Thiopalmitoylation of altered peptide ligands enhances their protective effects in an animal model of multiple sclerosis.
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.
University of Queensland Centre for Clinical Research, University of Queensland, Brisbane, Queensland 4029, Australia.
Nancy C
NC
Cloake
Wissam
W
Beaino
Elisabeth
E
Trifilieff
Judith M
JM
Greer
D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology*; D008024:Ligands; D054878:Lipoylation; D051379:Mice; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D010455:Peptides / Q000276:immunology / Q000494:pharmacology*
D000949:Histocompatibility Antigens Class II; C556062:IL10 protein, mouse; D008024:Ligands; D010455:Peptides; D016753:Interleukin-10