Strategies to improve posttransplant immunity - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 128

its stability (Swedish Orphan Biovitrium product information). Clinical tri-
als have focused on the efficacy of palifermin for the prevention of muco-
sitis and led to its approval for this indication [106] . There is no published
clinical data, however, evaluating palifermin's ability to promote immune
reconstitution after HSCT. We performed a retrospective analysis of the
effect of KGF on immune recovery in allo-HSCT patients, but depending
on the patient population analyzed, we had inconsistent results. Positive
effects of palifermin on CD4 recovery were demonstrated in certain subsets
of patients receiving TBI-based TCD allo-HSCT, while no effect was seen
in other patient subsets. Because of the retrospective nature of these stud-
ies, we were not able to fully correct for other factors that may influence
immune recovery, including changes over time in the conditioning regi-
men and method of T-cell depletion. Therefore, based on strong pre-clinical
data, we are planning a prospective study evaluating palifermin's effect on
immune recovery in the TBI-based TCD allo-HSCT population to determine
if palifermin has an effect on immune recovery in this patient population.

Sex steroid ablation

130

From the onset of puberty, and correlating with an increase in the produc-
tion of sex steroids, there is a profound shift in hematopoiesis and in par-
ticular a decline in lymphopoiesis [107] . These functional changes highlight
the considerable impact of sex steroids on the immune system. Sex steroids
can act as a negative regulator of cells as early as lymphoid primed multipo-
tent progenitors (LPMPs) and common lymphoid progenitors (CLPs), which
are selectively depleted by estrogen treatment [108] . Moreover, sensitivity to
sex steroids may actually be a branching point in lympho-myeloid diver-
gence [109] , a result that is confirmed by the observations that myelopoiesis
is initiated by estrogen-resistant cells [110] . In the thymus, treatment with
androgens leads to significant involution of the thymus, primarily mediated
by the induction of apoptosis in developing thymocytes [111] , although sex
steroid receptors are expressed by both developing lymphocytes and their
supporting stromal cells [112-115] .

As such, several studies have focused on using sex steroid ablation (SSA) as
a means of boosting lymphoid regeneration in periods after immune insult.
Pharmacologically, sex steroids can be abrogated by disrupting upstream
hormone signals such as leuteinizing hormone releasing hormone (LHRH),
blocking the binding of sex steroid receptors, or by inactivating the hor-
mones themselves. One of the most widely utilized methods of SSA clini-
cally is with LHRH analogs (LHRH-Ag) and antagonists (LHRH-Ant). LHRH
is a small peptide hormone that is released from the hypothalamus and acts
on the pituitary to regulate the release of follicle stimulating hormone (FSH)
and leuteinizing hormone (LH), which in turn act on the gonads to mediate
the release of sex steroids (reviewed in reference [116] ). While both forms
block further binding to the LHRH receptor (LHRH-R) in the pituitary,
LHRH-Ant immediately blocks signalling [117] while LHRH-Ag initially
stimulates the receptor resulting in an initial surge of sex steroids [116] .

Ablation of sex steroids leads to reorganized thymic architecture, an
enhanced ability to import circulating progenitors [118] and enhances