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models, in which models for the event-time distribution and longitudinal
data depend on a common set of latent random effects
[43]
.
aGVHD biomarkers: from the identification of
candidates to their validation
The paucity of validated biomarkers for GVHD is partly due to the complex
pathology of GVHD, which can be considered in the framework of distinct
sequential phases of immune system cellular activation and cytokine pro-
duction, which are expected to influence specific cellular and protein levels in
the blood of GVHD patients
[44]
. GVHD is not only a systemic immunological
disorder but also affects specific organ systems, including the skin, GI tract,
and liver. Below, we review systemic and target-specific aGVHD biomarkers,
their diagnostic and prognostic values, and whether they were identified
using the pathology of aGVHD or via a proteomics discovery approach. If the
workflow did not include proteomics discovery, only studies with a sample
size larger than 40 patients were reviewed.
Table 19.1A
summarizes these
studies. The reader should keep in mind that studies with small sample sizes
preclude the performance of any relevant statistical analyses of protein sig-
nificance and biomarker validation, meaning that additional studies must
be performed to validate the findings from small-size studies. Details about
important findings are described in the following paragraphs.
460
Biomarkers identified using the pathology of aGVHD:
systemic biomarkers of aGVHD
Because of the long-recognized “cytokine storm” that occurs early after
donor graft infusion, cytokines and their receptors have been tested as
potential aGVHD biomarkers (reviewed in
[45]
). Noteworthy biomarkers
that emerged from these studies are summarized below. Soluble interleukin
(IL)-2 receptor α chain (sIL-2Rα) concentrations were found to be increased
in aGVHD patients in many studies
[46-50]
. In two studies, concentrations of
IL-18 were closely correlated with IL-2Rα
[49]
. A correlation between sIL-2Rα
and syndecan-1 concentrations was also observed
[48]
. IL-2Rα concentra-
tions were correlated with GVHD severity
[49]
. However, some of these stud-
ies found that sIL-2Rα concentrations were also increased in patients with
other transplantation-related complications, such as veno-occlusive dis-
ease and sepsis
[46]
. Similarly, TNF-α and its receptors, particularly TNFR1,
were implicated in the pathology of aGVHD; their concentrations were ele-
vated in aGVHD patients compared to patients without GVHD
[42,51-54]
.
The same precautions used to evaluate sIL-2Rα concerning its elevation in
other transplant-related complications (TRC) should be applied to TNF-α
and TNFR1. The roles of TNF-α/TNFR1 and IL-2/IL-2Rα in aGVHD patho-
genesis are supported by evidence that suggests that antibodies directed
against TNF-α or TNFR1, or IL-2/IL-2Rα, are effective therapies for steroid-
refractory aGVHD (reviewed in
[55]
). C-reactive protein (CRP), a nonspecific
inflammatory protein, was found to be increased in patients with GVHD as
well as was IL-6, the main cytokine that induces the release of CRP
[53,56-58]
.
Concentrations of IL-8 were clearly correlated with aGVHD in one study
by Uguccioni et al.
[59]
. However, Schots et al. showed that IL-8 (as well as
IL-6 and TNF-α) were released in response to all types of TRC, rather than
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