A T cell receptor antagonist peptide induces T cells that mediate bystander suppression and prevent autoimmune encephalomyelitis induced with multiple myelin antigens

Nicholson, Lindsay B.; Murtaza, Anwar; Hafler, Brian P.; Sette, Alessandro; Kuchroo, Vijay K.

doi:10.1073/pnas.94.17.9279

Cited by 155 publications

(114 citation statements)

References 39 publications

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“…Furthermore, APLs are often immunogenic in their own right, expanding populations of APL-reactive T cells with the potential to cross-react with the native antigen (Nicholson et al, 1995;Das et al, 1997;Nicholson et al, 1997;Anderton et al, 1998;Anderton et al, 1999;Ausubel et al, 1999). This effect cannot be detected using monoclonal autoantigenspecific T cells.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…This effect cannot be detected using monoclonal autoantigenspecific T cells. APL-reactive T cells will produce cytokines which may mediate bystander suppression of autoimmune responses (Nicholson et al, 1995;Greer et al, 1997;Nicholson et al, 1997;Cloake et al, 2014) or which may exacerbate inflammatory responses (Anderton et al, 1998;Anderton et al, 1999). Often, therefore, the immunogenic properties of an APL, rather than its direct effect on autoreactive T cells, have proven more valuable in the treatment of disease.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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Predicting the effects of potentially therapeutic modified peptides on polyclonal T cell populations in a mouse model of multiple sclerosis

Sauer

Trifilieff

Greer

2017

Journal of Neuroimmunology

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Altered peptide ligands (APLs) have routinely been studied in clonal populations of Th cells that express a single T cell receptor (TCR), but results generated in this manner poorly predict the effects of APLs on polyclonal Th cells in vivo, contributing to the failure of phase II clinical trials of APLs in autoimmune diseases such as multiple sclerosis (MS). We have used a panel of APLs derived from an encephalitogenic epitope of myelin proteolipid protein to investigate the relationship between antigen cross-reactivity in a polyclonal environment, encephalitogenicity, and the capacity of an APL to provide protection against experimental autoimmune encephalomyelitis (EAE) in SJL mice. In general, polyclonal Th cell lines specific for encephalitogenic APLs cross-reacted with other encephalitogenic APLs, but not with non-encephalitogenic APLs, and vice versa. This, alongside analysis of TCR Vβ usage, suggested that encephalitogenic and non-encephalitogenic subgroups of APLs expand largely non-cross-reactive Th cell populations. As an exception to the rule, one non-encephalitogenic APL, L188, induced proliferation in polyclonal CD4 + T cells specific for the native encephalitogen, with minimal induction of cytokine production. Co-immunization of L188 alongside the native encephalitogen slightly enhanced disease development. In contrast, another APL, A188, which induced IL-10 production without proliferation in CD4 + T cells specific for the native encephalitogen, was able to protect against development of EAE in a dose-dependent fashion when co-immunized alongside the native encephalitogen. These results suggest that testing against polyclonal Th cell lines in vitro may be an effective strategy for distinguishing between potentially therapeutic and non-therapeutic APLs.

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Section: Accepted Manuscriptmentioning

confidence: 99%

Section: Accepted Manuscriptmentioning

confidence: 99%

Predicting the effects of potentially therapeutic modified peptides on polyclonal T cell populations in a mouse model of multiple sclerosis

Sauer

Trifilieff

Greer

2017

Journal of Neuroimmunology

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“…Variant peptides have therefore been exploited to manipulate autoreactive T cell responses in various autoimmune models including EAE. Several studies have demonstrated that altered peptide ligands (APL), which contain amino acid substitutions at TCR contact residues, are capable of preventing and ameliorating EAE [18][19][20][21]. Recently, we reported that a variant peptide containing an amino acid substitution at an MHC anchor residue anergized polyclonal MOG 35-55-specific T cells in vitro and reduced their encephalitogenicity in vivo upon adoptive transfer [22].…”

