Looking toward the future: an individualized approach to allogeneic transplantation - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 491

Blazar and colleagues reported expansion of nTregs >3000-fold with a single
additional restimulation, with few conventional T cells contaminating the
final product and preservation of regulatory function [22] . Similarly, large
numbers of bulk CD4 + T cells can be induced to become Treg cells using
GMP-certified reagents [23] . Such large-scale expansion should allow rigor-
ous testing of Treg potency in the context of allogeneic hematopoietic stem
cell transplantation (HSCT) within the next few years.

In addition to ex vivo expansion, a number of strategies may support the
expansion of Treg populations in vivo. Low-dose IL-2 administration
expanded Treg populations eightfold or more in patients with chronic
GVHD, without increases in either GVHD or relapse [24] . Similarly, Sirolimus
administration inhibits Th1 effector function while sparing regulatory T cell
proliferation in vivo [25] . However, clinical trials of Sirolimus for GVHD pro-
phylaxis have thus far yielded mixed reports, and results from an ongoing
phase III Blood and Marrow Transplant Clinical Trial Network clinical trial
are eagerly awaited. Finally, it should be noted that extracorporeal photo-
phoresis (ECP) induces regulatory T cells in animal models by injection of
ECP-treated cells that are primed for apoptosis [26] . ECP is used in many
centers for GVHD, but its mechanism of action in humans and its optimal
application to allogeneic HSCT remain areas of active investigation.

497

The bone marrow environment, in addition to harboring hematopoietic
stem cells, is also filled with nonhematopoietic mesenchymal stem cells
(MSCs) that can be rapidly expanded ex vivo [27] . MSC infusions can induce
complete responses in >50% of patients with steroid-refractory GVHD
[28,29] , but MSC infusion at the time of transplantation has led to conflict-
ing results [30,31] . Thus, while MSC use in allogeneic transplant remains
intriguing, until their phenotype and mechanism of action are sufficiently
clarified to standardize their isolation and expansion, MSC technology is
unlikely to gain widespread clinical acceptance.

Inhibitors of histone deacetylase

An interesting class of drugs that may have efficacy in treating both GVHD
and malignancy is that of histone deacetylase inhibitors. Reversible inhi-
bition of deacetylation enzymes affects the transcription of a number of
genes and the acetylation of many proteins and exerts antineoplastic effects
[32,33] . One deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA),
is already FDA approved for treatment of cutaneous T-cell lymphoma [34] .

SAHA also has a number of important effects on immune responses. In
GVHD animal models, administration of SAHA significantly reduces serum
levels of tumor necrosis factor α, IL-1, and interferon-γ; modulates dendritic
cell function via the induction of indolamine 2,3-dioxygenase [35] ; and
reduces GVHD while preserving GVL effects [36] . Histone deacetylase inhi-
bition may also expand regulatory T-cell populations [37] and can potenti-
ate the lysis of tumors by natural killer (NK) cells [38,39] . Thus, inhibition of
deacetylation is clinically attractive because it: [1] downregulates inflam-
matory cytokine cascades and the function of dendritic cells, [2] increases
regulatory T cells, [3] preserves cytotoxic lymphocyte (CTL) effects (neces-
sary for GVL), [4] potentiates NK-mediated killing of tumor cells, and [5]