Overview of the immune biology of allogeneic hematopoietic stem cell transplantation - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 8

and Peyer patches (reviewed in chapter 11 and in reference [61] ). In mice,
naive CD44(lo)CD62L(hi) CD8 + T cells generate and sustain allogeneic CD8 +
T cells in GVHD reactions [62,63] . Murine memory T cells isolated from non-
allosensitized donors fail to induce GVHD in experimental models [62] . In
contrast, alloantigen-sensitized effector memory CD44(hi)CD62L(lo) as well
as naïve phenotype CD44(lo)CD62L(hi), but not central memory CD44(hi)
CD62L(hi) CD8 + T cells, cause GVHD following adoptive transfer into sec-
ondary recipients [30] . Both alloantigen-sensitized effector memory CD4 +
and CD8 + T cells are involved in the transfer of GVHD under these conditions.

In the clinic, quantification of the degree and location of early T-cell expan-
sion is not readily possible given the limitations of current technology that
can be applied to HSCT recipients. Nonetheless, clinical studies currently
evaluate transferring enriched memory T cells rather than naïve T cells
to the recipient at the time of HSCT. Such studies will provide important
proof-of-concept as to whether the removal of naïve T cells from the donor
graft is sufficient to reduce or prevent acute GVHD.

REGULATORY T CELLS

8

CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) have potent suppressor activity
both in vitro and in vivo (reviewed in chapter 12). Donor Treg cell infusion
blocks acute GVHD. Murine L-selectin (CD62L) expressing Treg cells prefer-
entially home to secondary lymphoid organs, and in particular lymph nodes,
resulting in GVHD prevention [64] . Conversely, depletion of CD25 + T cells
from the donor graft or in the recipient immediately following allogeneic
HSCT promotes acute and chronic GVHD in various mouse models while
still maintaining a graft-versus-hematopoietic cell malignancy response in
most but not all studies [65-69] . Because of the relatively low frequency of
Tregs in lymphoid organs, ex vivo expansion of Tregs has often been used to
increase the number and to activate Tregs prior to in vivo adoptive trans-
fer. Immunosuppressive drugs given to prevent or control GVHD also affect
Treg cell expansion and function. Calcineurin inhibitors such as cyclosporin
decrease IL-2 production, leading to a reduction in Treg proliferation and
function. In contrast, rapamycin preferentially spares Tregs as opposed to
effector T cells and induces or functionally increases murine and human
Tregs in ex vivo culture systems, albeit at the expense of overall cell yield [70] .

Some challenges have arisen in the manipulation of human Tregs dur-
ing allogeneic HSCT. A combination of CD4, CD25 and CD127 (IL-7R) has
permitted the isolation of a highly purified Treg population that included
both CD4 + CD25 + and CD4 + CD25 − T-cell subsets both of which were as sup-
pressive as the classic CD4 + CD25(hi) Treg cell subset [71,72] . However, it
is unknown whether the expansion of this Treg subpopulation will permit
retention of as high a level of suppressor function as the CD4 + 25 + popula-
tion [73] . Furthermore experimental data both in mice and in vitro human
studies has demonstrated the extraordinary potential of T helper cell sub-
sets (Th1, Th2 and Th17) and of Tregs to exhibit plasticity, shifting from one
phenotype to another one (reviewed in references [74,75] ). This aspect of
“plasticity” may also be of concern when administering Tregs to patients
with inflammatory diseases. However, early phase I-II clinical trials have
demonstrated the feasibility of using Treg in the clinical setting [76,77]