Biology Reference
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Since adoptive transfer of allogeneic T-cells has been associated with acute
graft-versus-host disease (GVHD), a life-threatening complication initiated by the
donor alloreactive T-cells against the normal host tissues, alternative approaches
have been attempted to reduce the risk of GVHD while maintaining the benefi-
cial aspects of this treatment modality. One scenario was to use allogeneic T-cells
genetically-engineered to express the herpes simplex virus thymidine kinase (HS-
VTK) suicide gene that would lead to the depletion of the gene-modified T-cells
following treatment with the drug ganciclovir if GVHD arises [1]. This strategy
gave promising results in a number of clinical studies [2,3]. In a second approach,
in vitro enriched antigen-specific T-cells were used instead of total allogeneic T-
cell populations to mount antiviral or antitumour responses. Donor-derived cyto-
megalovirus (CMV)-specific cytotoxic T lymphocyte (CTL) clones were success-
fully used to treat patients suffering from CMV viral infection following marrow
transplants [4]. Similarly, infusion of Epstein-Barr virus (EBV)-specific CTLs was
used to prevent and to treat EBV lymphoma in immuno-compromised patients
post BMT [5]. Interestingly, more recent approaches in cancer immunotherapy
investigated the use of T-cells primed in vitro against minor histocompatibility
antigens [6], or against tumor associated antigens [7,8].
Moreover, autologous T-cells genetically engineered to express antiviral trans-
genes have been used for the treatment of HIV [9,10]. Similar studies investigated
the use of autologous T-cells engineered to express anti-inflammatory cytokines
for the treatment of autoimmune diseases [11,12]. The success of these approaches
is dependent on the stable transfer of the therapeutic gene into all infused T-cells
and its subsequent expression upon T-cell activation. On the other hand, success-
ful use of antigen-specific T-cells is dependent upon their rapid in vitro selection
and enrichment. Therefore, stable and selective expression of a gene marker in
activated antigen-specific T-cells would improve their therapeutic utility.
Integrating retroviral vectors have been successfully used for stable expression
of transgenes in T-cells [2,10,13]. Recently, the development of new retroviral
pseudotypes and improved transduction protocols have made it possible to gene
modify T-cells with high efficiency [14]. Furthermore, it was documented that
the level of transgene expression can vary with the activation status of T-cells
[15]. In fact, it has long been known that the enhancer machinery within the
retroviral long terminal repeat (LTR) such as that of Moloney murine leukemia
virus (MoMLV) incorporates elements that confer transcriptional preference to
activated T-cells [16,17]. However, LTR-driven transgene expression is neither
exclusive to the activated subset of gene-modified T-cells nor does it guarantee
that all activated transduced T-cells express the transgene if the vector integrates
in a transcriptionaly silent chromosomal background [18-20].
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