Biology Reference
In-Depth Information
In summary, both donor and recipient Tregs, either freshly activated or
expanded
in vitro
, can support marrow engraftment in allogeneic recipients
through interactions with cells that would otherwise cause rejection. The
use of antigen-specific Tregs might ultimately prove to be very important by
reducing the total numbers of Tregs required to ensure engraftment and by
diminishing unwanted suppressive effects on beneficial immune responses
against pathogens. Several reagents have been proposed to expand Treg
populations
in situ
, which could offer more effective strategies for generat-
ing the necessary numbers of cell and for ensuring their persistence and
continued function
in vivo
. In the future, better understanding the Treg
cell niche and its role in supporting Treg
in vivo
will be needed in order
to develop applications for therapeutic regulation of alloreactive responses
by these cells. The use of better defined Treg subpopulations, including,
for example, a repopulating progenitor-like subset for longer persistence
in vivo
or a terminally differentiated subset expressing killer cell lectin-like
receptor subfamily G member 1 (KLRG1) that is unable to regenerate might
make it possible to control the persistence of Treg cells according to the
desired response.
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Impact of post-transplant immunosuppression
on risk of rejection
The ability of immunosuppressive agents given after HCT to prevent rejec-
tion has been studied primarily in canine models reviewed in
[90]
. In one
such model, recipients were given marrow cells from DLA-mismatched
unrelated donors after conditioning with 9.2 Gy TBI. Under these condi-
tions, only 3 of 36 recipients (8%) had sustained engraftment. When metho-
trexate was given on days 1, 3, 6 and 11 after HCT, however, 6 of 10 recipients
(60%) had sustained engraftment, indicating that methotrexate had an
inhibitory effect on the recipient cells that cause rejection in this model. In
a variant of this model, recipients were given marrow cells after condition-
ing with 9.2 Gy TBI, followed by infusion of buffy coat cells from the DLA-
mismatched unrelated donors on days 1 and 2 after HCT. In the absence
of immunosuppression after HCT, 68 of 91 recipients (91%) had sustained
engraftment, indicating that infusion of donor buffy coat cells was able to
overcome graft rejection under these conditions. Immunosuppression with
methotrexate had no effect on engraftment in this model. When cyclosporin
was given after HCT, however, only 5 of 13 recipients (39%) had sustained
engraftment, suggesting that cyclosporin inhibited the graft-facilitating
effect of T cells in the buffy coat infusions, without suppressing the recipient
cells that cause rejection. When both cyclosporin and methotrexate were
given, 30 of 31 recipients (97%) had sustained engraftment, again showing
that methotrexate had an inhibitory effect on the recipient cells that cause
rejection in this model.
In another canine model, recipients were given marrow cells from DLA-
identical donors after conditioning with different TBI exposures, with or
without immunosuppressive treatment after HCT
[160]
. After condition-
ing with 9.2 Gy TBI, 20 of 21 recipients (95%) had sustained engraftment,
but after conditioning with 4.5 Gy TBI, only 16 of 39 recipients (41%) had
sustained engraftment. When cyclosporin was given after HCT, sustained
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