Strategies to improve posttransplant immunity - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 126

monocytes and macrophages. IL-7 induced an increase in the same thymo-
cyte populations in middle aged (9 month old) recipients of MHC-matched
HSCT, although thymic cellularity was lower when compared to 3-month-
old recipients. CYT 99 007 also enhanced T-cell function and increased the
proliferative capacity of T cells. However, CYT 99 007 did not affect the T-cell
repertoire. Mortality from leukemia was unchanged in CYT 99 007-treated
recipients of TCD-BM, which suggests that IL-7 probably exerts no effect
on leukemia cells and/or graft-versus-tumor activity [80] .

A potential concern with any agent targeting T cells in the setting of allo-
HSCT is the risk of GVHD. IL-7 did not aggravate the development of GVHD
in any of our models in which we induced GVHD by adding splenic donor
T cells to the allogeneic TCD-BM graft [80,81] . In fact, in one model (B6 →
(B6xC3H)F1), IL-7 significantly decreased GVHD morbidity and mortality
[80] . Sinha et al. [82] studied a different preparation of IL-7 at high dose for
4 weeks after a TCD-HSCT and mixed with increasing doses of lymph node
T cells. Although their studies confirmed that IL-7 did not increase GVHD
after TCD-HSCT, IL-7 did lower the threshold dose of donor T cells required
to induce lethal GVHD. Gendelman et al. [83] compared the effect of a post-
transplant 10-day IL-7 treatment on GVHD induction in irradiated and non-
irradiated hosts, using a model of haplo identical HCT transplanting ex vivo
T-cell-depleted bone marrow of “parent” B6 mice into F1 B6AF1/J recipi-
ents. These studies demonstrated that a short IL-7 course did not exacer-
bate GVHD lethality. The differences observed between the different studies
may, in part, be explained by the different murine models, differences in the
IL-7 preparations, the dose and duration of IL-7 treatment, and differences
in allogeneic effector T cells in the splenic versus lymph node preparations
administered. Based on existing data, IL-7 would not be expected to increase
the risk of GVHD following a TCD-HSCT. However, the relative capacity of
IL-7 to potentiate the development or severity of GVHD in the setting of a
conventional allo-HSCT remains uncertain and may depend on many vari-
ables, such as dose and timing of IL-7, and conditioning of the host.

128

In addition to the above studies, IL-7 has also been studied in primate mod-
els. Storek et al [84] assessed CYT 99 007, given daily for 4 weeks starting
several weeks after transplantation, in the setting of autologous HSCT after
a myeloablative TBI conditioning in a juvenile baboon model. CYT 99 007
increased CD4 + cell recovery, while the enhancement of CD8 + cells was less
pronounced, and B-cell count was not increased. The effects appeared to
be greater for effector/memory (CD45RA − ) than naïve (CD45RA + ) CD4 + T
cells. In addition, the IL-7-treated animals had greater mean increases in
the volume of lymph nodes and spleen but not the thymus, suggesting that
CYT 99 007 mainly stimulated peripheral expansion. TREC results were
consistent with the absence of increased thymopoiesis [84] . Finally, Lu et al.
[85] reported the results of long-term (2 months) administration of IL-7 in
baboons rendered severely lymphopenic by TBI and ATG. IL-7 induced a
higher median CD4 + T-cell count, mainly through peripheral expansion
rather than de novo generation. CMV-specific CD4 + T cells also increased in
IL-7-treated animals.

Initial clinical trials in humans with rhIL-7 (CYT 99 007) demonstrated a
dose-dependent expansion of CD4 + and CD8 + T cells in patients with solid