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Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2179-2191
REVIEW ARTICLE
In Utero Hematopoietic Stem Cell Transplantation: Ontogenic
Opportunities and Biologic Barriers
By
Alan W. Flake and
Esmail D. Zanjani
From the Department of Surgery and the Center for Fetal Diagnosis and
Therapy, Children's Hospital of Philadelphia, University of
Pennsylvania, Philadelphia, PA; and the Department of Medicine,
Veterans Administration Medical Center, University of Nevada, Reno, NV.
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INTRODUCTION |
IN UTERO HEMATOPOIETIC stem cell
transplantation (IUHSCTx) is a theoretical alternative to postnatal
stem cell transplantation (SCT) for the treatment of congenital
hematologic disorders that can be cured by SCT, and can be diagnosed
early in gestation. Advances in prenatal diagnosis and molecular
analysis now allow diagnosis of the majority of congenital hematologic
disorders by10 to 12 weeks' gestation. The evolution of
high-resolution ultrasound and precise interventional techniques have
solved the technical obstacles to performing early gestational cellular
transplants. Considering these advances, it stands to reason that there
is increasing clinical interest in performing IUHSCTx and that there will inevitably be an increasing number of attempts to treat fetuses with hematologic disorders in utero.
The rationale for consideration of IUHSCTx is based on normal
developmental ontogeny. The early gestational fetus is immunologically immature and uniquely tolerant to foreign antigen, allowing acceptance of allogeneic or xenogeneic cells without the need for
immunosuppression. Under specific circumstances, the fetal environment
appears permissive to engraftment of HSC without the requirement for
myeloablation. The maternal womb is the ideal sterile isolette,
allowing the potential for immunologic reconstitution before birth.
Finally, successful prenatal transplantation could preempt clinical
manifestations of the disease, avoiding the need for postnatal
treatment and the high cost in human suffering, and expense to society,
currently associated with SCT.1,2 This is the clinical
promise of IUHSCTx. To date, this promise remains unfulfilled. With
increasing experimental and clinical experience, the naive concept that
a simple transplant in utero might cure a large number of diseases has
given way to a realistic appreciation of the obstacles to successful
engraftment. Reality has forced reconsideration of the original
assumptions about fetal transplant biology, and resulted in formulation
of new questions. It has also resulted in the consideration of new strategic approaches for the therapeutic application of IUHSCTx, in a
variety of clinical circumstances.
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"NATURAL" HEMATOPOIETIC CHIMERISM |
The best supporting evidence that IUHSCTx might work remains an
"experiment of nature" first described by Owen in
1945.3 He observed that dizygotic cattle twins that share
cross-placental circulation were born chimeric for their siblings'
blood elements. This state of "mixed chimerism" persists for life
and is associated with specific transplantation
tolerance.4,5 Natural chimerism has been observed in other
species as well, most notably, humans6,7 and the cotton-top
tamarin (primate).8,9 Interestingly, it has been observed
that donor hematopoiesis in some chimeric animals can actually
predominate, with the persistence of very high levels of donor-derived
cells. This experiment of nature represents "proof in principle"
that, under specific circumstances, allogeneic donor cells can
competitively populate a hematopoietically normal recipient, with
substantial and stable levels of donor cell expression.
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EXPERIMENTAL HEMATOPOIETIC CHIMERISM AFTER IUHSCTx IN NORMAL ANIMAL
MODELS |
Efforts to reproduce "natural" chimerism in the laboratory by the
prenatal transplantation of allogeneic or xenogeneic HSC have had
variable degrees of success. The most successful animal model remains
the sheep. Early gestational transplantation of allogeneic, fetal
liver-derived HSC into normal sheep fetuses results in a high rate of
sustained multilineage hematopoietic chimerism10 that
persists for many years and is typically in the range of 10% to 15%
bone marrow (BM) and peripheral blood donor cell
expression.11 The fetal sheep model is also permissive for
widely disparate xenogeneic engraftment. Multilineage hematopoietic chimerism has been well documented after human fetal liver-derived HSC
transplantation12 and after transplantation of a variety of
human cord blood and adult BM-derived populations.13-18 In
addition, we have shown that chimerism in the human sheep model is
caused by the engraftment of pluripotent HSC by documentation of
long-term engraftment by donor cells on retransplantation into
second-generation fetal lamb recipients.19 In contrast to
the sheep, however, other normal animal models have shown much greater
resistance to engraftment after in utero transplantation. Although
chimerism has been achieved in the normal primate,20
goat,21 rat,22 and mouse,23-26 the
levels of engraftment are much lower and well below what might be
expected to be therapeutic for most hematologic diseases.
