Strategies to improve posttransplant immunity - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 125

family molecules [64,66] , and enhancing in vivo survival of CD4 + and CD8 +
T cells (both naïve and memory). IL-7 can co-stimulate T-cell activation by
enhancing proliferation and cytokine production, particularly in the setting
of suboptimal TCR triggering [67-69] , an effect that is at least partly inde-
pendent of IL-2 [67] . IL-7 augments responses to IL-12 by upregulating the
IL-12R on mature T cells [70] , and stimulates the lytic activity of CD8 + cyto-
toxic T lymphocytes (CTLs), NK, NK-T cells and γδ T cells [54,71,72] .

A number of studies have shown the benefit of IL-7 in enhancing immune
recovery in the lymphopenic host. IL-7 administration to cyclophosphamide-
treated or irradiated mice improves T and B lymphocyte recovery [73,74] .
IL-7 increases thymic cellularity after murine syngeneic HSCT [75] acts as
a survival factor for peripheral naïve T cells and increases T-cell function
[75-77] . Fry et al. [76] also demonstrated in athymic T-cell-depleted hosts
that IL-7 could enhance extrathymic peripheral expansion and restore pri-
mary or recall immune responses through the inhibition of programmed
cell death. IL-7 also improved the costimulatory and antigen-presenting cell
functions of antigen presenting cells. Mackall et al. [77] found that, among
all of the cytokines they tested (including IL-2, IL-3, IL-6, IL-7 and IL-12),
IL-7 had, by far, the most potent effect on peripheral T-cell expansion after
a syngeneic HSCT.

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Recombinant human IL-7 (non-glycosylated CYT 99 007 and glycosylated
CYT 107, Cytheris Inc.) has been evaluated in pre-clinical models and, more
recently, in clinical trials. Broers et al. [78] studied CYT 99 007 after T-cell-
depleted or T-cell replete congenic HSCT in T-cell-deficient RAG − / − mice.
After TCD-HSCT, CYT 99 007, given for 5 weeks or more, induced a strong
expansion of bone-marrow-derived T cells, which might be due to increased
thymopoiesis, but also to an expansion of recent thymic emigrants. CYT
99 007 induced only a moderate increase in TREC levels in thymocytes, but
was associated with a drop in TREC frequency in peripheral T cells, dem-
onstrating that IL-7 induced an expansion of recent thymic emigrants, and
had a modest impact on thymopoiesis in this model. Although exogenous
IL-7 may improve thymopoiesis, it seems to be preferentially consumed by
rapidly proliferating recent thymic emigrants. After T-cell-replete HSCT,
CYT 99 007 mainly induced a peripheral expansion of mature T cells, at the
expense of newly developed bone-marrow-derived T cells, most likely by
competing for available IL-7. In both cases CYT 99 007 induced a preferen-
tial expansion of CD4 + T cells causing the CD4/CD8 ratio to increase dur-
ing treatment. In contrast, no effect on T-cell recovery was observed when
CYT 99 007 was administered for a shorter duration after transplantation in
RAG − / − mice with a syngeneic in vitro processed bone marrow with Sca 1 +
selected progenitors [79] .

Our group has explored the effects of CYT 99 007 in murine models of
allo-HSCT [80,81] . CYT 99 007 initiated at day 14 or day 21 after allogeneic
TCD-HSCT induced an accelerated restoration of the major T- and B-cell
populations at day 28. The treatment significantly enhanced thymopoi-
esis, increasing thymic cellularity, and also expanded post-thymic T cells
from CD4 + or CD8 + subsets, mainly populations of activated-memory CD4 +
and CD8 + T cells. No significant change in the CD4/CD8 ratio was noted.
Finally, CYT 99 007 enhanced the recovery of NK and NK-T cells as well as