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to disease. Regardless of the source of TNF-α, its importance in GVHD is
borne out with the demonstration that treatment of steroid-resistant GVHD
with a TNF-α blocker has shown efficacy, especially against gastrointestinal
disease, in some studies
[94-96]
or when administrated for GVHD prophy-
laxis
[97]
. Although preliminary clinical studies also suggested that an anti-
TNF-α antibody (Etanercept) in addition to steroids was superior to steroids
alone as initial treatment for acute GVHD
[96]
, a recent multicenter four-
arm BMT-CTN randomized trial designed to identify the most promising
agent(s) for initial therapy for AGVHD indicated that Etanercept was not the
most effective agent to be combined with steroids for GVHD therapy
[98]
.
Promise from molecular biology and proteomics?
New molecular tools including proteomic and gene profiling (reviewed in
chapters 19 and 21) have already begun to pave the way for such a response,
allowing for a more precise definition of acute GVHD or the construction
of a predictive model for acute GVHD severity both in humans and in the
experimental setting. In this regard, a recent paper measured the gene-
expression profiles of CD4
+
and CD8
+
T cells from 50 donors with microarray
technology. Using quantitative PCR, established statistical tests, and analy-
sis of multiple independent training-test datasets, Perreault and colleagues
found that “dangerous donor” trait (occurrence of GVHD in the recipient) is
under polygenic control and is shaped by the activity of genes that regulate
transforming growth factor-beta signaling and cell proliferation
[99]
. These
findings strongly suggest that the donor gene-expression profile can have
a dominant influence on the occurrence of chronic GVHD in the recipient.
However, it should be stressed that currently no gene-expression profiling
data are available on acute GVHD. The application of proteomic tools that
allows screening for differentially expressed or excreted proteins in body
fluids has generated considerable interest in the field. Using proteomics,
authors have screened for plasma proteins specific for GVHD. Paczesny
et al.
[100]
aimed to isolate candidate proteins using high throughput assays
on a large number of patient samples, and to determine their significance
with respect to patient outcome (reviewed in chapter 19).
11
The graft-versus-leukemia effect
The graft-versus-leukemia (GVL) reaction refers to the ability of donor
immune cells to eliminate host leukemic cells after allogeneic HSCT. In 1956,
Barnes et al. were the first to report cure of leukemia in mice after total body
irradiation and HSCT. Key insights into its mechanisms were reported in a
landmark study from the International Bone Marrow Transplant Registry in
1990
[101]
. Strikingly, the latter study, that was based on data from over 2000
subjects, showed that GVL was abrogated if T cells were depleted from the
graft or if the HSCT donor was an identical twin. On the basis of these data, it
was therefore inferred that GVL depended on donor T cells and on the exis-
tence of histocompatibility differences between the donor and its recipient
(reviewed in reference
[102]
).
The GVL effect has been extensively reviewed elsewhere
[102-104]
and almost
every chapter in this topic aims to review the relative contribution of the dif-
ferent cell subsets implicated in its genesis. Although the evidence for a GVL
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