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EXPERIMENTAL HEMATOPOIETIC CHIMERISM AFTER IUHSCTx IN IMPAIRED ANIMAL
MODELS |
In contrast to normal animal models, it is clear that under
circumstances where there is a competitive advantage for normal cells,
high levels of donor cell engraftment can be expected. This was first
shown by Fleischman and Mintz27 in studies in W mutant anemic mouse strains that have a stem cell deficiency based on
the absence of c-kit. In utero transplantation of normal allogeneic
fetal liver cells by transplacental injection at 11 days gestation
resulted in rescue of severely anemic mice and complete reconstitution
by donor hematopoiesis. The degree of erythroid replacement correlated
with the degree of underlying anemia, with complete early replacement
by donor erythroid cells in the lethally anemic W/W homozygotes, and
partial but progressively increasing replacement by donor erythroid
cells in the sublethally anemic Wv/Wv
homozygotes. Donor white blood cell (WBC) engraftment was also seen in
the Wv/Wv recipients, but was not as extensive
as erythroid engraftment, mirroring the underlying severity of the
lineage defect. In a less severe model of anemia based on a different
mutation of c-kit (W41/W41),28 Blazar et al29
documented high levels of multilineage chimerism of congenic donor
cells with confirmation of HSC engraftment by repopulation of
irradiated secondary recipients. Similarly, in the mouse severe
combined immunodeficiency disease (SCID) model in which there is early
arrest of T- and B-cell development, Blazar et al30 have
demonstrated lymphoid reconstitution after IUHSCTx. In successfully
reconstituted animals, T and B lymphocytes were entirely of donor
origin. Although donor myeloid and erythroid elements could not be
consistently detected, the engraftment of donor HSC in the marrow was
clearly documented by retransplantation experiments. Thus, in the
presence of a lineage deficiency, IUHSCTx can selectively reconstitute
the defective lineage, but it appears that competitive pressure from
the normal host lineages prevents high-level multilineage donor cell
expression. More recently, engraftment was compared in the SCID mouse
model following IUHSCTx versus nonconditioned postnatal
SCT.31 There were a number of advantages favoring IUHSCTx
found in this study, including a lower risk of graft-versus-host
disease (GVHD) and more rapid and earlier lymphoid reconstitution of
the thymic and splenic compartments. Recent studies in the nonobese
diabetic (NOD)/SCID mouse confirm and expand upon these
observations.32 In this model, the defect in T- and B-cell
development is the same as the SCID mouse but in addition there are
known defects in natural killer (NK) cells and antigen
presentation.33 IUHSCTx in NOD/SCID recipients results in
multilineage engraftment with increasing donor cell expression over time.
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CLINICAL EXPERIENCE WITH IUHSCTx |
There have now been 26 human cases of IUHSCTx that have been reported
in the literature or are personally documented by the authors. There
have also been a significant number of attempts that are either pending
or have not been reported that cannot be commented upon in this review.
Transplants have been performed by numerous investigators, for many
different diseases, using a variety of transplant protocols. The
authors have recently reviewed the reported clinical experience with
IUHSCTx2 and this is updated in
Table 1. It is important to note that of
the 20 non-SCID cases, 12 have been performed beyond 14 weeks'
gestation, when the human fetus would be expected to be
immunocompetent. In addition there have been at least 3 early deaths, 1 from sepsis (fetal liver source) and 2 procedural that should, in the
modern era, be avoidable. Two cases (1 SCID and 1  -thalassemia)
underwent umbilical blood sampling at 24 weeks, and termination was
performed when no peripheral donor cell expression was
found.34,35 We now know that peripheral expression of
engrafted donor cells does not occur until near term and it is
interesting that at autopsy, the -thalassemia fetus had donor cells
detected in multiple areas of extramedullary hematopoiesis.
The only clear successes, or claims of success, have been in
immunodeficiency disorders in which there is a selective advantage for
donor cells.36-39 It is clear from these reports that
X-SCID can be effectively reconstituted by paternal CD34-enriched BM. Our patient is now 4 years old and maintains excellent cellular reconstitution and has shown the ability to specifically respond to
vaccinations, including the novel T-cell antigen  X174, which requires intact T-cell help for B-cell Ig class switching (unpublished data, June 1999). In other immunodeficiency disorders,
such as chronic granulomatous disease (CGD) (3 cases)40-42
or Chediak-Higashi Syndrome,34 no engraftment was observed
at birth. Two recent CGD cases were of particular interest because they
failed, despite early gestational transplantation and the use of either
the same protocol utilized for successful treatment of
X-SCID,41 or transplantation of more highly HSC-enriched
donor cells.42
The treatment of hemoglobinopathies by IUHSCTx has thus far been
unsuccessful. There have been 5 cases of  -thalassemia attempted, of
which 2 were intrauterine deaths.35,40,43,44 The 3 others were transplanted at 12,18, and 25 weeks' gestation. The transplant at
12 weeks used fetal liver as a donor source and was initially reported
as being engrafted with polymerase chain reaction (PCR), evidence of the presence of Y chromosome and HbA levels of 0.9% at
birth, which subsequently increased to 30% at 1 year of
life. This patient has since been reported to have lost
engraftment and remains transfusion dependent.37,40 There
have been 3 reported attempts to treat -thalassemia by
IUHSCTx.34,44,45 One used cryopreserved fetal liver as a
donor source at 15 weeks' gestation and failed. One had evidence of
donor cell engraftment in areas of extramedullary hematopoiesis, but
was terminated because of lack of peripheral donor cell expression at
24 weeks. The third received the same protocol of CD34-enriched
paternal BM successfully used for X-SCID, with the first transplant
administered at 13 weeks' gestation. The fetus required blood
transfusions for fetal anemia and had only microchimerism of donor
cells detected at birth. This patient was, by report, tolerant to donor
antigen by mixed lymphocyte reaction. Only one attempt has been
reported for sickle cell disease.44 Cryopreserved fetal
liver was used at 13 weeks' gestation and no detectable engraftment
was noted after birth.
