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production of interleukin-7 (IL-7) by thymic stromal cells. This suggests
that radiation and potentially other cytotoxic agents may impair physio-
logical mechanisms of T-cell regeneration driven by IL-7
[22]
. Post-trans-
plant T-cell recovery is significantly affected by approaches that deplete T
cells from the graft to reduce GVHD. Studies of
ex vivo
T-cell depletion have
shown a delay in immune recovery, particularly in adult patients
[2,16,18,
21]
. Alemtuzumab, an antibody that targets CD52, which is expressed on
T cells, B cells, NK cells and dendritic cells, is commonly used in combina-
tion with reduced intensity conditioning regimens to reduce GVHD
[23-26]
.
Because of its profound effects on immune cells, its use has been associ-
ated with a dose-dependent delay in immune recovery and an increased
risk of post-transplant infections, particularly reactivation of CMV
[24-26]
.
Similar results have been reported with the use of anti-thymocyte globu-
lin (ATG), which is often used in matched unrelated donor transplants to
reduce GVHD, as well as in T-cell-depleted transplants to promote engraft-
ment
[27-29]
. Interestingly, different formulations of ATG may cause dif-
ferent levels of immune suppression
[29]
. Finally, GVHD has a significant
impact on immune recovery through direct effects on the thymus
[30,31]
,
and because of the requirement of immunosuppressive drugs required to
treat GVHD
[32-37]
.
125
GVHD of the thymus
While the classical target organs of acute GVHD are the GI tract, the liver
and the skin, the thymus has also been recognized as a recipient tissue that
can be severely damaged by the alloreactive donor immune response. This
thymic damage can have significant clinical consequences, as thymic dam-
age from GVHD can lead to prolonged T-cell deficiency after hematopoietic
transplantation
[38]
. Indeed, thymic involution has long been recognized as
a complication of experimental GVH reactions, although the effect of GVHD
on the thymus was initially thought to result solely from a corticosteroid-
induced stress response
[39]
. Subsequent studies demonstrated that thy-
mic damage from GVH reactions included the loss of distinct cortical and
medullary architecture, as well as loss of both thymic lymphocytes and epi-
thelium, and that this damage was not limited to involution due to surges
in corticosteroids
[40,41]
. These early experimental studies were notable
at the time for identifying similar thymic pathology in recipients of bone
marrow transplants who died with GVHD
[40,42]
. More recent experimen-
tation has both confirmed interpretations that thymic damage in GVHD is
independent of steroid-induced involution and also highlighted the com-
plexity of thymic damage, indicating that impaired thymopoiesis is due
not only to structural damage with elimination of both lymphoid and epi-
thelial elements within the thymus, but also impaired function of the cells
that remain
[43,44]
. A hallmark feature of acute experimental thymic GVHD
was identified to be the loss of double positive (DP) thymocytes, and this
was related to impairment in the cell cycle progression and proliferation
of T-cell precursors, perhaps in response to IFN-γ produced by infiltrating
mature donor T cells
[44]
. Surprisingly, thymic infiltration by donor T cells
during GVHD is dependent on homing molecules important for migration
to the GI tract as well as homing molecules typically involved in migration
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