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

Sauer, Evan L., Trifilieff, Elisabeth and Greer, Judith M. (2017) Predicting the effects of potentially therapeutic modified peptides on polyclonal T cell populations in a mouse model of multiple sclerosis. Journal of Neuroimmunology, 307 18-26. doi:10.1016/j.jneuroim.2017.03.011


Author Sauer, Evan L.
Trifilieff, Elisabeth
Greer, Judith M.
Title Predicting the effects of potentially therapeutic modified peptides on polyclonal T cell populations in a mouse model of multiple sclerosis
Journal name Journal of Neuroimmunology   Check publisher's open access policy
ISSN 1872-8421
0165-5728
Publication date 2017-06-15
Sub-type Article (original research)
DOI 10.1016/j.jneuroim.2017.03.011
Open Access Status Not yet assessed
Volume 307
Start page 18
End page 26
Total pages 9
Place of publication Amsterdam, Netherlands
Publisher Elsevier BV
Collection year 2018
Language eng
Abstract 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.
Formatted abstract
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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Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
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