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Blood, Vol. 95 No. 8 (April 15), 2000:
pp. 2482-2483
FOCUS ON HEMATOLOGY
Introduction: TH2-inducing DC2 for immunotherapy
Yong-Jun Liu and
Bianca Blom
From the Department of Immunobiology, DNAX Research Institute of
Molecular and Cellular Biology, 901 California Avenue, Palo Alto, CA
94306.
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Introduction |
The concept of tolerogenic dendritic cells (DCs)
came from experiments in mice showing that thymic DCs mediated clonal
deletion of emerging autoreactive T cells within thymus.1
The finding that lymphoid precursors give rise to both T cells and
CD8+CD11b DCs within the thymus suggests the
existence of a lymphoid pathway, in addition to a well-established
myeloid DC pathway giving rise to CD8CD11b+
DCs.2 In mouse spleen, both
CD8CD11b+ myeloid DCs and
CD8+CD11b lymphoid DCs were identified. The
finding that lymphoid DCs express higher levels of self-peptide-MHC
class II complex3 and FAS-binding protein4
suggests that lymphoid DCs may be tolerogenic for T cells, in contrast
to immunogenic myeloid DCs. This hypothesis was not, however, supported
by studies showing that CD8+CD11b lymphoid
DCs produce a high level of IL-12 and induce potent TH1 response to
foreign antigens.5-8 The existence of tolerogenic or
TH2-inducing DCs in peripheral tissues was, however, further suggested
by studies of DCs from Peyer's patches, liver, and lung. These DCs
were shown to preferentially induce TH2 responses, in contrast to
splenic DCs and bone-marrow-derived DCs that preferentially induce TH1
responses.9-11 The TH2-inducing function of Peyer's patch
DCs and liver DCs may contribute to the mechanism underlying tolerance
to food antigens or to allo-liver transplants,
respectively.
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TH2-inducing dendritic cell precursors (pre-DC2) are derived from
hematopoietic stem cells (HSC) in bone marrow.
Signals regulating HSC differentiation into pre-DC2 are currently
unknown. G-CSF appears to mobilize bone marrow pre-DC2 into peripheral
blood. Recipients of blood stem cell transplantation from
G-CSF-treated donors received 5- to 6-fold more pre-DC2 than did
recipients of bone marrow stem cell products. Pre-DC2 may capture
alloantigen and undergo maturation after transfer into the host. These
DC2 may present alloantigen to donor T cells and induce them to undergo
TH2 differentiation and to limit GVHD.
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To find tolerogenic or TH2-inducing DCs in humans and to develop a way
to grow and manipulate these DCs for use in immunotherapy for
autoimmune diseases and GVHD have been an immunologist's fantasy. Recently, human lymphoid DCs (DC2) have been generated from human blood
CD4+IL-3R ++CD11c precursors
(pre-DC2) in culture with IL-3 and CD40-ligand.13-17 In
contrast to CD40-ligand-activated monocyte-derived DC1 that produce a
large amount of IL-12 and induce TH1 differentiation, CD40-ligand-activated DC2 produce a lower amount of IL-12 and induce
TH2 differentiation.13 Although TH1-inducing myeloid DC1
and CD11c+ blood DCs have been used in immunotherapy for
certain human cancers,18-21 potential application of
TH2-inducing DC2 in immunotherapy for autoimmune diseases and GVHD has
been limited. This is because the frequency of pre-DC2 in human blood
is low (0.2% to 0.8%), and the identity and function of mature DC2 in
vivo is unclear.
In this issue of Blood, Dr Arpinati and colleagues report a
major advancement in human DC biology, which may pave the way toward
DC2-based immunotherapy for autoimmune disease and GVHD.22 They show that G-CSF treatment, which is widely used to mobilize hematopoietic stem cells into blood for stem cell transplantation, induced a more than 5-fold increase in blood pre-DC2 numbers. Interestingly, the number of blood myeloid CD11c+DC were
found unchanged in the same donor. The authors further showed that
while DC1 derived from CD11c+ blood immature DCs cultured
with GM-CSF, IL-3, and TNF-a preferentially induced TH1
differentiation, pre-DC2-derived DC2 cultured with the same cytokines
preferentially induced TH2 differentiation. Together with a recent
study by Rissoan et al,13 Arpinati's study suggests that T
helper cell differentiation depends not only on the maturation stage of
DCs, but also on the type of DCs.
The question is what the functional consequence is of transferring more
DC2 or pre-DC2 into patients. This study showed that recipients of
blood stem cell preparations from G-CSF-treated donors received 5- to
6-fold more pre-DC2 than did recipients of bone marrow stem cell
products. Interestingly, human G-CSF-mobilized blood stem cells do not
cause a higher incidence of GVHD than marrow grafts,23,24
despite containing 10-fold more T cells.25 In mice,
pretreatment of donor mice with G-CSF enhances TH2-cytokine production
and reduces severity of experimental GVHD.26,27 These
studies suggest that pre-DC2 in G-CSF-treated blood may capture
alloantigen and undergo maturation after transfer into the host. These
DC2 may present alloantigen to donor T cells and induce them to undergo
TH2 differentiation and to limit GVHD (Figure).
The combination of G-CSF treatment and blood leukapheresis may offer,
for the first time, the possibility of generating sufficient DC2s for
immunotherapy of certain autoimmune diseases and GVHD. Understanding
the developmental pathway and regulation of pre-DC2 from hematopoietic
stem cells will be the next critical step in generating a large number
of DC2 for immunotherapy. Because the identity of mature DC2 in vivo
and the fate of the transferred pre-DC2 in recipient patients are
unclear, a direct correlation between pre-DC2 transfer with an
increased TH2 differentiation and a decreased GVHD remains to be established.
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Acknowledgments |
We thank Dr M. Andonian for graphic works and M. Gilliet for
critical reading of the manuscript. DNAX Research Institute is fully
supported by Schering-Plough.
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Footnotes |
Reprints: Yong-Jun Liu, Department of Immunobiology, DNAX
Research Institute of Molecular and Cellular Biology, 901 California
Avenue, Palo Alto, CA 94306.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Introduction
Acknowledgments