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Recombinant T cell receptor molecules can prevent and reverse experimental autoimmune encephalomyelitis dose effects and involvement of both CD4 and CD8 T cells

Recombinant T cell receptor molecules can prevent and reverse experimental autoimmune encephalomyelitis dose effects and involvement of both CD4 and CD8 T cells
Recombinant T cell receptor molecules can prevent and reverse experimental autoimmune encephalomyelitis dose effects and involvement of both CD4 and CD8 T cells

Autoimmune diseases are often characterized by spontaneous remission followed by relapses. Although the mechanism(s) controlling pathogenic self-reactive T cells are not fully understood, recent data in experimental autoimmune encephalomyelitis (EAE), a prototype for CD4 T cell-mediated autoimmune diseases, indicate that spontaneous recovery is mediated by regulatory T cells (Treg) specific for peptides derived from the β-chain of the TCR. Here we have tested whether recombinant single-chain TCRs (scTCRs) containing Vβ domains can be used as vaccines for efficient priming of Treg. A single injection of mice with these recombinant proteins leads to efficient in vivo priming of Treg and almost complete protection from Ag-induced EAE. Significantly, administration of scTCRs during ongoing disease at a 10-fold lower dose than that required for prophylactic treatment also reverses established EAE. However, if a higher dose of scTCR is administered during ongoing disease, paralytic symptoms become exacerbated and the majority of treated animals die from severe and chronic EAE. Furthermore, we demonstrate that regulatory determinants are processed and presented from scTCRs resulting in the recruitment of both CD4 and CD8 regulatory T cells which are required for efficient regulation induced by scTCR. Reversal of established disease following an optimum dose of recombinant TCRs suggests that proteins expressing appropriate Vβ domains could be used for the treatment of a variety of T cell-mediated pathologic conditions.

0022-1767
5150-5156
Kumar, Vipin
492e5247-f499-42a8-80ec-b5ed3487a7c2
Coulsell, Eric
4bb17e28-b05b-4895-8423-dc2c2e46af98
Ober, Bertram
fdc0003e-6a7a-4894-bd4a-32d9d27f7c93
Hubbard, Greg
f3de9504-a984-4652-beb9-0df75b7d5387
Sercarz, Eli
614be174-8001-4b60-98b7-fe62a70fa7ac
Ward, E. Sally
b31c0877-8abe-485f-b800-244a9d3cd6cc
Kumar, Vipin
492e5247-f499-42a8-80ec-b5ed3487a7c2
Coulsell, Eric
4bb17e28-b05b-4895-8423-dc2c2e46af98
Ober, Bertram
fdc0003e-6a7a-4894-bd4a-32d9d27f7c93
Hubbard, Greg
f3de9504-a984-4652-beb9-0df75b7d5387
Sercarz, Eli
614be174-8001-4b60-98b7-fe62a70fa7ac
Ward, E. Sally
b31c0877-8abe-485f-b800-244a9d3cd6cc

Kumar, Vipin, Coulsell, Eric, Ober, Bertram, Hubbard, Greg, Sercarz, Eli and Ward, E. Sally (1997) Recombinant T cell receptor molecules can prevent and reverse experimental autoimmune encephalomyelitis dose effects and involvement of both CD4 and CD8 T cells. The Journal of Immunology, 159 (10), 5150-5156.

Record type: Article

Abstract

Autoimmune diseases are often characterized by spontaneous remission followed by relapses. Although the mechanism(s) controlling pathogenic self-reactive T cells are not fully understood, recent data in experimental autoimmune encephalomyelitis (EAE), a prototype for CD4 T cell-mediated autoimmune diseases, indicate that spontaneous recovery is mediated by regulatory T cells (Treg) specific for peptides derived from the β-chain of the TCR. Here we have tested whether recombinant single-chain TCRs (scTCRs) containing Vβ domains can be used as vaccines for efficient priming of Treg. A single injection of mice with these recombinant proteins leads to efficient in vivo priming of Treg and almost complete protection from Ag-induced EAE. Significantly, administration of scTCRs during ongoing disease at a 10-fold lower dose than that required for prophylactic treatment also reverses established EAE. However, if a higher dose of scTCR is administered during ongoing disease, paralytic symptoms become exacerbated and the majority of treated animals die from severe and chronic EAE. Furthermore, we demonstrate that regulatory determinants are processed and presented from scTCRs resulting in the recruitment of both CD4 and CD8 regulatory T cells which are required for efficient regulation induced by scTCR. Reversal of established disease following an optimum dose of recombinant TCRs suggests that proteins expressing appropriate Vβ domains could be used for the treatment of a variety of T cell-mediated pathologic conditions.

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Published date: 15 November 1997

Identifiers

Local EPrints ID: 425118
URI: https://eprints.soton.ac.uk/id/eprint/425118
ISSN: 0022-1767
PURE UUID: 2af5088c-2d9a-4620-92d0-96451d478e01
ORCID for E. Sally Ward: ORCID iD orcid.org/0000-0003-3232-7238

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Date deposited: 11 Oct 2018 16:30
Last modified: 22 May 2019 00:21

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Contributors

Author: Vipin Kumar
Author: Eric Coulsell
Author: Bertram Ober
Author: Greg Hubbard
Author: Eli Sercarz
Author: E. Sally Ward ORCID iD

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