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numbers in GI biopsies of patients with acute gastrointestinal GVHD and,
in particular, a diminished ratio of Treg to Tconv
[144,145]
. In contrast,
other groups found normal Treg levels in gastric biopsies of GVHD patients
[135]
or even increased Treg in acute and chronic GI GVHD compared to
transplant recipients without GVHD, but diminished Th17 cells
[146]
.
Overall, these conflicting findings illustrate the difficulty in interpreting
immune monitoring data. The various trials applied different immune moni-
toring techniques, a fact that impedes comparisons between transplantation
centers. Furthermore, center-specific effects such as patient age and selec-
tion, underlying disease, conditioning intensity, GVHD prophylaxis and treat-
ment, and the occurrence and therapy of opportunistic infections may all
influence the outcome of immune monitoring trials. Most importantly, how-
ever, diminished Treg numbers or altered Treg ratios may simply be a surro-
gate marker of GVHD, not an explanation of GVHD pathophysiology. It is well
known that GVHD impairs the reconstitution of the lymphoid compartment
and alterations in Treg numbers may thus primarily be a consequence of dis-
turbed Treg regeneration in ongoing GVHD, but not the cause of aggravated
GVHD. Matsuoka and colleagues
[140]
showed that Treg preferentially pro-
liferate after SCT, but such proliferating Treg are prone to Fas-mediated
apoptosis thus causing Treg exhaustion. Thymic regeneration of Treg in
patients with prolonged lymphopenia (measured at 6 months after SCT)
was impaired and correlated with an increased incidence of chronic GVHD
in this prospective study. Although the authors mainly conclude that lym-
phopenia determines Treg homeostasis after SCT, their findings also suggest
that lymphopenia is an indicator of subclinical GVHD that affects (among
other organs) the thymus and impairs Tconv and Treg cell regeneration.
In this case, disturbed thymic function may promote the development of
autoreactive Tconv (recognizing even nonpolymorphic donor/recipient
peptides) and impair peripheral tolerance to self- and/or alloantigens by
the inability to regenerate the Treg compartment. In clinical immune moni-
toring studies, however, the composition of the Treg compartment with
respect to regenerated versus cotransplanted Treg cannot be differentiated.
258
Adoptive Treg transfer
The encouraging findings from animal models concerning the protective
effect of cotransplanted donor Treg on the development of GVHD led to the
initiation of the first clinical trials. At the University of Minnesota, Treg cells
were isolated from third-party cord blood units using anti-CD25-labeled
magnetic beads and then expanded
in vitro.
The generated cell products
contained on average 64% FOXP3
+
Treg (range 31-96%) and were trans-
fused to 23 patients receiving double cord blood transplantation (CBT). The
cells were given at the time of CBT in a dose escalation trial (1 × 10
5
to 3 ×
10
6
/kg body wt) and 13 patients received additional Treg around the time of
engraftment (day 15; 3 × 10
6
/kg body wt) that were previously cryopreserved
from the same Treg culture. No infusion-related toxicities were observed in
this phase I feasibility trial. As expected, the efficacy of Treg cells in the pre-
vention of GVHD could not be examined as standard GVHD prophylaxis
with cyclosporin A/mycophenolate mofetil or sirolimus/mycophenolate
mofetil was coadministered. A slight and transient increase in Treg was
observed at day 2 after Treg infusion, suggesting that the
in vitro
-expanded
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