and high HLA-A2 binding ability.…”

“…However, modifications between P2-P3, P3-P4, P5-P6 and P8-P9 dramatically reduced peptide binding to HLA-A2 [103]. Finally, oral administration of the retro-inverso analogue of MBP [87][88][89][90][91][92][93][94][95][96][97][98][99] was shown to decrease experimental autoimmune encephalitis in mice while being resistant to proteolytic degradation, highlighting the therapeutic value of retro-inverso peptides [104].…”