The University of Southampton
University of Southampton Institutional Repository

DNA fusion vaccines induce epitope-specific cytotoxic CD8(+) T cells against human leukemia-associated minor histocompatibility antigens

DNA fusion vaccines induce epitope-specific cytotoxic CD8(+) T cells against human leukemia-associated minor histocompatibility antigens
DNA fusion vaccines induce epitope-specific cytotoxic CD8(+) T cells against human leukemia-associated minor histocompatibility antigens
The graft-versus-leukemia effect of allogeneic stem-cell transplantation is believed to be mediated by T-cell recognition of minor histocompatibility antigens on recipient cells. For minor histocompatibility antigens HA-1 and HA-2, normal cell expression is restricted to hemopoietic cells, and boosting the immune response to these antigens may potentiate graft-versus-leukemia effect without accompanying graft-versus-host disease. To increase efficacy, expansion of HA-1- or HA-2-specific CTL before transplantation is desirable. However, primary HA-1- or HA-2-specific CTL expanded in vitro are often of low avidity. An alternative approach is to prime specific CTL responses in vivo by vaccination. Clearly, donor vaccination must be safe and specific. We have developed DNA fusion vaccines able to induce high levels of epitope-specific CTL using linked CD4(+) T-cell help. The vaccines incorporate a domain of tetanus toxin (DOM) fused to a sequence encoding a candidate MHC class I binding peptide. This design generates antitumor CD8(+) T-cell responses and protective immunity in preclinical models. For clinical application, we constructed vaccines encoding HLA-A*0201-restricted peptides from human HA-1 and HA-2, which were fused to DOM, and tested their performance in HLA-A*0201-transgenic mice. Priming induced epitope-specific, IFNgamma-producing CD8(+) T cells with cytotoxic function boosted to high levels with electroporation. Strikingly, these mouse T cells efficiently killed human lymphoblastoid cell lines expressing endogenous HA-1 or HA-2. High avidity is indicated by the independence of cytolysis from CD8/MHC class I interaction. These safe epitope-specific vaccines offer a potential strategy to prime HA-1- or HA-2-specific CTL in transplant donors before adoptive transfer.
0008-5472
5436-5442
Rice, Jason
d58d4fcd-8dc0-4599-bf96-62323d579227
Dunn, Stuart
e6fd3eb2-4487-45ed-b9d7-948febd5b7ea
Piper, Karen
9e8b2383-59f5-42ac-8291-c8411df68713
Buchan, Sarah L.
9ade187d-f127-45de-ad90-9d544d64718a
Moss, Paul A.
a4623127-aaa7-4e69-b236-b75b70528bba
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Rice, Jason
d58d4fcd-8dc0-4599-bf96-62323d579227
Dunn, Stuart
e6fd3eb2-4487-45ed-b9d7-948febd5b7ea
Piper, Karen
9e8b2383-59f5-42ac-8291-c8411df68713
Buchan, Sarah L.
9ade187d-f127-45de-ad90-9d544d64718a
Moss, Paul A.
a4623127-aaa7-4e69-b236-b75b70528bba
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c

Rice, Jason, Dunn, Stuart, Piper, Karen, Buchan, Sarah L., Moss, Paul A. and Stevenson, Freda K. (2006) DNA fusion vaccines induce epitope-specific cytotoxic CD8(+) T cells against human leukemia-associated minor histocompatibility antigens. Cancer Research, 66 (10), 5436-5442. (doi:10.1158/0008-5472.CAN-05-3130).

Record type: Article

Abstract

The graft-versus-leukemia effect of allogeneic stem-cell transplantation is believed to be mediated by T-cell recognition of minor histocompatibility antigens on recipient cells. For minor histocompatibility antigens HA-1 and HA-2, normal cell expression is restricted to hemopoietic cells, and boosting the immune response to these antigens may potentiate graft-versus-leukemia effect without accompanying graft-versus-host disease. To increase efficacy, expansion of HA-1- or HA-2-specific CTL before transplantation is desirable. However, primary HA-1- or HA-2-specific CTL expanded in vitro are often of low avidity. An alternative approach is to prime specific CTL responses in vivo by vaccination. Clearly, donor vaccination must be safe and specific. We have developed DNA fusion vaccines able to induce high levels of epitope-specific CTL using linked CD4(+) T-cell help. The vaccines incorporate a domain of tetanus toxin (DOM) fused to a sequence encoding a candidate MHC class I binding peptide. This design generates antitumor CD8(+) T-cell responses and protective immunity in preclinical models. For clinical application, we constructed vaccines encoding HLA-A*0201-restricted peptides from human HA-1 and HA-2, which were fused to DOM, and tested their performance in HLA-A*0201-transgenic mice. Priming induced epitope-specific, IFNgamma-producing CD8(+) T cells with cytotoxic function boosted to high levels with electroporation. Strikingly, these mouse T cells efficiently killed human lymphoblastoid cell lines expressing endogenous HA-1 or HA-2. High avidity is indicated by the independence of cytolysis from CD8/MHC class I interaction. These safe epitope-specific vaccines offer a potential strategy to prime HA-1- or HA-2-specific CTL in transplant donors before adoptive transfer.

Text
5436.pdf - Version of Record
Restricted to Repository staff only
Request a copy

More information

Published date: 15 May 2006

Identifiers

Local EPrints ID: 44615
URI: http://eprints.soton.ac.uk/id/eprint/44615
ISSN: 0008-5472
PURE UUID: bf3a536b-3099-4a1d-b0ba-5ffbd3d7511f
ORCID for Freda K. Stevenson: ORCID iD orcid.org/0000-0002-0933-5021

Catalogue record

Date deposited: 06 Mar 2007
Last modified: 20 Jul 2019 01:16

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×