Finally, 5 attempts have been reported to treat fetuses with metabolic
storage diseases by IUHSCTx.40,43,46,47 Two of these were
performed too late in gestation (34 and 23 weeks) to expect
engraftment, and none was observed. One was performed for Nieman-Pick
Type A at 14 weeks and the engraftment status is unclear, but there was
no clinical benefit. A patient with Hurler's disease was transplanted
using fetal liver and had evidence of low-level engrafment with
evidence of increasing enzyme production, but had severe clinical
manifestations of the disease, with death at age 2. In the third case,
an attempt was made to transplant a fetus with globoid leukodystrophy
with a higher dose of CD34-enriched BM cells. Adequate T-cell depletion
was not performed, and in excess of 107 CD3+
cells/kg fetal weight were delivered to a 13-week gestation fetus. The
fetus died at 20 weeks' gestation, with autopsy findings in an
autolyzed fetus of "overwhelming myelopoiesis" as documented by
myeloperoxidase staining.47 A more likely cause of death was GVHD, which has not been convincingly excluded by the authors.
In total, this limited experience supports the presence of significant
barriers to engraftment in human fetuses after IUHSCTx in diseases
where there is little or no selective advantage for normal cells. The
nature of this barrier is poorly understood.
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THE ENGRAFTMENT BARRIER |
The primary determinant for expanding the clinical application of
IUHSCTx will be the ability to improve engraftment in the hematopoietically competitive recipient. To improve engraftment in
competitive prenatal environments, the unique transplantation biology
of the prenatal recipient must be better defined and the barriers to
engraftment identified. IUHSCTx differs in 3 major respects from
postnatal SCT. First, there is abundant evidence that the myeloablative
regimens and irradiation used to permit engraftment after postnatal SCT
alters the biology of the recipient hematopoietic
microenvironment.48-53 Second, after IUHSCTx, there is
competition from a preexisting, vigorous, host hematopoietic compartment that is not present after myeloablation. Third, there is
the underlying framework of normal hematopoietic and immunologic ontogeny. Therefore, the paradigm of postnatal SCT does not necessarily apply to IUHSCTx. Insight into the barriers to prenatal engraftment can
only be obtained by consideration of biologically relevant competitive
model systems. Figure 1
schematically depicts the models and contrasts the
competitive circumstances for donor cells. The following discussion
summarizes what, in the authors' view, is the current experimental
evidence derived from these models that is directly relevant to
IUHSCTx. This evidence will be presented in the context of 3 assumptions that have been used in the past as a presumptive basis for
IUHSCTx.
Assumption no. 1: There is "space" in the expanding fetal
hematopoietic compartment that is available for homing and engraftment
of donor cells.
During fetal development, there is sequential migration of
hematopoiesis from the yolk sac and/or para-aortic splanchnopleure to
the fetal liver and, subsequently, to the BM.54,55 There is
an associated exponential expansion of the hematopoietic compartment with presumably continuous formation of new microenvironmental sites,
or "niches," for homing and engraftment of circulating HSC. We
and others have suggested that the number of "niches" available
for engraftment in the prenatal microenvironment probably exceeds the
availability of niches in the postnatal environment, offering one
explanation for the ability to engraft fetal recipients without
myeloablation. That precept has been challenged by a number of recent
prenatal and postnatal observations. The dogma that the creation of
"space" is required for the engraftment of donor cells after
birth has been increasingly challenged, primarily on the basis of data
derived from the syngeneic nonmyeloablated mouse model, originally
described by Brecher et al56 and recently revitalized by
Stewart et al.57 In this model system, analogous to
IUHSCTx, there is no irradiation effect and the host hematopoietic compartment is intact. However, it differs from allogeneic IUHSCTx in
that engraftment occurs in the postnatal BM environment and donor and
recipient cells are genetically equal and syngeneic with stromal elements.
