Proteomics in graft-versushost disease and graftversus-leukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 456

Table 19.1A Candidate Acute GVHD Biomarkers with Diagnostic and Prognostic Significance Identified Based
on GVHD Pathology—cont'd

No. of
Patients
in Study

Biofluid
Source Method

Target
Organ Protein Reference Diagnosis Prognosis Predictive

Synde-
can-1

[48] Serum ELISA 60 Systemic Yes ND No

TNF- α [52] Serum ELISA 56 Systemic Yes but also

increased in
other com-
plications

ND Yes

[51] Plasma ELISA 80 Systemic No ND ND

[53] Serum ELISA 84 Systemic Yes but also

increased in
other com-
plications

Yes Yes

TNFR1 [42] Plasma ELISA 438 Systemic No ND Yes

[95] Plasma ELISA 82 (chil-

dren)

Systemic No ND Yes

462

[54] Plasma ELISA 62 Systemic ND ND Yes

Tryptophan
metabo-
lites

[67] Urine LC-MS 51 Systemic Yes Yes ND

ND, not done; TRC, transplant-related complications.
*Validation sets.

specifically in cases of aGVHD [53] . Similarly, increases in IL-8 and other
cytokines (e.g., IL-6, IL-10, and IL-18) as aGVHD diagnoses were not con-
firmed in a study that included only patients receiving a reduced-intensity
conditioning regimen [60] . However, this same study found IL-12 to be
elevated in association with aGVHD development [60] . Chemokines and
chemokine receptors that were also implicated in the pathology of GVHD,
particularly in the migration of immune cells from lymphoid organs to tar-
get organs, were also found to be elevated in patients with aGVHD [61,62] .

Hepatocyte growth factor (HGF) is a multifunctional cytokine that is secreted
by mesenchymal cells and acts primarily on cells of epithelial origin. Oka-
moto et al. [63] observed increased serum HGF concentrations in patients
who developed aGVHD compared to patients who did not develop the dis-
ease; these authors also found that these increased HGF concentrations
correlated significantly with the severity of aGVHD. HGF appears to belong
to a different category of biomarkers, representing a physiologic response
to GVHD damage. In this respect, HGF seems similar to cytokeratin-18 frag-
ments (KRT18), markers of epithelial apoptosis that have been associated
with intestinal and hepatic GVHD damage [64] . However, HGF possesses
antiapoptotic properties and acts as a mitogen for hepatocytes, enhanc-
ing liver repair and regeneration; HGF administration has been shown to
prevent aGVHD in a murine model [65] . HGF therefore not only appears to
indicate the extent of target organ damage from GVHD, but may also reflect
the physiologic response intended to limit further damage from GVHD.