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of soluble B-cell activating factor (sBAFF)
[81]
. The prolonged imbalance
of CD4
+
CD25
+
FOXP3
+
regulatory T cells versus conventional CD4
+
T cells
following HSCT has been associated with a loss of tolerance and significant
cGVHD manifestations
[82]
. In addition, it has been demonstrated that the
combination of sBAFF and three other proteins (i.e., anti-dsDNA, IL-2Rα,
and sCD13) was used to diagnose early extensive cGVHD with high specific-
ity and sensitivity in children
[79]
. This finding suggests that a similar panel
of proteins could be developed for the diagnosis of cGVHD in adults. All of
the current biomarkers of cGVHD have recently been reviewed
[83]
. In addi-
tion, the roles of BAFF and the balance of B-cell subsets during B-cell recon-
stitution as potential cGVHD biomarkers have been reviewed recently
[84]
.
However, no biomarkers for cGVHD have been validated in a large cohort.
Identification of GVL and minimal residual disease
(MRD) biomarkers
Reciprocal immune reactions between donor and recipient are a key feature
of allo-HSCT. In the majority of cases, donor T lymphocytes react against
both the patient's normal host cells, causing GVHD, and the patient's tumor
cells, leading to the GVL effect. Although the GVL effect is the most impor-
tant in the subset of allo-HSCT recipients with GVHD, the risk of disease
relapse is also reduced in patients without GVHD
[85]
. Thus, the funda-
mental question in the field is whether the mechanisms or effectors of GVL
differ from those of GVHD or whether GVL represents a subset of GVHD
reactions. The potency of the GVL effect is illustrated by the use of donor-
lymphocyte infusion (DLI) to treat patients with tumors such as leukemia,
lymphoma, and myeloma
[86]
. The recognition of the GVL effect is driving
the evolution of allo-HSCT toward an immunotherapeutic approach that
does not require toxic chemoradiotherapy for tumor eradication. Indeed,
both experimental models and human studies have shown that nonmy-
eloablative conditioning can sufficiently suppress recipient immunity to
allow allogeneic stem cell and immune cell reconstitution
[87]
. However,
the immunological mechanisms and target molecules that are required
for the elimination of malignant cells are only partly understood. Immune
cells that are implicated include CD8
+
and CD4
+
T cells, natural killer cells,
and dendritic cells. Target molecules of classical T cells include the minor
histocompatibility antigens (mHAs) and tumor-associated proteins overex-
pressed by tumors. These targets have been recently identified using labor-
intensive methods, including high-performance LC-MS, cDNA expression
cloning, genetic linkage analysis, and polymorphic-peptide screening
[88]
.
mHAs have either broad tissue expression (e.g., UGT2B17, HY, PANE1) or
expression restricted to hematopoietic cells (e.g., HA-1, HA-2, HB-1, CD19),
which is optimal for a GVL response without GVHD. This exclusive expres-
sion on leukemic cells and not on epithelial cells has been used by research-
ers to augment the GVL effect and to distinguish GVL from GVHD. Another
strategy is to use adoptive transfer of T cells that are specific for proteins
that are overexpressed by leukemic cells. Nonpolymorphic proteins such
as Wilms tumor 1, proteinase 3, survivin, telomerase reverse transcriptase,
CYPB1, and laminin have been investigated as targets for T cells, and several
trials are currently ongoing
[88]
.
469
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