By Gérard Socié, MD, PhD
2008-05-01
Dr. Socié indicated no relevant conflicts of interest.
Hori T, Naishiro Y, Sohma H, et al. CCL8 is a potential molecular candidate for the diagnosis of graft-versus-host disease. Blood. 2008. [Epub ahead of print]
Although graft-versus-host disease (GVHD) is a life-threatening
complication of hematopoietic stem cell transplantation (HSCT), its
current diagnosis mainly depends on clinical manifestations and
invasive biopsies. Early diagnosis of GVHD, preferably based on
unbiased laboratory screening tools, may increase the safety of
allogeneic HSCT and thus further broaden its application to even larger
patient populations. In the past, many efforts were made to use
single-protein biomarkers, which were specific for infection or
inflammation after allogeneic HSCT but not specific for acute GVHD.
Although some of these reports seem to hold promise, in many cases
there was a high probability that a single marker was not specific,
thus making differential diagnosis of similar diseases difficult. It is
reasonable to believe that the simultaneous monitoring of more than one
protein or peptide within a sample holds greater promise for the
differential diagnosis of diseases, including GVHD. Recently, the
application of proteomic tools allowing screening for differentially
expressed or excreted proteins in body fluids is becoming more
important.
Using proteomics, a Japanese group from Saporo screened for plasma
proteins specific for GVHD in a mouse model. One peak retained a
discriminatory value in two diagnostic groups (GVHD and normal
controls) with increased expression in the disease, decreased
expression during cyclosporine treatment, and was barely detectable in
syngeneic transplantation. Purification and mass analysis identified
this molecule as CCL8, a member of a large chemokine family. In human
samples, the serum concentration of CCL8 correlated closely with GVHD
severity. All non-GVHD samples contained less than 48 pg of CCL8 per
mL. In sharp contrast, CCL8 was highly up-regulated in GVHD sera.
Strikingly, two patients with severe fatal GVHD had extremely high
levels of CCL8. Thus, CCL8 seems to be a promising specific serum
marker for the early and accurate diagnosis of GVHD.
This study is of major importance for several reasons:
It confirms preliminary results reported by Weissinger and co-workers1 published in Blood
in which authors describe the application of capillary electrophoresis
coupled online with mass spectrometry to 13 samples from 10 patients
with acute GVHD of grade II or more and 50 control samples from 23
patients without GVHD. About 170 GVHD-specific polypeptides were
detected and as a result a tentatively acute GVHD-specific model
consisting of 31 polypeptides was chosen, allowing correct
classification of 13 of 13 acute GVHD samples and 49 of 50 control
samples in a training set. The subsequent blinded evaluation of 599
samples enabled diagnosis of acute GVHD greater than grade II, even
prior to clinical diagnosis, with a sensitivity of 83 percent and a
specificity of 76 percent.
The study by Hori and colleagues took advantage of a
murine model (in which many parameters could be controlled for) to set
up the search for specific markers that allows the characterization of
proteins following a huge amount of work that would not have been
easily feasible from human samples analyzed by Weissinger and
colleagues.1
CCL8 discovery makes the bridge even stronger between
chemokines and acute GVHD pathophysiology. Indeed, the migration of
cells from vascular to extra-vascular compartments implies a sequential
cascade of events, involving interplay between adhesion molecules and
chemokines. Acute GVHD requires that effector cells reach their target
tissues. Lymphocytes do not enter specific tissues because they
"recognize" a given antigen; they enter because they possess the
requisite combination of homing receptors and chemokine receptors to
engage the endothelium at the target tissue(s). Because GVHD is
relatively organ-specific — principally affecting the skin, gut, and
liver — our increasing knowledge of the pertinent adhesion molecules
and chemokines directing effector-cell trafficking to these sites
offers novel therapeutic approaches for prevention or treatment of
GVHD.
Finally, the use of proteomics opens the door to
exciting developments in the understanding of GVHD, the main one (at
least in my opinion) being to use this tool to, finally, try to
understand why and how some patients may develop a self-limited disease
with an accompanying graft-versus-leukemia effect while others will
develop a fatal steroid-resistant disease.
- Weissinger EM, Schiffer E, Hertenstein B, et al. Proteomic patterns predict acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Blood. 2007;109:5511-9.
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