Tolerance Induction by Acylated Peptides: Effect on Encephalitogenic T cell lines

Louis, Joanne St.; Zhang, Xiangming; Heber‐Katz, Ellen; Uniyal, Shashi; Robbinson, D.; Singh, Bhagirath; Strejan, Gill H.

doi:10.1006/jaut.1998.0275

Cited by 6 publications

(4 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

“…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%

See 1 more Smart Citation

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

et al. 2004

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 49%

Section: Introductionmentioning

confidence: 99%

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

et al. 2004

View full text Add to dashboard Cite

show abstract

“…Using these routes of administration, several antigens have already been used successfully in the EAE system to induce tolerance. The list includes peptides 141520 or peptide derivates modified by acylation 22 or amino acid substitution 23, but also proteins 2124 and protein–protein 25 and immunoglobulin–protein chimeras 26. However, these experiments were usually carried out in transgenic animals, which express only the TCR specific for the peptide antigen 1520.…”

Section: Introductionmentioning

confidence: 99%

Induction and Suppression of an Autoimmune Disease by Oligomerized T Cell Epitopes

Falk

Rötzschke

Santambrogio

et al. 2000

The Journal of Experimental Medicine

View full text Add to dashboard Cite

T cell epitope peptides derived from proteolipid protein (PLP139–151) or myelin basic protein (MBP86–100) induce experimental autoimmune encephalomyelitis (EAE) in “susceptible” strains of mice (e.g., SJL/J). In this study, we show that the encephalitogenic effect of these epitopes when injected subcutaneously in complete Freund's adjuvant was significantly enhanced if administered to the animal in a multimerized form as a T cell epitope oligomer (i.e., as multiple repeats of the peptide epitope, such as 16-mers). Oligomer-treated SJL/J mice developed EAE faster and showed a more severe progression of the disease than animals treated with peptide alone. In addition, haplotype-matched B10.S mice, “resistant” to EAE induction by peptide, on injection of 16-mers developed a severe form of EAE. Even more striking, however, was the dramatic suppression of incidence and severity of the disease, seen after single intravenous injections of only 50 μg of the PLP139–151 16-mer, administered to SJL/J mice 7 d after the induction of the disease. Although relapse occurred at about day 45, an additional injection several days before that maintained the suppression. Importantly, the specific suppressive effect of oligomer treatment was also evident if EAE was induced with spinal cord homogenate instead of the single peptide antigen. By contrast, the PLP139–151 peptide accelerated rather than retarded the progression of disease.

show abstract

“…Moreover, results from vaccine research has shown that acylation with fatty acids can boost the immune response [ 7 , 8 ]. On the other hand, a decrease in the stimulatory capacity for a peptide linked to palmitic acid has also been observed in vivo [ 9 ] as well as in vitro [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

The effect of acylation with fatty acids and other modifications on HLA class II:peptide binding and T cell stimulation for three model peptides

et al. 2018

View full text Add to dashboard Cite

Immunogenicity is a major concern in drug development as anti-drug antibodies in many cases affect both patient safety and drug efficacy. Another concern is often the limited half-life of drugs, which can be altered by different chemical modifications, like acylation with fatty acids. However, acylation with fatty acids has been shown in some cases to modulate T cell activation. Therefore, to understand the role of acylation with fatty acids on immunogenicity we tested three immunogenic non-acylated peptides and 14 of their acylated analogues for binding to 26 common HLA class II alleles, and their ability to activate T cells in an ex vivo T cell assay. Changes in binding affinity associated with acylation with fatty acids were typically modest, though a significant decrease was observed for influenza HA acylated with a stearic acid, and affinities for DQ alleles were consistently increased. Importantly, we showed that for all three immunogenic peptides acylation with fatty acids decreased their capacity to activate T cells, a trend particularly evident with longer fatty acids typically positioned within the peptide HLA class II binding core region, or when closer to the C-terminus. With these results we have demonstrated that acylation with fatty acids of immunogenic peptides can lower their stimulatory capacity, which could be important knowledge for drug design and immunogenicity mitigation.

show abstract

Tolerance Induction by Acylated Peptides: Effect on Encephalitogenic T cell lines

Cited by 6 publications

References 49 publications

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

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

Induction and Suppression of an Autoimmune Disease by Oligomerized T Cell Epitopes

The effect of acylation with fatty acids and other modifications on HLA class II:peptide binding and T cell stimulation for three model peptides

Contact Info

Product

Resources

About