Strategies to improve posttransplant immunity - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 127

tumors or HIV infection [86-90] . Rosenberg et al. [86] reported the results
of a phase I study of CYT 99 007 in 12 patients with relapsed solid tumors
(melanoma =11, sarcoma =1). They observed a dose-dependent increase in
absolute lymphocyte counts as well as the CD4 + and CD8 + T lymphocyte over
the 21-day period. No consistent impact on B cells or NK cells was noted. At
the highest dose (60 μg/kg) there was a trend toward an increase in CD45RA +
and decrease in CD45RO + cells in both CD4 + and CD8 + T cells. There was
also a relative decrease in the number of Tregs. In a second phase I study in
16 patients with solid tumors, CYT 99 007 induced dose-dependent marked
increases in circulating CD3 + , CD4 + and CD8 + lymphocytes [89] . IL-7 also
induced in vivo T-cell cycling, bcl-2 upregulation, preferential expansion of
naïve T cells, including recent thymic emigrants, and a broadening of the
T-cell receptor (TCR) repertoire diversity [87] . In another phase I study in
13 HIV-infected patients, IL-7 induced a sustained increase in naïve and
central memory CD4 + and CD8 + T cells. In addition, the expanded T cells
responded to HIV antigen by producing IFN-γ and/or IL-2. Importantly, a
phase I study with glycosylated rhIL-7 (CYT107) was recently completed in
patients after allogeneic TCD-HSCT and also demonstrated rises in CD4 +
and CD8 + T cells (Perales et al., unpublished).
129
Keratinocyte growth factor
Keratinocyte growth factor-1 (KGF) is a 28-kDa endogenous protein in the
fibroblast growth factor family [91,92] . The KGF receptor is expressed on a
variety of epithelial tissues including the buccal mucosa, esophagus, stom-
ach, intestine, salivary gland, lung, liver, pancreas, kidney, bladder, pros-
tate, mammary gland, skin, the lens of the eye and the thymus [93-95] , but
not on hematopoietic cells [96] . KGF induces the proliferation, differentia-
tion, and migration of epithelial cells, and has been shown to have cytopro-
tective, trophic or regenerative effects as well as effects on cytokine profiles
[97] . The effects of KGF on mucosal membranes and the thymus likely
explain preclinical data that KGF can mitigate mucositis in autologous and
allogeneic HSCT and promote immune recovery in total body irradiation
(TBI)-based allo-HSCT [98-103] .
KGF plays an important role in T-cell homeostasis and immune recovery
through its regulation of the proliferation and differentiation of thymic epi-
thelium in preclinical models. In mouse models of TBI-based allo-HSCT,
KGF is necessary for thymic regeneration and pre-HSCT administration of
KGF results in increased thymopoiesis and peripheral T-cell numbers post-
HSCT [100] . In addition, KGF was shown to promote immune recovery fol-
lowing murine allogeneic umbilical cord blood transplant, with increased
donor-derived T and NK cells seen in the spleen of recipients, as well as an
increase in TRECs [103] . The immune recovery following KGF can be further
increased by leuprolide [102] , or administration of a p53 inhibitor during
radiotherapy [104] . In the autologous HSCT setting, KGF promotes thymus-
mediated immune recovery in rhesus macaques with an increased number
of naïve T cells in lymph nodes and an increase in levels of TRECs [105] .
Palifermin is a recombinant human KGF that differs from endogenous
KGF in a deletion of the first 23 N-terminal amino acids, which improves