Biology Reference
In-Depth Information
may contribute to delayed B-cell reconstitution, persistent elevation in
the BAFF/B-cell ratio, and survival of activated allo- and autoreactive B
cells. Recently, however, examination of bone marrow biopsies 30 days
following ASCT has demonstrated a significant increase in bone marrow
B-cell precursors in patients who do not develop cGVHD [92] . Although
the cGVHD patients in this study also had a history of aGVHD, which may
be responsible for this difference, BAFF is not necessary for survival of
this precursor B-cell population. This suggests that while BAFF elevation
may be necessary for the survival of these B cells once they leave the bone
marrow, it may not be primarily responsible for the alteration in B-cell
reconstitution seen in cGVHD. BAFF is also produced by myeloid cells in
the setting of inflammation, and this may be another factor driving BAFF
production once B-cell numbers recover in patients with cGVHD. Inter-
estingly, high doses of corticosteroids have been shown to lower BAFF lev-
els, and this may represent one of the mechanisms by which these agents
lead to improvements in cGVHD. Targeting BAFF for the treatment of
cGVHD using the agents that have been developed and approved for the
treatment of autoimmune diseases is an attractive approach that warrants
further investigation.
308
Graft-versus-leukemia and graft-versus-tumor effects
of allogeneic transplantation
The inverse association between GVHD and disease relapse following trans-
plantation supports the notion of a GVL/GVT effect of ASCT [93-96] . When
over 2000 transplant patients with a history of acute leukemia or chronic
myelogenous leukemia (CML) were followed for disease relapse after ASCT,
the highest rates of relapse were seen with syngeneic twin grafts, followed
by T-cell-depleted grafts [93] . Recipients who did not develop cGVHD had
less disease relapse than these two cohorts but a higher rate of relapse
than patients who developed aGVHD, cGVHD, or both, with decreasing
rates of relapse in these three groups, respectively. That the rate of relapse
was lowest in patients who developed cGVHD, either with or without
prior aGVHD, suggested that the anti-tumor effect of GVHD was primarily
related to cGVHD. However, the rate of relapse was lower in patients with-
out a history of GVHD compared with syngeneic transplants, suggesting
that it was possible to achieve a GVL/GVT effect in the absence of clini-
cal GVHD. In patients with hematologic malignancies, this suggests that
GVL/GVT can result from specific anti-tumor immunity driven by unique
or mutated tumor antigens and by mHAs present on all host hematopoietic
cells. However, this response can also be directed against mHAs that are
widely expressed by host tissues, in which case GVHD would also result
( Figure 14.2 ). The failure of the original host immune system to mount
an immune attack against the tumor may reflect the fact that the tumor
developed in the context of that immune system, which had become tol-
erant to the tumor cells. Alternatively it can be the result of the immune-
suppressing effects of the tumor itself and its previous therapies. Given the
high morbidity and mortality associated with GVHD, there has been great
interest in understanding the mechanisms of both GVL/GVT and GVHD in
hopes of identifying important differences in their biology that can then be
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