Biology Reference
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Urine proteins and metabolites are also attractive and noninvasive
biomarkers for GVHD. In 2007, the Hanover group used capillary electro-
phoresis followed by mass spectroscopy to define a spectral signature spe-
cific to the urine of acute GVHD patients, with a sensitivity and specificity
of 83% and 75%, respectively
[7]
. Although, these “signature” approaches
have not yet identified GVHD-specific proteins, they suggest that a combi-
nation of biomarkers from minimally invasive sources (urine + blood) may
allow rapid diagnosis of acute GVHD with a high degree of accuracy. Indeed,
such diagnostic tests are certain to expand over the coming decade, so that
a majority of future GVHD diagnoses will be confirmed by less invasive
means, possibly supplanting the need for a traditional biopsy.
Beyond diagnosis, biomarkers might also predict the future severity of
GVHD. Such important information could risk-stratify patients at the time
of diagnosis and allow for optimal therapeutic approaches in individual-
ized patients. Both elafin and REG3α levels at the time of GVHD diagno-
sis predicted future nonrelapse mortality and levels of urinary tryptophan
metabolites also correlate with both severity of acute GVHD and response
to first-line therapy
[8]
. In BMT patients presenting with rash, a high elafin
level correlated with a 24% drop in overall survival (53% to 29%). Similarly,
high REG3α concentrations at the onset of biopsy-proven GI GVHD pre-
dicted:
[1]
response to therapy at 4 weeks,
[2]
1-year nonrelapse mortality,
and
[3]
1-year overall survival. Because of their prognostic utility, these bio-
markers are currently being incorporated into prospective treatment trials
for acute GVHD.
495
It is highly unlikely that any single biomarker will capture the entire risk
for an individual patient, and so the combination of several biomarkers
into a composite algorithm is much more likely to be effective. In ongo-
ing work, the combination of six biomarkers was able to predict both day
28 response to treatment and nonrelapse mortality 6 months later in 112
patients entered on a multicenter trial of GVHD treatment (published
online at
http://dx.doi.org/10.1182/blood-2012-01-403063
)
.
The best time to treat acute GVHD is early in the disease course. Biomark-
ers capable of predicting disease prior to the onset of symptoms would be
enormously valuable in assigning risk and calibrating the appropriate level
of initial therapy. The quest to identify such markers remains an area of
intense investigation and the current pace of discovery suggests that such
predictions will be possible within the near future.
The future of GVHD: treatment
The most successful treatment of acute GVHD remains corticosteroids, but
their use is associated with both increased morbidity and (indirect) mor-
tality. It is hoped that improved knowledge of basic transplantation biol-
ogy will soon result in more specifically targeted therapies. The current
paradigm of graft-versus-host pathophysiology proposes a multistep pro-
cess beginning with activation of host and donor antigen-presenting cells
(APCs) by the conditioning regimen and other factors. This stimulation is
followed by activation and migration of effector T cells, with resultant cyto-
kine release, inflammation, and tissue destruction in the skin, liver, and
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