Looking toward the future: an individualized approach to allogeneic transplantation - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 490

intestine [9] . Future methods to control acute GVHD will probably interact
with specific pathways in this schema by targeting specific subsets of cells
or their functions (regulatory T cells, effector T cells, and APCs). Such an
approach may avoid generalized immunosuppression and thus spare key
aspects of immune reconstitution. The use of predictive biomarkers may
also facilitate a preemptive treatment approach in asymptomatic patients
who are at high risk and allow a more focused use of steroids. We highlight
here particularly interesting and novel approaches to alter the post-trans-
plant immune environment: cell-based regulatory therapies, in vivo stabili-
zation of regulatory populations, modifiers of acetylation, and strategies to
improve immune reconstitution.

Cellular therapy

In 1995, Sakaguchi and colleagues demonstrated that CD4 + , CD25 + T cells
could control autoimmune disease [10] , and further groundbreaking work
demonstrated the critical role of the transcription factor FOXP3 in these
cells (reviewed in [11] ). While most regulatory T cells (Tregs) develop in
the thymus (natural Treg), a second set of Tregs can be induced to express
FOXP3 in the presence of tumor growth factor β (inducible Treg) and a third
subset arises when peripheral CD4 + T cells are stimulated in presence of
interleukin-10 (IL-10) (Tr1) [12] .

496

Animal models clearly demonstrate the ability of Tregs to control
GVHD [13-15] and, importantly, their transfer preserves beneficial
graft-versus-leukemia (GVL) effects [16,17] . Based upon these preclinical
data, several groups are actively pursuing the use of Tregs to treat or pre-
vent GVHD in humans. The Regensburg group has infused purified natural
Tregs (nTregs) followed by an infusion of similar numbers of conventional
donor T cells in 5 patients: none experienced increased toxicity (including
infectious complications) or increased GVHD [18] . Similarly, Di Iianni et al.
administered bead-purified nTregs to 28 patients 3 days before haploiden-
tical transplantation and only 2 of 26 evaluable patients developed acute
GVHD (7.7%), despite the lack of other post-transplant immunosuppres-
sion [19] . In both studies, the total number of conventional T cells, as well as
the ratio between Tregs and conventional T cells, appeared to be important.

The major impediment to successful use of regulatory T cells is the inability
to purify large numbers of homogeneous cells with appropriate function.
The need for large numbers of Tregs has led to efforts to expand them
in vitro, as demonstrated by a University of Minnesota protocol evaluat-
ing the expansion of Tregs from umbilical cord blood. In that trial, patients
received a double cord blood transplant and Tregs from a third cord blood
unit [20] . Forty-three percent of patients developed acute grade II-IV GVHD
(significantly less than historical controls), thus encouraging further stud-
ies with this approach.

Many groups have also expanded natural Tregs from the peripheral blood
more than 1000-fold within 3 weeks of initial stimulation [21] , but these
expanded Tregs can lose regulatory function and often contain large num-
bers of effector T cells. Novel reagents such as artificial APCs and the addi-
tion of rapamycin to the culture medium may overcome these difficulties.