Thiopalmitoylation of Altered Peptide Ligands Enhances Their Protective Effects in an Animal Model of Multiple Sclerosis

Abstract

Previously, we have shown that conjugation of a palmitic chain via a thioester bond to a cysteine residue in weakly or nonencephalitogenic or neuritogenic peptides markedly enhances their ability to induce autoimmune disease in an MHC class II–restricted manner. From those studies, however, it was not clear whether thiopalmitoylation of the peptides was merely enhancing their disease-inducing potential or whether the lipid was itself playing a pathogenic role. To investigate this further, we have now tested the effects of thiopalmitoylation on MHC class II–restricted altered peptide ligands (APLs), which are normally protective in experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. We hypothesized that if thiopalmitoylation of a peptide merely enhances its innate potential, then thiopalmitoylated APLs (S-palmAPLs) should show enhanced protective effects. Alternatively, if thiopalmitoylation itself can make a peptide pathogenic, then S-palmAPLs should have decreased therapeutic potential. We synthesized APLs and corresponding S-palmAPLs and showed that the S-palmAPLs were much more effective than the nonconjugated APL at inhibiting the development of experimental autoimmune encephalomyelitis. This was due to several features of the S-palmAPL:S-palmAPL–primed cells show an enhanced ability to proliferate and produce the anti-inflammatory cytokine, IL-10, in vitro. Furthermore, the bioavailability of S-palmAPL was greatly enhanced, compared with the nonpalmitoylated APL, and S-palm APL was taken up more rapidly into dendritic cells and channeled into the MHC class II processing pathway. These results show that thiopalmitoylation of MHC class II–restricted peptides is a simple way to enhance their effects in vivo and could have wide therapeutic application.

Taming the TCR: Antigen-Specific Immunotherapeutic Agents for Autoimmune Diseases

“…A dendrimer linking two different APLs (designed to treat Celiac disease) increased the ability of the APLs to competitively block T cell activation by native peptides at significantly lower doses than those at which they could act individually [149,150]. Finally, it has recently been shown that thioacylation of APL by attachment of a palmitic acid chain via a thioester bond to a cysteine residue can markedly enhance the immunogenic and therapeutic properties of APL in an EAE model [151]. Of note, thioacylation of APL markedly enhances the half-life of the APL in serum, and drives uptake of the peptide into the MHC class II presentation pathway [152].…”

“…Another recent phase 1 trial in MS involved the intravenous administration of autologous peripheral blood mononuclear cells (PBMCs) coupled (using ECDI) with seven myelin peptides (MOG 1-20 , MOG , MBP 13-32 , MBP [83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99] , MBP and PLP [139][140][141][142][143][144][145][146][147][148][149][150][151][152][153][154] ) to a group of nine MS patients, who were selected based on reactivity to at least one of these peptides [120]. This trial was not set up to show clinical efficacy, but it showed that the method appears safe in humans.…”

Effects of biological sex and pregnancy in experimental autoimmune encephalomyelitis: It’s complicated

“…Neuroantigen-specific CD4 + Th1 and Th17 cells are the main cells responsible for the induction of EAE. Although many papers state that Th17 cells are critical for disease development, there are quite a number showing that, at least in both the models of MOG-induced EAE in C57BL/6 mice and PLP-induced EAE in SJL mice, Th1 cells, Th17 cells, and cells producing both IFNγ and IL-17 appear to be equally able to induce EAE ( 76 , 98 – 101 ). However, there do appear to be differences in the site of induction of antigen-specific T cells in male and female mice.…”

Unnatural amino acids improve affinity and modulate immunogenicity: Developing peptides to treat MHC type II autoimmune disorders

“…A follow‐up study to determine the mechanism for increased immunogenicity determined that lipopeptides are absorbed more efficiently in antigen presenting cells . Cloake and coworkers then modified PLP APLs which were shown to ameliorate EAE disease progression by promoting the uptake and preferential presentation of the modified peptides . These studies show that the consideration of post translational modifications of the peptides’ side chains is important.…”