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Potential of allospecific gene-engineered T cells in transplantation gene therapy: specific T cell activation determines transgene expression in vitro and in vivo.

Abstract：

:T lymphocytes, regardless of their specificity, are considered key targets for genetic modification in the treatment of inherited or acquired human diseases. In this study, we generated Lewis T cell lines specific for Dark Agouti rat alloantigens and tested the potential of allospecific T lymphocytes as carriers of genes encoding therapeutic proteins in transplantation gene therapy. These allospecific T lymphocytes were successfully, stably transduced with enhanced green fluorescent protein (EGFP) by an Mo-MuLV-based retrovirus vector. A novel gene delivery protocol was utilized, resulting in nearly 100% EGFP-expressing T cells. This approach enabled tracking of allospecific transduced T cells in vivo and illustrates their transgene production by fluorometric determination after ex vivo isolation. Quantitation of EGFP transgene expression was used to determine the influence of T cell receptor-specific activation on transgene regulation. A strict positive correlation between activation state and expression level was detected in vitro and in vivo. The activation-induced increase in transgene expression could be blocked by interference with T cell activation signaling pathways by cyclosporin A, anti-CD4 MAb, or CTLA4-Ig. These data provide strong evidence that direct or indirect effects caused by activation-induced transcription factors are crucial in transgene upregulation. Allospecific activation in spleens, lymph nodes, and transplanted grafts can be considered as antigen-specific targeting strategy. This activation might be useful in expressing therapeutic proteins such as TGF-beta or IL-10 specific to these sites. T lymphocyte priming and activation might be prevented or altered by modification of the local microenvironments, thereby exerting a therapeutic influence on acute and chronic graft rejection processes.

journal_name

Hum Gene Ther

journal_title

Human gene therapy

authors

Hammer MH,Flügel A,Seifert M,Lehmann M,Brandt C,Volk HD,Ritter T

doi

10.1089/10430340050032401

keywords:

subject

Has Abstract

pub_date

2000-06-10 00:00:00

pages

1303-11

issue

eissn

1043-0342

issn

1557-7422

journal_volume

pub_type

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Potential of allospecific gene-engineered T cells in transplantation gene therapy: specific T cell activation determines transgene expression in vitro and in vivo.