In this model, stepwise increases in donor cell engraftment can be
achieved with repetitive large doses (1 to 2 × 109
cells/kg) of syngeneic donor BM cells.57,58 This suggests that there is a steady state of open receptive sites in normal bone
marrow. More recent interesting observations in this model include the
observation that no saturation point could be demonstrated with
increasing doses of donor cells (up to a dose of 1 to 2 × 109 cells/kg administered on 5 consecutive days), and that
a single overwhelming dose of cells (0.5 to 1 × 1010
cells/kg) resulted in equivalent engraftment at 7 to 14 weeks after
transplantation.59 The observations of no saturation point
and equal engraftment with overwhelming doses of cells support actual
displacement of host cells by an excess of circulating donor cells. In
this model, donor cell engraftment appears quantitative at the stem
cell level so that peripheral donor cell expression is determined by
the ratio of donor to host HSC. This is in keeping with observations on
stem cell kinetics in nonirradiated systems. Whereas in the irradiated
mouse or large animal it is well documented that engraftment of a
single or few HSC can provide oligoclonal reconstitution, providing an
"amplified" readout of engraftment,60,61 studies of
stem cell kinetics in normal mice62-64 and allophenic
mice65-67 suggest that nearly all HSC regularly cycle and
that the sum of hematopoiesis is provided by many simultaneously
cycling HSC. Thus, engraftment in this system of a single or few HSC
would be relatively difficult to detect, corresponding to the
observations in the in utero models
(Fig 2).
View larger version (58K):
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| Fig 2.
Comparison of engraftment characteristics in various
hematopoietic systems that differ in their donor and host HSC
competitive capacity, assuming a model of relatively frequent stem cell
cycling in nonirradiated systems. (A) Irradiated postnatal environment.
Damaged microenvironment results in engraftment of a few donor HSC that
reconstitute the recipient by oligoclonal expansion, allowed by the
absence of host cell competition. There is an amplified "readout"
of a few engrafted donor HSC. (B) Allogeneic IUHSCTx. Although a few
donor HSC may engraft, they are at best equal, or more likely, at a
competitive disadvantage to host HSC (mismatched stroma). Therefore,
the engraftment is obscured by host hematopoiesis leading to a readout
of minimal or microchimerism. (C) The syngeneic nonmyeloablated model.
Engraftment through serial transplants or massive doses of donor cells
results in multiple-donor HSC engrafted that can equally compete
(genetically identical HSC/matched stroma) with host HSC. Engraftment
readout is quantitatively reflective of No. Donor HSC/No. Host HSC. (D)
Allogeneic IUHSCTx into a host with impaired HSC. Only a few donor HSC
engraft, but oligoclonal expansion can occur despite stromal mismatch,
due to reduced host HSC competition, leading to an amplified readout of
donor HSC engraftment.
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In the fetus, we have assumed that "space" would be relatively
available due to the rapid expansion of the fetal hematopoietic compartment that, by necessity, must include the rapid formation of new
niches. In reality, however, the availability of niches for donor cell
engraftment would depend on the dynamic balance of stromal and
hematopoietic cell expansion. What is the balance of stromal receptive
sites and circulating hematopoietic progenitors in the fetus? There is
limited direct data available. In a developmental study of stromal
(CFU-F) and hematopoietic elements in the fetal liver and BM, Wolf et
al68 observed that stroma formation preceded hematopoiesis
in the fetal liver (at 13 days) and BM, but that hematopoietic activity
increased very rapidly after the establishment of stroma. It has been
well documented that the number of HSC and progenitors circulating in
fetal peripheral blood is much higher than the number in cord blood, or
after birth, supporting relative HSC excess.69 Thus, there
is little reason to expect that once a niche forms in the fetal
environment it will remain available for donor cell engraftment.
There are also a number of direct observations that support limited
host receptivity as a barrier to engraftment in utero. In the fetal
lamb model using allogeneic or xenogeneic fetal liver- or BM-derived
donor cells, log-fold increases in donor cell dose (106 to
1010 cells/kg) increase engraftment to some extent, but a
plateau is reached where further increases in donor cell dose have no
effect.70 This suggests that available receptive sites can
be saturated with donor cells, limiting further increases in donor cell
engraftment. In contrast to the syngeneic, nonmyeloablated mouse model,
the ability of overwhelming doses of donor cells to "displace"
host cells in the fetus has not yet been shown. Also in the fetal lamb
model, transplantation of divided doses of donor cells at intervals
increases engraftment significantly above that achieved by
transplantation of the same number of cells in a single
dose.46 This observation is identical to the results in the
syngeneic nonmyeloablative mouse model and suggests that new receptive
sites form, or become open, in the time interval between transplants to
allow engraftment of additional donor HSC. Thus, the available evidence
suggests that there is not an abundance of space available in the
fetal microenvironment, relative to the postnatal BM microenvironment,
and that a limited number of receptive sites is at least one component
of the barrier to engraftment in normal fetal recipients.
Assumption no. 2: Donor HSC can effectively compete with host
HSC to achieve significant donor cell expression after IUHSCTx.