Section: Introductionmentioning

confidence: 99%

An MHC anchor‐substituted analog of myelin oligodendrocyte glycoprotein 35–55 induces IFN‐γ and autoantibodies in the absence of experimental autoimmune encephalomyelitis and optic neuritis

Ford

Evavold

2004

Eur J Immunol

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Previous strategies to ameliorate experimental autoimmune encephalitis (EAE) include the treatment of autoreactive T cells with altered peptide ligands, which contain amino acid substitutions at TCR contact residues. We recently showed that a variant of myelin oligodendrocyte glycoprotein (MOG) 35-55 possessing low affinity for MHC (45D) induced anergy in MOG 35-55-specific T cells and reduced their encephalitogenicity upon adoptive transfer. Here we investigate the characteristics of the primary immune response to this MHC anchorsubstituted peptide. Overall, we observed that immunization with 45D resulted in the production of IFN-+ and anti-MOG 35-55 autoantibodies at levels similar to those of MOG 35-55-immunized mice with active EAE. However, no symptoms of clinical or histological EAE or overt histological optic neuritis were observed in 45D-immunized mice. Consistent with this finding, 45D-immunized mice did not exhibit CD4 + infiltrates into the CNS. Therefore, MOG 35-55-specific precursors stimulated with a weak ligand (45D) mediate some EAE-associated effector functions but are unable to fully initiate the inflammatory process in the central nervous system that leads to clinical manifestation of EAE.

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“…MP4 is processed into multiple determinants and can eliminate rodent EAE by promoting tolerance to different epitopes (19,20). This is important in view of epitope or determinant "spreading" in MS and EAE (19,20,(22)(23)(24)(25)(26)(27)(28). We previously documented epitope spreading in EAE in marmosets (29).…”

Section: Ultiple Sclerosis (Ms)mentioning

confidence: 99%

“…We previously documented epitope spreading in EAE in marmosets (29). Epitope spreading poses a challenge for Ag-specific therapies, but even single epitopes can be effective in treating disease in some circumstances (27,28). For example, severe EAE induced in (PL/J ϫ SJL)F 1 mice by immunization with MOG [41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] and MBP Ac 1-11 peptides can be treated effectively by the MBP peptide alone (28).…”

Section: Ultiple Sclerosis (Ms)mentioning

confidence: 99%

Effective Antigen-Specific Immunotherapy in the Marmoset Model of Multiple Sclerosis

McFarland

Lobito

Johnson

et al. 2001

The Journal of Immunology

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Mature T cells initially respond to Ag by activation and expansion, but high and repeated doses of Ag cause programmed cell death and can suppress T cell-mediated diseases in rodents. We evaluated repeated systemic Ag administration in a marmoset model of experimental allergic encephalomyelitis that closely resembles the human disease multiple sclerosis. We found that treatment with MP4, a chimeric, recombinant polypeptide containing human myelin basic protein and human proteolipid protein epitopes, prevented clinical symptoms and did not exacerbate disease. CNS lesions were also reduced as assessed in vivo by magnetic resonance imaging. Thus, specific Ag-directed therapy can be effective and nontoxic in primates.

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A T cell receptor antagonist peptide induces T cells that mediate bystander suppression and prevent autoimmune encephalomyelitis induced with multiple myelin antigens

Cited by 155 publications

References 39 publications

Predicting the effects of potentially therapeutic modified peptides on polyclonal T cell populations in a mouse model of multiple sclerosis

Predicting the effects of potentially therapeutic modified peptides on polyclonal T cell populations in a mouse model of multiple sclerosis

An MHC anchor‐substituted analog of myelin oligodendrocyte glycoprotein 35–55 induces IFN‐γ and autoantibodies in the absence of experimental autoimmune encephalomyelitis and optic neuritis

Effective Antigen-Specific Immunotherapy in the Marmoset Model of Multiple Sclerosis

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