Cytokines in graft-versushost disease and graft-versusleukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 363

and STAT3 [73,74] . Within Tregs, IL-2 signaling is predominantly JAK/STAT
dependent (as opposed to PI3-K) and it is thought that this is a potential
reason for the differential effect of IL-2 on T-effector and Treg populations.

PRECLINICAL EVIDENCE SURROUNDING IL-2 IN GVHD

Protection from aGVHD with administration of IL-2 cytokine was dem-
onstrated in mouse models in the 1990s [75,76] , and these early studies
showed a retention of GVL and engraftment effects with the IL-2 treatment
regimen. Subsequent studies by the same group demonstrated that the
protection from GVHD occurred via a CD4 + T-cell-mediated mechanism,
with a resultant expansion of CD25 + CD4 T cells, and that treatment was
associated with a reduction in the early IFN-γ peak seen in control animals
[77,78] . It is unclear whether this protective effect was due to the induction
of AICD in effector T-cell populations, expansion of regulatory T cells, or a
combination of both.

Interestingly, administration of the immunosuppressive agent Sirolimus
(rapamycin) and either IL-2 alone [79] or IL-2 antibody complexes [80] has
been shown to expand regulatory T-cell populations and thereby reduce
lethal aGVHD.

367

CALCINEURIN INHIBITORS AND THE ROLE OF IL-2 IN GVHD PROPHYLAXIS
AND TREATMENT

Current prophylactic and therapeutic regimens for GVHD include the cal-
cineurin inhibitors cyclosporin and Tacrolimus. These drugs inhibit calci-
neurin phosphatase, and subsequently, calcium-dependent intracellular
events are impaired, including the synthesis of IL-2 [81] . Recently, there has
been concern that while these therapies are effective for the reduction of
donor T-cell-mediated alloreactivity, this benefit may come at the expense
of providing appropriate conditions for regulatory T-cell expansion.

IL-2 has been used in the clinical setting and has been successful in
case-control studies at improving rates of overall disease-free survival, and
when the patients analyzed (who did not have GVHD, as this was an exclusion
criterion in the study) were compared with non-GVHD case controls, there
was a relative decrease in relapse rate [82] . IL-2 therapy has been shown to
induce NK cell expansion and augment FOXP3 + Treg number in the post-
transplant setting [83] . The induction of FOXP3 expression was dependent
on STAT3 and STAT5 binding to a highly conserved STAT-binding site located
in the first intron of the FOXP3 gene.

Low-dose IL-2 has recently been studied as therapy for chronic GVHD,
based on the hypothesis that this therapy may preferentially enhance Treg
populations and decrease clinical GVHD [84] . This critically important
preliminary trial reported successful control of cGVHD with daily subcu-
taneous injection of IL-2 cytokine; however, further studies are required to
confirm these results.

IL-1

IL-1 is a potent proinflammatory cytokine that has been implicated in
GVHD and a multitude of other acute and chronic inflammatory diseases