Strategies to improve posttransplant immunity - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 129

thymopoiesis in aged mice and humans [118-126] . The effects of SSA, how-
ever, are not restricted to the thymus with enhanced B-lymphopoiesis and
lymphoid progenitors also observed [127-132] , as well as enhancing overall
immune recovery following autologous [133] or allogeneic [134] HSCT and
cytoablative therapy [124,125,131] . Taken together these studies indicate the
wide-ranging implications on immune recovery following SSA and provide
evidence for the clinical application of SSA in treatments where immune
depletion is an unavoidable side effect. In fact, prostate cancer patients,
who are routinely given sex steroid ablation as a therapy for the malignancy,
exhibit increased numbers of naïve T cells as a response to thymic regenera-
tion [135] . Moreover, clinical trials using an LHRH analog have shown that it
can enhance naïve T-cell numbers in recipients of allo-HSCT [136] . In both
experimental and clinical trials, an LHRH analog has been given at least 3
weeks prior to transplant to account for the sex steroid spike that occurs dur-
ing sensitization of the receptor. However, with the advent of more advanced
LHRH antagonists, which result in almost immediate cessation of sex steroid
production and subsequently significantly shorter time to sex steroid abla-
tion, these could conceivably be used successfully closer to the transplant.
131
Growth hormone
Use of growth hormone (GH) has also been proposed as a possible regen-
erative therapy. Treatment with exogenous GH regenerates the aged thymus
[137,138] and enhances hematopoietic progenitor cell function in the BM
[139] . GH has also been shown to reverse irradiation-associated loss of BM
function determined by colony formation [139] . The clinical experience
with GH and T-cell recovery is limited to studies in HIV patients but has
been demonstrated to significantly enhance thymus function [140-142]
and anti-viral responses [140-143] . Clinical studies in HSCT patients are
currently underway (personal communication, Nelson Chao, Duke Univer-
sity Medical Center).
T-cell precursors
Another potential approach to overcome post-transplant T-cell deficiency is
the use of adoptive transfer of T cells or T-cell precursors. Several groups are
investigating the use of donor-derived or third-party mature T cells to treat
or prevent post-transplant infections, including viral infections such as CMV,
EBV or adenovirus. An alternative approach would be to transfer T-cell precur-
sors that would develop into mature T cells in the host. Tissue culture systems
using Notch1 signaling have been shown to drive the in vitro development of
T lineage cells from hematopoietic progenitors [144,145] . Notch1 is essential
for T-cell lineage commitment and differentiation [146] . Dr Zuniga-Pflucker
and his colleagues have developed an in vitro culture method using a murine
bone marrow stromal cell line OP9 transduced with the Notch ligand Delta-
Like 1 (DL1). This system allows the development of mature T cells from
hematopoietic or embryonic stem cells in mouse and man [144,145,147] .
In preclinical mouse studies, we have used the OP9-DL1 culture system to
generate large populations of T-cell precursors with a phenotype similar
to triple negative (TN; CD3 − CD4 − CD8 − ) 2 and 3 early thymocytes [148] . We