By this assumption, successful reconstitution is dependent on the
ability of an initial inoculum of donor HSC to survive and expand into
the host hematopoietic space. If donor cells have a competitive
advantage, then even the engraftment of a relatively limited number of
donor HSC could ultimately reconstitute the recipient. In
normal animal models, we have observed after IUHSCTx little evidence
that donor cells can expand their presence in the host milieu, except
in the human/sheep model when a competitive advantage is conferred by
infusion of donor species-specific human cytokines.12,71 In
contrast, there is abundant evidence that in circumstances of donor
cell competitive advantage, donor cells rapidly expand into a deficient
compartment. The high levels of donor hematopoiesis achieved in
c-kit-deficient mouse strains in which there is a proliferative defect
in host HSC support this hypothesis. Mintz et al72 have
documented full reconstitution in this model after IUHSCTx by 1 or 2 normal HSC. In a separate study, Fleischman73 showed that
when donor cells have equivalent c-kit function to host cells, W mutant
mice do not accept grafts more readily than wild-type animals,
supporting a competitive advantage, rather than space, as the primary
determinant of donor cell expression.
Experimental evidence also supports the ability of limited numbers of
donor HSC to fully reconstitute specific defects in host lineage
development. In the mouse SCID model30 as well as in a
human X-SCID patient,38 the number of engrafted HSC in the
BM remains relatively low despite full reconstitution of the defective
lineage. In this system, there is no selective advantage at the HSC
level. Thus, the number of donor HSC do not appear to expand over time,
consistent with a mechanism of reconstitution by expansion of
lineage-committed cells that are replenished from a limited pool of
stem cells.
In another recent study, the syngeneic nonmyeloablation model was
modified by exposure of the host to minimally myeloablative radiation
(100 cGy). Syngeneic donor cells showed high levels of donor cell
engraftment despite transplantation of relatively low numbers of
cells.74 Transplantation of donor cells receiving the same
dose of radiation reduced donor cell engraftment to 14% of that seen
with nonirradiated cells, strongly supporting the concept that it is
primarily the ability of host cells relative to recipient cells to
compete, rather than space, that determines ultimate engraftment.
Another model system that is highly analogous to the
biology of IUHSCTx is the allophenic mouse.75 In this
model, allogeneic cells coexist, in an immunologically tolerant system,
from the embryonic stage forward. As in IUHSCTx, allogeneic cells may
have genetic differences in their competitive capacity; however, there is complete developmental mixing of the cells from day 2 of gestation and, more importantly, all cells, including stroma, thymus, and other
tissues, are chimeric. In allophenic mice in which one strain has an
HSC pool with relatively rapid cycling kinetics (DBA/2 v
C57BL/6),76 the early kinetics of engraftment favor DBA/2 stem cells until they become senescent and C57BL/6-derived
hematopoiesis becomes predominant.65 The allophenic studies
show that in a chimeric microenvironment in which allogeneic cells
compete, the level of expression is a function of the genetically
defined competitive capacity of the HSC.
However, the ability of donor cells to compete is not purely HSC
derived. A number of recent findings suggest that in nonirradiated systems, HSC stromal interaction is at least partially MHC restricted. Transplantation of a donor microenvironment (bone containing intact stroma) allows engraftment of donor HSC in usually resistant strain combinations.77,78 In a compelling study, Hashimoto et
al79 transplanted donor autologous microenvironment (bone)
and major or minor major histocompatibility complex (MHC) mismatched
microenvironment into irradiated allogeneic recipients. Observations
included the following: (1) increased cellularity and number of
progenitors in MHC-matched BM versus recipient or third-party BM; (2)
the ability to engraft HSC when combined with the autologous, but not
mismatched, microenvironment into previously resistant strain combinations; (3) the dependence of this advantage on MHC with no
restriction demonstrated for minor antigen disparity; and (4) MHC
restriction was abrogated by pretransplant irradiation of the donor
microenvironment. In addition, in other studies autologous but not MHC
disparate "facilitator cells" are effective in enhancing engraftment.80,81 In combination, these studies support the concept that in nonirradiated recipients, donor cells must have their
own supporting stromal elements to optimally compete with recipient cells.
In summary, there is clearly overlap between the hypotheses that
available space and competitive capacity limit donor cell engraftment.
Data suggest that if donor and host cells are truly competitively
equal, donor cell expression will quantitatively reflect the ratio of
donor to host HSC. Thus, a large number of HSC would need to be
engrafted to provide clinically significant levels of donor cell
expression, and the number of receptive sites may be a critical
limitation. However, under circumstances of even minimal imbalance
favoring host hematopoiesis, the primary barrier to donor cell
engraftment and expression will be host cell competition. Thus, it
would appear that after IUHSCTx, donor hematopoiesis is limited by both
an inability to engraft an adequate number of donor cells, because of a
lack of receptive sites, and the subsequent inability of this limited
number of engrafted cells to expand into the host hematopoietic
compartment, because of what is probably a competitive disadvantage.
Hypothesis no. 3: The early gestational fetus is immunologically
tolerant of foreign antigen.
