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on thymic epithelial cells (TECs) and promotes their proliferation and sur-
vival. Through thymus crosstalk
[161-164]
, this epithelial regeneration leads
to commensurate rejuvenation of thymopoiesis. This is the first instance
demonstrating that depletion of thymic cellularity triggers a molecular net-
work to aid in its own regeneration. Importantly, IL-22 administration could
enhance overall thymic cellularity and proliferation and survival of TECs.
These studies not only define a novel mechanism governing endogenous
thymic regeneration, but also offer an innovative therapeutic strategy for
immune regeneration in patients whose thymus has been damaged due to
cytoreductive therapies, infection or other causes.
Flt3L
Preclinical studies have shown that exogenous Flt3L enhances both thy-
mic-dependent and independent T-cell reconstitution
[165,166]
. The
effects of Flt3L are predominantly due to an expansion in Flt3
+
progeni-
tors in the BM
[167]
. However, increases in T-cell reconstitution can be
at the expense of B-lymphopoiesis, which is significantly declined with
exogenous Flt3L administration and, in particular, its effects on the early
progenitors with lymphoid and myeloid potential (EPLM) subset of BM
progenitors
[168,169]
.
133
Other cytokines and growth factors
Several other cytokines and growth factors have been evaluated for a ben-
eficial role in regenerating the immune system. These include IGF-1, which
promotes TEC expansion and enhances reconstitution following HSCT
[170-172]
; IL-15, which predominantly promotes proliferation of circulat-
ing NK and T cells
[173,174]
; and IL-12, which stimulates thymic expres-
sion of IL-7 and enhances hematopoietic engraftment after transplant
[175-177]
. IL-12 and IL-15 have been recently found to also act on regula-
tory lymphoid-tissue inducer cells and NK cells
[178,179]
. Evidence has also
emerged that stem cell factor (SCF), the ligand for ckit, may also be used to
enhance thymic function. Although SCF is unable to reverse the impacts of
aging on the thymus
[180]
, it is critical for T-cell lineage commitment
[181]
and, in the setting of HSCT, treatment with SCF can significantly improve
thymopoiesis
[182]
suggesting that it could be used as a therapy to boost
thymic function after transplant.
Conclusions
In conclusion, post-transplant immune deficiency is due to a variety of
factors (including conditioning-induced thymic damage, age-associated
thymic involution, thymic GVHD, GVHD prophylaxis or treatment with
immune suppressive drugs) and is a major cause of morbidity and mortal-
ity from infections and relapse. In recent years new strategies have been
developed to enhance post-transplant T-cell recovery and several of those
are now in clinical trials, such as IL-7, KGF, SSA and GH.
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