Table 1.

Candidate aGVHD biomarkers based on aGVHD’s pathology.

Protein	Studies	Biofluid Sources	No. of patients in studies	Function(s)	Role in aGVHD
Soluble factors
Albumin	Rezvani 2011124	Serum	401	Comprises about one-half of the blood serum proteins; functions to regulate oncotic pressure and to carry proteins.	Decreased serum concentration before transplantation and up until treatment is associated with development of grade III/IV aGVHD and increased mortality.
α4β7 Integrin	Chen 2009119	Blood	59	Lymphocyte-trafficking to the intestines and lymph nodes.	Increased expression on naïve and memory T cells prior to intestinal aGVHD.
Angiopoietin-2	Luft 2011123	Serum	48	Promotes maturation of blood vessels and pro-inflammatory cytokine activity.	High Angiopoietin-2 levels and Angiopoietin-2/VEGF ratios prior to HSCT are associated with refractory aGVHD.
Calprotectin	Rodriguez-Otero 201249	Feces	72	Fecal marker of leukocyte influx into intestinal mucosa.	Increased levels at the time of GI-GVHD diagnosis are predictive of treatment responsiveness.
	Chiusolo 201250		68
CD8	August 2011102	Plasma	61	Class I MHC TCR co-receptor.	Elevated levels on day 15 post-transplantation are associated with severe aGVHD.
CRP	Schots 2002110	Serum, plasma	96	Acute phase reactant.	CRP levels reflect the risk of transplant-related mortality and major transplant-related complications.
	Pihusch 2006108		350
	Malone 2007109		147
CXCL10	Piper 2007117	Serum	34	Ligand of CXCR3 on T cells.	Significant elevation at the time of aGVHD diagnosis.
HGF	Okamoto 2001120	Serum	38	Mitogen for hepatocytes; enhances liver repair and regeneration.	HGF is increased in patients with aGVHD and correlates to the grade of aGVHD. Predictive of 1-year non-relapse mortality and treatment unresponsiveness.
	Harris 2012126
IL-2Rα	Miyamoto 199699	Serum, plasma	30	Soluble form released after IL-2R expression; presence is an indication of T cell proliferation.	Early post-transplantation levels are high prior to clinical signs of aGVHD.
	Foley 1998100		36
	Seidel 200398		60
	Visentainer 200396		13
	Shaiegan 200697		67
	August 2011102		62
IL-6	Mohty 2005112	Serum	113	B cell maturation; pleiotropic cytokine during inflammation.	Elevated at the onset of aGVHD.
	Pihusch 2006108		350
	Malone 2007109		147
IL-7	Dean 2008116	Serum, plasma	31	Homeostatic proliferation of lymphocytes.	Levels increase significantly post-transplantation with an inverse correlation to absolute T-cell count.
	Thiant 2010115		40
	Thiant 2011114		45
IL-8	Uguccioni 1993111	Serum	30	Neutrophil chemotaxis and adhesion; angiogenesis promoter.	Early increase post-transplantation is associated with increased mortality. Some studies show no difference between aGVHD and other complications.
	Schots 2003103		84
	Mohty 2005112		113
IL-10	Visentainer 200396	Serum	13	Inhibits Th1 cells; promotes regulatory T cells.	Levels increase transiently following HSCT.
IL-12	Mohty 2005112	Serum	113	Maturation of Th1 cells.	Associated with grade II to IV aGVHD development after receiving reduced intensity conditioning.
IL-18	Fujimori 2002101	Serum	14	Stimulates release of IFN-γ.	Correlates with the levels of IL-2Rα.
	Shaiegan 200697		67
KRT18	Luft 2007121	Serum	55	Intermediate filament cleaved during apoptosis.	Increased levels during hepatic and intestinal aGVHD. Increased levels correlate to treatment unresponsiveness.
	Luft 2011123		48
	Harris 2012126		954
TNFα / TNFR1	Holler 1990104	Serum, Plasma	56	Key cytokine involved in the cytokine storm after HSCT.	Elevation early post-transplantation is associated with severe aGVHD and treatment-related mortality. Increased levels during period of clinical symptoms.
	Abdallah 1997105		80
	Schots 2003103		84
	Mohty 2005112		113
	Choi 2008106		438
	August 2011102		62
TGFβ	Visentainer 200396	Serum	13	Tissue regeneration.	Decreased levels after transplantation are associated with aGVHD.
VEGF	Luft 2011123	Serum	48	Stimulates angiogenesis.	High Angiopoietin-2/VEGF ratios prior to HSCT are associated with refractory aGVHD.
miRNAs
miR-100	Leonhardt 201323	Intestinal Tissue	12	Blocks intestinal neovascularization.	Expression is down-regulated throughout the progression of aGVHD.
miR-155	Ranganathan 201222	Intestinal Tissue	8	Crucial for lymphocyte differentiation, maturation, and proliferation.	Up-regulated in T cells following HSCT. Preventing expression decreases aGVHD severity and increases survival.
Cellular Biomarkers
CD30	Hubel 201031	Serum, Plasma, Blood	30	Expressed on activated memory T cells.	Increased plasma levels and expression on T cells during aGVHD. Increased levels are associated with the severity of aGVHD.
	Chen 201230		53
Dendritic Cells	Lau 200735	Blood	40	Antigen-presenting cells; connection between innate and acquired immunity.	Decreased total blood DC count is associated with severity and development of aGVHD.
	Ahktari 201034		25
Invariant Natural Killer T cells	Chaidos 201232	Donor Grafts, Recipient Blood	57	Respond to glycolipids presented by the polymorphic class I-like molecule CD1d.	Increased iNKT/T cell ratio is associated with the occurrence of aGVHD and increased non-relapse mortality.
	Rubio 201233		71
Regulatory T cells	Rezvani 200627	Blood, Donor Grafts	32	Maintenance of immune tolerance.	Promotes immune reconstitution after HSCT and increased levels prevent aGVHD. Prognostic indicator after diagnosis. Levels are inversely correlated with the severity of aGVHD.
	Wolf 200728		58
	Magenau 201029		215
	Koreth 201124		23
	Di Ianni 201126		28
	Matsuoka 201325		45

^*VEGF= Vascular Endothelial Growth Factor, TGF= Tumor Growth Factor, CTL = Cytotoxic T Lymphocytes