Since Billingham et al's82 classic observations of
"acquired" immunologic tolerance, the phenomenon of fetal
tolerance has been relatively accepted. Evidence is now overwhelming
that the fetal thymic microenvironment plays a primary role in
determination of self recognition and repertoire of response to foreign
antigen. Pre-T cells undergo positive and negative selection during a
series of maturational steps in the fetal thymus that are controlled by
thymic stromal cells.83,84 The end result is deletion of T-cell clones with high affinity for self antigen in association with
self-MHC, and preservation of a T-cell repertoire against foreign
antigen. Therefore, theoretically at least, introduction of foreign
antigen before thymic processing should result in presentation of donor
antigen in the thymus with clonal deletion of alloreactive T cells.
However, it is important to note that the mechanism of central thymic
tolerance has been defined primarily in T-cell receptor
(TCR) transgenic mice. In these mice, thymic maturation of lymphocytes
occurs in an environment of unregulated high levels of TCR with high
affinity for a specific self antigen, which is expressed from the
earliest to the latest stages of thymic development.85-87 This is distinct from the clinical situation after IUHSCTx in which
there are a large number of circulating antigens interacting with
recipient TCRs of varying affinity for donor antigen. Differences in
thymic maturation of lymphocytes in normal mice from the defined mechanisms in TCR transgenic mice have been
recognized.88,89 In addition, there are other mechanisms of
rejection including NK- or B-cell-mediated response that are
relatively poorly understood. In fact, experimental efforts to induce
tolerance by prenatal presentation of antigen have had inconsistent
results. In the initial report of Billingham et al,82 only
3 of 5 survivors were tolerant of donor skin grafts (in an MHC class I
disparate but class II matched strain combination), and in many other
investigations, particularly in xenogeneic combinations, results have
been inconsistent.90-92 These classical studies are
difficult to interpret because no analysis of donor cell chimerism
could be performed. In more recent studies, we failed to demonstrate
specific tolerance induction for allogeneic renal grafts in recipient
lambs made chimeric by in utero transplantation of T-cell-depleted
adult marrow, despite the measured presence of 2% to 5% donor
hematopoietic engraftment.93 Carrier et al24
documented specific tolerance to skin grafts in only 3 of 22 mice with
microchimerism after fully allogeneic IUHSCTx. In this same
microchimeric model we have shown that tolerant animals exhibit a
combination of partial clonal deletion and clonal anergy of residual
donor reactive cells, whereas in nontolerant animals no evidence of
deletional tolerance is present.94 In general, these
studies support the existence of the phenomenon of fetal tolerance but
suggest that it may be conditional and dependent on timing and
appropriate presentation of antigen in the fetus.
| |
OVERCOMING THE ENGRAFTMENT BARRIER |
Consideration of IUHSCTx in the context of the above discussion
suggests a number of strategies by which higher levels of engraftment
in competitive systems might be achieved. These strategies fall into
the category of either increasing the number of donor HSC engrafted or
increasing the competitive capacity of donor-derived hematopoiesis
relative to host hematopoiesis. Strategies designed to increase the
number of donor HSC engrafted must assume a model of at least equal
competitive capacity of the donor cells after engraftment. In this
model, the level of engraftment would be equal to the fractional
representation of donor HSC in the host environment. By this model, it
is clear that far higher numbers of HSC would need to be engrafted than
are currently engrafted after IUHSCTx. Direct approaches of increasing
the number of donor HSC by increasing cell number or HSC enrichment
have been tested to a limited extent in animal models without dramatic
increases in engraftment. However, it is fair to say that the upper
limits of this strategy have not been explored in fetal models, and if host cells can be "displaced" by massive doses of donor
cells,59 such a strategy might be successful. The clinical
limitation to this strategy when using adult BM as a donor cell source
is the T-cell dose administered with higher numbers of
CD34+ cells.47 Another direct approach is to
perform multiple transplants in hopes of maintaining circulating levels
of donor cells to engraft as niches form or become available. This
strategy has been highly successful in the sheep with significant
increases in engraftment even when the same absolute numbers of cells
are given.46 Multiple prenatal transplants have also been
given clinically with success in X-SCID,38,39 where there
is a selective advantage for normal cells, but no appreciable
engraftment was achieved using similar protocols in CGD or
-thalassemia.2,45 Other approaches, such as selective
strategies to improve homing and engraftment of donor HSC or the use of
specific populations of donor cells with optimal engraftment
characteristics, may be useful but await experimental support. Finally,
methods to minimally ablate the fetus to increase the number of
receptive sites have, in general, not been investigated and would
require absolute assurances of safety and absence of long-term
morbidity before clinical application.
