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DNA fusion vaccines induce targeted epitope-specific CTLs against minor histocompatibility antigens from a normal or tolerized repertoire

DNA fusion vaccines induce targeted epitope-specific CTLs against minor histocompatibility antigens from a normal or tolerized repertoire
DNA fusion vaccines induce targeted epitope-specific CTLs against minor histocompatibility antigens from a normal or tolerized repertoire
We have designed DNA fusion vaccines able to induce high levels of epitope-specific CD8+ T cells, using linked CD4+ T cell help. Such vaccines can activate effective immunity against tumor Ags. To model performance against minor histocompatibility (H) Ags important in allogeneic hemopoietic stem cell transplantation, responses against the H2Db-restricted Uty and Smcy male HY epitopes have been investigated.
Vaccination of females induced high levels of tetramer-specific, IFN-{gamma}-producing CD8+ T cells against each epitope. Vaccines incorporating a single epitope primed effector CTL able to kill male splenocytes in vitro and in vivo, and HYDbUty-specific vaccination accelerated rejection of syngeneic male skin grafts. Priming against either epitope established long-term memory, expandable by injection of male cells. Expanded CD8+ T cells remained specific for the priming HY epitope, with responses to the second suppressed. To investigate vaccine performance in a tolerized repertoire, male mice were vaccinated with the fusion constructs. Strikingly, this also generated epitope-specific IFN-{gamma}-producing CD8+ T cells with cytotoxic function. However, numbers and avidity were lower than in vaccinated females, and vaccinated males failed to reject CFSE-labeled male splenocytes in vivo.
Nevertheless, these findings indicate that DNA fusion vaccines can mobilize CD8+ T cells against endogenous minor H Ags, even from a profoundly tolerized repertoire. In the transplantation setting, vaccination of donors could prime and expand specific T cells for in vivo transfer. For patients, vaccination could activate a potentially less tolerized repertoire against similar Ags that may be overexpressed by tumor cells, for focused immune attack.
0022-1767
4492-4499
Rice, Jason
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Buchan, Sarah
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Dewchand, Hamlata
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Simpson, Elizabeth
20315be3-48c3-41e9-a67a-cc8f5f7dbecc
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Rice, Jason
d58d4fcd-8dc0-4599-bf96-62323d579227
Buchan, Sarah
9ade187d-f127-45de-ad90-9d544d64718a
Dewchand, Hamlata
d6a3e6bf-fb5a-4fb0-80c0-55b815ab1d59
Simpson, Elizabeth
20315be3-48c3-41e9-a67a-cc8f5f7dbecc
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c

Rice, Jason, Buchan, Sarah, Dewchand, Hamlata, Simpson, Elizabeth and Stevenson, Freda K. (2004) DNA fusion vaccines induce targeted epitope-specific CTLs against minor histocompatibility antigens from a normal or tolerized repertoire. Journal of Immunology, 173 (7), 4492-4499.

Record type: Article

Abstract

We have designed DNA fusion vaccines able to induce high levels of epitope-specific CD8+ T cells, using linked CD4+ T cell help. Such vaccines can activate effective immunity against tumor Ags. To model performance against minor histocompatibility (H) Ags important in allogeneic hemopoietic stem cell transplantation, responses against the H2Db-restricted Uty and Smcy male HY epitopes have been investigated.
Vaccination of females induced high levels of tetramer-specific, IFN-{gamma}-producing CD8+ T cells against each epitope. Vaccines incorporating a single epitope primed effector CTL able to kill male splenocytes in vitro and in vivo, and HYDbUty-specific vaccination accelerated rejection of syngeneic male skin grafts. Priming against either epitope established long-term memory, expandable by injection of male cells. Expanded CD8+ T cells remained specific for the priming HY epitope, with responses to the second suppressed. To investigate vaccine performance in a tolerized repertoire, male mice were vaccinated with the fusion constructs. Strikingly, this also generated epitope-specific IFN-{gamma}-producing CD8+ T cells with cytotoxic function. However, numbers and avidity were lower than in vaccinated females, and vaccinated males failed to reject CFSE-labeled male splenocytes in vivo.
Nevertheless, these findings indicate that DNA fusion vaccines can mobilize CD8+ T cells against endogenous minor H Ags, even from a profoundly tolerized repertoire. In the transplantation setting, vaccination of donors could prime and expand specific T cells for in vivo transfer. For patients, vaccination could activate a potentially less tolerized repertoire against similar Ags that may be overexpressed by tumor cells, for focused immune attack.

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Published date: 1 October 2004

Identifiers

Local EPrints ID: 26571
URI: http://eprints.soton.ac.uk/id/eprint/26571
ISSN: 0022-1767
PURE UUID: dd34ae73-bef1-4aaa-a25f-f5a382df2234
ORCID for Freda K. Stevenson: ORCID iD orcid.org/0000-0002-0933-5021

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Date deposited: 20 Apr 2006
Last modified: 16 Mar 2024 02:54

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Contributors

Author: Jason Rice
Author: Sarah Buchan
Author: Hamlata Dewchand
Author: Elizabeth Simpson

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