Biology Reference
In-Depth Information
of this strategy are the reduced expansion rates of Treg in the presence of
rapamycin
[165]
and the risk that induced Treg may revert to effector T cells
in vivo.
Similarly, contaminating Tconv cells, masked under the pressure
of rapamycin in culture, may revert after transfusion. Nevertheless, the
expansion of Treg in rapamycin seems the easiest approach for Treg trials
in clinical situations in which comparably pure Treg products and high cell
numbers are required. The repetitive restimulation or the use of cellular
stimulators instead of artificial beads may improve the limited expansion
rate of Treg in the presence of rapamycin
[166]
.
A matter of ongoing discussions is the issue whether alloantigen-specific
Treg would be preferable to polyclonal Treg products
[167]
. In MHC-
mismatched BMT models, Treg primed by host hematopoietic cells provide
more efficient protection from GVHD compared to freshly isolated poly-
clonal Treg or Treg primed against third-party cells
[85,168]
. Since Treg gain
suppressive activity only after their own activation, it is not surprising that
prestimulated and antigen-selected Treg provide better protection in such
models. However, for clinical applications in HLA-matched SCT, such pre-
selection strategies may not necessarily be beneficial, as the preselection of
Treg using hematopoietic stimulator cells may primarily select for hema-
topoiesis-specific Treg, but not for tissue-restricted minor antigens that
drive GVHD. In this case, graft-versus-hematopoiesis effects would be sup-
pressed efficiently, but not preferentially GVHD. Of the vast range of poten-
tial minor antigens in SCT, only very few are thus far identified and it may
be a disadvantage to use such a limited set of defined antigens for
in vitro
priming. Interestingly, it has recently been shown that a broad TCR reper-
toire within donor Treg is required for the prevention of GVHD in a mouse
model and that the TCR repertoires of Treg populations differ between dis-
tinct target tissues and priming sites
[169]
. Based on these considerations,
we advocate the use of polyclonal Treg, at least in HLA-identical SCT, while
antigen-specific Treg would be preferable for the treatment of autoimmu-
nity or for tolerance induction after solid organ transplantation.
261
In vivo
expansion
As a conventional stem cell graft contains limited numbers of donor Treg,
it would be ideal to identify strategies that selectively promote Treg survival
and expansion
in vivo
while inhibiting the alloaggressive Tconv compart-
ment. Thus far, no exclusive Treg stimulation agent has been identified
and efforts to use CD28 superagonistic antibodies for the
in vivo
expan-
sion of Treg went terribly wrong, as these reagents caused a massive cyto-
kine release in healthy volunteers, although they seemed safe and specific
in preclinical models, even in nonhuman primates
[170]
. IL-2/anti-IL-2
complexes have been shown to increase Treg frequencies in mice
[171]
and
to support allograft survival in islet transplantation
[172]
, suggesting that
IL-2 may preferentially enhance Treg proliferation
in vivo.
Such an
in vivo
expansion of Treg has also been observed in humans after low-dose IL-2
administration
[173,174]
, and a first clinical trial confirming the increase
in Treg after IL-2 treatment has been performed in patients with steroid-
refractory chronic GVHD. Importantly, none of the treated patients pro-
gressed under treatment, but 12 of 23 patients showed major responses
[175]
. Of course, these results do not directly prove that Treg contributed to
Search WWH ::
Custom Search