As delineated above, there is no reason to believe that engraftment of
more HSC would necessarily lead to higher levels of engraftment. The
weight of evidence suggests a model for engraftment following IUHSCTx
in which there is not only limited receptivity to engraftment, but also
a competitive disadvantage for donor cells. In this circumstance,
engraftment of even a large number of donor cells would be overwhelmed
by host hematopoiesis. Strategies to improve engraftment assuming this
model generally depend on improving the relative competitive capacity
of the donor cell population. Once again there is overlap between the
models. The use of donor-specific stromal
cotransplantation has been experimentally promising in the sheep model
and significantly increases short- and long-term donor cell
expression.96 Whether the improvement in engraftment is due
to BM "conditioning" to provide more receptive sites, or to
improved competition by donor cells caused by their interaction with
matched stromal elements is unknown. However, even if competitive
capacity were equalized, clinically significant donor cell expression
would still require the engraftment of higher numbers of donor HSC than
have generally been achieved after experimental or clinical IUHSCTx. On
the other hand, strategies that would provide an actual competitive
advantage for donor cells would theoretically be effective with
engraftment of even a few donor cells, because they would be able to
expand into the host compartment. It should be emphasized that the
strategy of prenatal tolerance induction, by establishment of minimal
chimerism, followed by postnatal boosting of engraftment using
minimally ablative regimens, would theoretically not only engraft more
cells, but, depending on the regimen (ie, sublethal irradiation), might
also provide a competitive advantage to the postnatally transplanted
donor cells. There is experimental and clinical evidence for the
feasibility of this strategy.74,97 At the present time,
most of the other proposed strategies require experimental support.
| |
MATERNAL AND FETAL RISK |
Any consideration of fetal therapy must take into consideration
maternal and fetal risk. The risks of IUHSCTx can be divided into
procedural risks and biological risks for the mother and fetus. The
procedural risks are relatively well characterized and can be
extrapolated from extensive obstetric experience with chorionic villus
sampling (CVS), amniocentesis, and fetal transfusion and
blood sampling. The maternal risks from these procedures (ie, infection, hemorrhage, infertility) independent of fetal loss is
negligible. The risk of fetal loss or other fetal complications from
CVS has been well documented and is less than 1%.98 The procedural risk of IUHSCTx before 14 weeks' gestation has been previously analyzed and is probably also less than 1% per
transplant.2 Therefore, using our current protocol of 3 transplants, we would anticipate a procedural fetal loss rate of no
more than 4%. The biologic risks to the mother and fetus include
infection with bacterial, fungal, or viral pathogens from the donor
cells, fetal GVHD, Rh sensitization for future pregnancies (if the
donor cells are Rh-positive and mother and fetus are Rh-negative), and
maternal graft-versus-host phenomenon ("autoimmune" disease) if
donor lymphocytes cross the placental barrier and survive in the
mother.99 Many of these risks can be minimized by using
adult sources of donor cells (rather than fetal liver) with careful
screening for infectious disease, and scrupulous T-cell depletion. We
currently limit the T-cell dose to less than 1 × 105
CD3+ cells/kg estimated fetal weight as a precaution
against GVHD. The risk of Rh sensitization can be avoided by the use of
Rh-negative donor cells, if possible; if not, sensitization can be
prevented by administration of Rh-immune globulin. The risk of donor
cells crossing the placenta and surviving in the maternal circulation is probably remote, but no data exist. An important concern is whether
IUHSCTx would in any way prohibit what is considered current optimal
standard of care for a given disease after birth. At the present time
there is no rationale to expect that it will, and in fact there is good
reason to think that it can potentially facilitate postnatal SCT if
tolerance is achieved.
| |
DISEASES THAT MAY CURRENTLY BENEFIT FROM IUHSCTx |
It is clear from the above discussion that there are a large number of
diseases that might be considered as targets for IUHSCTx. However, it
is also clear that each disease must be considered individually and may
or may not have favorable enough biology or an adequate rationale for
attempting IUHSCTx. Table 2
categorizes selected candidate diseases by rationale for
IUHSCTx. In contrast to a decade ago, there is now
adequate clinical and experimental information available to guide
rational clinical application of this approach.
In contrast to postnatal SCT, IUHSCTx strives to create a level of
mixed chimerism adequate to ameliorate the clinical manifestations of
the disease. Therefore, in consideration of various diseases, two
important questions must be asked: (1) What level of engraftment would
be adequate to treat a specific disease? and (2) Is there reason to
believe a competitive advantage for donor cells is present? From the
preceding discussion, it would be unreasonable at the present time to
expect a conventional protocol for IUHSCTx to be successful, in the
absence of either a selective advantage for donor cells, or the
requirement for a very low level of donor cell engraftment to treat the
disease. This limits considerably the number of diseases for which
IUHSCTx, as currently practiced, can be rationally applied with
reasonable expectation of success.
The most biologically favorable target diseases are those that offer a
prenatal selective advantage for donor cells. The best examples of
diseases in this category are the SCID disorders, particularly the
characterized mutations encoding the common cytokine receptor  chain
(X-SCID), or components of it's signaling pathway (ie, Jak 3 or
ZAP-70).100 Based on the available clinical and experimental evidence, it is likely that any member of this group of
disorders can be effectively treated by IUHSCTx, using established protocols, with results comparable to the reported results for X-SCID.38 It is important to emphasize that early postnatal T-cell-depleted haploidentical SCT is highly successful for T-cell reconstitution in these patients, but that B-cell function often remains deficient.101 Whether IUHSCTx can improve
on the reconstitution achieved by early postnatal transplantation can
only be addressed by further clinical trials comparing the two approaches.
