Tolerance induction by acylated peptides: suppression of EAE in the mouse with palmitoylated PLP peptides

Louis, Joanne St.; Uniyal, Shashi; Xu, Li; Chan, Edwin; Singh, Bhagirath; Chan, Bosco M.C.; Strejan, Gill H.

doi:10.1016/s0165-5728(01)00265-x

Cited by 16 publications

(15 citation statements)

References 47 publications

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“…Since Npalmitoylated peptides are weak agonists, the generation of anergic T cells by these peptides is consistent with recent reports indicating that very low concentrations of agonist peptides can induce T cell anergy [23]. The demonstration that administration of low doses of PALPCC 81-104 inhibits the ability of T cells to proliferate after immunization with PCC 81-104 in CFA, provides broad biological significance in vivo, in support of previous reports that N-palmitoylated peptides protect against EAE [15][16][17].…”

Section: Discussionsupporting

confidence: 89%

“…Several reports have indicated that N-palmitoylation of antigenic peptides can reduce T cell-dependent responses in vivo [15][16][17][18]. We show here for the first time that the mechanistic base for such an effect at the T cell clonal level is that N-palmitoylation weakens the agonist properties of the wild-type peptide.…”

Section: Discussionsupporting

confidence: 49%

“…For example, it has been previously shown that the type of linkage between the peptide and the palmitic acid can affect the immunogenicity and encephalogenicity of the modified peptide in vivo [17]. While Npalmitoylation of encephalitogenic peptides can prevent the induction and reduce the clinical and pathological manifestations of EAE [15][16][17], thiopalmitoylation does not protect but in fact, increases immunogenicity [17,28,29]. This is important since some of the autoantigens (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Since previous in vivo studies in EAE implied that Npalmitoylation of antigenic peptides converted them into effective tolerogens [15][16][17], we decided to study their mechanism of action. We used the response to PCC , and tested the effect of N-palmitoylation of PCC to modify the response of a PCC 81-104 -specific T cell clone.…”

Section: T-cell Proliferation and Cytokine Production In Response To mentioning

confidence: 99%

“…We chose Npalmitoylation because previous work has shown a therapeutic effect of N-palmitoylated peptides on experimental autoimmune encephalomyelitis (EAE). This work involved three peptides (PALPLP [139][140][141][142][143][144][145][146][147][148][149][150][151] , Npalmitoylated myelin basic protein (MBP) fragment 68-86, and N-palmitoylated myelin oligodendrocyte glycoprotein (MOG) fragment 35-55), in two species (mouse and rat), and with three different restriction elements ( [15][16][17][18] and GHS, personal observation). Using PCC and its N-palmitoylated version PALPCC we show that this modification converts a strong agonist peptide into a weak agonist of the TCR as indicated by the signaling pattern through this receptor and by the responses induced by PALPCC .…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of modulation of T cell responses by N‐palmitoylated peptides

et al. 2004

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Small structural changes in the antigenic peptides recognized by TCR can alter the biological properties of those peptides and convert them into weak agonists, partial agonists, or antagonists of these receptors. These altered peptide ligands (APL) are usually generated by conservative amino acid substitutions at TCR contact residues. Here, we show that APL with therapeutic properties can also be generated by attachment of palmitic acid at the N terminus of the peptide without the need to modify the peptide's primary sequence. Using Npalmitoylated pigeon cytochrome-c peptide 81-104 (PALPCC 81-104 ), we were able to induce T cell hyporesponsiveness to the wild-type peptide in vitro. More importantly, administration of the PALPCC 81-104 to mice reduced the responsiveness to the native peptide when tested ex vivo. Biochemical and functional experiments indicated that the action of N-palmitoylated peptides was due to the conversion of the native peptide into a weak agonist that could then induce T cell anergy. Our results demonstrate that N-palmitoylation of antigenic peptides is a feasible strategy to generate APL, as it avoids the need to screen multiple amino acid variants of each specific antigen to identify those with therapeutic properties.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Section: T-cell Proliferation and Cytokine Production In Response To mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mechanism of modulation of T cell responses by N‐palmitoylated peptides

et al. 2004

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Contribution of peptides to multiple sclerosis research

Alcaro

Papini

2006

Biopolymers

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Multiple sclerosis (MS) is an autoimmune disease associated with chronic inflammatory demyelination of the central nervous system in genetically susceptible individuals. Because of the disease complexity and heterogeneity, its pathogenesis remains unknown despite extensive research efforts, and specific effective treatments have not yet been developed. Peptide-based research has been important in attempts to unravel particular aspects of this complex disease, including the characterization of the different molecular mechanisms of MS, with the goal of providing useful products for immune-mediated therapies. In fact, in the past decade, peptide-based research has been predominant in research aimed to identify and/or develop target antigens as synthetic probes for specific biomarkers as well as innovative immunomodulating therapies. This review presents an overview of the contributions of peptide science to MS research and discusses future directions of peptide-based investigations.

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