Proteomics in graft-versushost disease and graftversus-leukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 457

Induction of indoleamine 2,3-dioxygenase, the rate-limiting enzyme in
tryptophan degradation along the kynurenine pathway, functions in a
potent immunoregulatory loop and was found to be involved in the pathol-
ogy of GVHD [66] . Recently, one group used LC-MS/MS to measure major
tryptophan metabolites, such as quinolinic acid and kynurenine, in serial
urine specimens from 51 patients and found that surviving patients had
significantly lower metabolite levels on days 28, 42, and 90 following HSCT
compared with patients dying of GVHD. Kynurenine levels directly corre-
lated with severity and clinical course of GVHD [67] . As mentioned above,
KRT18 has been the only target-specific marker of GVHD found that is
based on the pathology of GVHD [64] .

Few of these studies have looked at prognostic information, such as NRM,
primarily because of small sample size. An exception is the study from Luft
et al. [68] that measured KRT18 along with markers of endothelial dysfunc-
tion (e.g., angiopoietin-2, VEGF, and thrombomodulin) and found that ste-
roid-refractory GVHD patients were not exposed to an overwhelming T-cell
attack but to a progressive microangiopathy that led to organ failure. For the
same reason of small sample size, few of these studies looked at the predic-
tive value of these biomarkers. Studies measuring the kinetics of cytokine
concentrations during the first month post-HSCT showed that monitoring
IL-2Rα and TNFR1 concentrations during the engraftment period allows
for early detection of aGVHD. The mean serum IL-2Rα concentration
appears to increase during the second week, and the mean serum TNFR1
concentration increases during the first 2 weeks following transplantation
in patients with aGVHD [42,46,47,49,52,53] . August et al. [54] reported that
sIL-2R, sTNFR1, and sCD8 had high predictive values for aGVHD occur-
rence. Using these three markers, the authors demonstrated the feasibility
of detecting severe aGVHD prior to the appearance of clinical symptoms
[54] . Another important study by Rezvani et al. [69] found that a decrease
of 0.5 g/dl in serum albumin from the pretransplantation baseline level to
the onset of treatment for aGVHD predicted the subsequent development
of grade III/IV aGVHD and OS at 6 months after initiation of aGVHD treat-
ment in a cohort of 401 patients with aGVHD grades II-IV after reduced
intensity HSCT. Because the measurement of serum albumin concentra-
tion is inexpensive and readily available, the authors suggest incorporat-
ing albumin into the set of other validated biomarkers to further improve
prediction of aGVHD severity and mortality. These studies are summarized
in Table 19.1B .

463

Biomarkers identified using proteomics discovery

Only a few aGVHD biomarker studies have attempted to identify candidate
biomarkers using proteomics discovery; some studies have also validated
these markers in one or more independent sets. These studies are summa-
rized in Table 19.1B .

SYSTEMIC BIOMARKERS OF aGVHD

Four studies have identified the proteomic pattern of aGVHD using MS-
based approaches on small sample sizes without validation on indepen-
dent sets of patients; one group of investigators identified a pattern that