Broxmeyer.qxp 14/3/08 16:35 Page 48
Transplantation
Enhanced Homing/Engraftment of Haematopoietic Stem positive for surface expression of CD26 (about 8% of the total
Cells by Inhibition of CD26/Dipeptidylpeptidase IV population).
32
A higher percentage of CD34
+
CD38- cells from human
Limited numbers of HSCs are a problem, especially when the source of CB, a population enriched for HSCs compared with HPCs, expresses
HSC is from CB.
27
While CB is efficacious when used in transplants CD26 compared with the more mature CD34
+
CD38
+
population.
34
in children, its successes are less apparent in adults and higher-weight CD26 is present on the surface of over 70% of mouse HSCs,
children, who may require more HSCs than present in a single phenotypically defined by their expression of c-kit and sca-1 antigens
and lack of lineage antigens (c-kit
+
sca1
+
lin-).
28,30
Both human and
mouse haematopoietic CD26+ cells have functional CD26 peptidase
Granulocyte colony-stimulating
activity measured by an in vitro enzymatic assay. That both mouse and
factor is the gold standard for
human HSCs/HPCs express functional CD26 suggested that it may play
a role in SDF-1/CXCL12-mediated functions such as chemotaxis and
mobilisation of haematopoietic stem
homing/engraftment.
(HSC) and progenitor (HPC) cells for
use in autologous and allogeneic
HSCs/HPCs from mouse and human sources express CXCR4 and
exhibit chemotaxis towards a positive gradient of SDF-1/
HSC transplantation.
CXCL12. Truncated SDF-1/CXCL12 blocked chemotaxis of mouse
HSC and human CD34
+
cells to full-length SDF-1/CXCL12.
28,32
By
collection of CB. Attempts to enhance the capacity of CB to treat using a selective inhibitor of CD26, such as Diprotin A or Val-Pyr,
33,35
adults and higher-weight children include ex vivo expansion of the full-length form of SDF-1/CXCL12 was protected from truncation
CB HSCs, use of multiple units of CB and intra-bone-marrow injection and significantly increased the percentage of cells able to migrate to
of cells. While mouse HSCs can be expanded ex vivo by combinations SDF-1/CXCL12.
32
This led us to evaluate inhibition of CD26 for
of growth factors/cytokines, there is little evidence at present that enhanced homing/engraftment of mouse BM HSCs.
28
Pre-treating
human HSCs have been successfully expanded ex vivo. Use of two
CBs for transplantation has had some success, but only one of the
CBs wins out; which one will win is not yet predictable, and there
While cord blood is efficacious when
are indications that use of multiple CBs may enhance graft-versus-host
disease (GVHD) in the recipients. This latter problem would distract used in transplants in children,
from one of the advantages of single CB transplantation, where
its successes are less apparent in
such efforts have shown less GVHD than that elicited by bone
marrow transplantation. It is not clear whether intra-marrow
adults and higher-weight children.
injection will demonstrate clinical efficacy. Thus, we focused
on enhancing the homing/engrafting capacity of limited numbers
of HSCs. donor HSCs/HPCs for transplant in a congenic mouse assay with
Diprotin A or Val-Pyr for short periods before transplant significantly
There is evidence that HSCs may not home with absolute efficiency increased short-term homing, long-term engraftment, non-
and that this homing can be enhanced.
28
Inhibition of CD26/DPPIV has competitive and competitive repopulation of the donor cells and
shown efficacy in enhancing homing and engraftment of mouse HSCs secondary repopulation of donor cells, the last being a measure of the
into lethally irradiated mice.
28
CD26 is a cell-surface dipeptidase self-renewal ability of donor HSCs.
28
Donor HSC from CD26-/- mice
expressed widely throughout the body.
29
It is a 110kDA glycoprotein were also found to have increased homing and engraftment.
28
These
with a small cytoplasmic region, a transmembrane section and an effects have since been reproduced by at least two independent
extracellular section containing the enzymatic activity.
29
The laboratories. The first showed that inhibition of CD26 enhanced
dipeptidylpeptidase region of CD26 cleaves the N-terminal dipeptide engraftment of limited numbers of virally transduced HSC expressing a
recombinant allogeneic MHC class I molecule.
36
The second group
demonstrated that CD26 inhibition significantly increased homing
and engraftment in the context of non-ablative, allogeneic in utero
There is evidence that haematopoietic
HSC transplantation.
37
stem cells may not home with
absolute efficiency and that this
To assess clinical feasibility, we evaluated the effect of short pre-
treatment of Diprotin A on engraftment of human CB CD34
+
cells in
homing can be enhanced.
NOD/SCID mice.
34
CD26 inhibitor pre-treatment significantly enhanced
CD34
+
cell engraftment, similar to that seen in mouse congenic
transplant studies. Interestingly, pre-treatment of a less pure
from various substrates, including chemokines, at the penultimate population of HSCs/HPCs (less than 40% CD34
+
) led to greater
proline or alanine residue.
29–31
The action of CD26 on SDF-1/CXCL12 enhancement of engraftment, suggesting effects of CD26 inhibition
has biological consequences regarding HSC chemotaxis.
32
also on cells in this population that are not HSCs/HPCs. Differentiation
of the human cells once engrafted in NOD/SCID animals was not
Immature HPCs/HSCs from human CB and mouse bone marrow significantly affected, suggesting that this treatment did not push cells
express CD26 on their surface.
28,32,33
CD34
+
cells from human CB are towards one lineage as opposed to others.
34
Studies by two
48 EUROPEAN HAEMATOLOGY 2007
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