Another immunodeficiency disorder in which a selective advantage for
normal cells exists is Wiskott-Aldrich syndrome (WAS). Direct evidence
of a selective advantage for normal cells is documentation of nonrandom
inactivation of the X chromosome in multiple lineages of peripheral
blood cells102,103 and early lineage hematopoietic cells104 in carriers of WAS, similar to that seen in the
T-cell lineage in carriers of X-SCID.105 A
selective advantage for normal progenitors and a proliferative defect
in host T cells should provide favorable biology for successful IUHSCTx.
A selective advantage for normal cells would also be expected in
diseases in which somatic mosaicism and spontaneous reversion have been
documented to occur. In these diseases there is presumably a survival
advantage for the spontaneously corrected cells.106 Such
correction has been noted in adenosine deaminase
deficient (ADA) SCID,107 Fanconi anemia,108 and
Bloom's syndrome,109 the latter two of which are
chromosomal breakage syndromes. This experiment of nature shows the
potential for selective expansion of a small number or single clone of
normal cells with correction of the disease.
Finally, in this category (and possibly the next) are diseases that
require very low levels of donor cell engraftment to effect a cure.
Therapeutic or near-therapeutic levels of engraftment might be
achievable by "standard" protocols of IUHSCTx in diseases such as
CGD and hyper IgM syndrome. It has been well documented in animal
models that the immune deficit in CGD can be corrected by as few as 5%
normal neutrophils.95 In X-linked hyper IgM syndrome, a
disease caused by a mutation in the CD40 ligand on T
cells,110 carriers have been identified in which the normal gene has been predominantly silenced.111 In these carriers
even a few percent of T cells expressing the normal gene can result in
normal class switching and IgG production. As discussed above, two
recent attempts to treat fetuses affected by CGD with enriched paternal
BM have resulted in no detectable engraftment, suggesting that to
effectively treat these diseases further optimization of current
IUHSCTx protocols will be needed.
| |
DISEASES THAT MAY BENEFIT FROM IUHSCTx IN COMBINATION WITH POSTNATAL
STRATEGIES |
Although in the absence of a selective advantage only low-level
chimerism can be reasonably expected after IUHSCTx, low-level chimerism may carry with it the tremendous advantage of donor-specific transplantation tolerance. This would have the clinical effect of
providing a donor without antigenicity after birth. As discussed above,
in the absence of immune response, there is increasing evidence that
engraftment can be achieved with minimally myeloablative strategies.
Particularly for diseases that have been shown to be treatable by
stable mixed chimerism, postnatal "booster" transplants could be
performed to augment the minimal chimerism achieved in utero with
relatively minimal toxicity (Fig 3).
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| Fig 3.
Strategy of combined IUHSCTx and minimally myeloablative
same-donor postnatal SCT. This strategy presupposes the use of
adult-derived donor cells and is dependent on specific tolerance
induction and, presumably, the establishment of at least minimal donor
HSC engraftment. Methods to improve the efficiency of tolerance
induction such as cotransplantation of donor-derived antigen-presenting
cells (APCs) may prove useful in the future. If effective, this
strategy could be rationally applied to diseases ameliorated by low or
moderate levels of mixed hematopoietic chimerism and, potentially, to
any disease effectively treated by postnatal SCT in which a matched
sibling donor is not available.
|
|
The hemoglobinopathies are the primary candidate diseases for this
approach.112 BM transplantation (BMT) is currently the only
curative therapy for the hemoglobinopathies. However, in the absence of
a matched sibling donor, results have been compromised by
treatment-related toxicity,113-116 limiting the option of
cellular therapy to the minority of affected patients. The early
gestational prenatal diagnosis of the hemoglobinopathies is well
established and could potentially be applied to all pregnancies known
to be at risk.117 Thus, prenatal strategies warrant consideration.
The prenatal hematopoietic biology of the - and -thalassemias and
sickle cell disease (SCD), in the context of IUHSCTx, are different and
should be considered separately. In the case of -thalassemia-1,
-globin-dependent hemoglobin production (Hb F) begins at 8 weeks'
gestation.118 By 10 weeks, physiologic evidence of fetal
anemia can be observed by ultrasound (placentomegaly). By 12 to 14 weeks, fetal hydrops (high-output cardiac failure) may be
observed.119 During this time the fetus develops
ineffective erythropoiesis in the fetal liver and abnormal sites of
extramedullary hematopoiesis. Therefore, the fetal hematopoietic
microenvironment is hypercellular and the fetus is anemic. In contrast,
-globin-dependent hemoglobin production does not occur until after
birth. Production of Hb F is normal in -thalassemia major and SCD
during fetal life and, therefore, the fetal microenvironment is
relatively normal in its competitive capacity. Ineffective
erythropoiesis begins with the switch to adult hemoglobin after birth
and may provide a postnatal selective advantage for donor-derived erythropoiesis.
There are experimental data available that support the concept of
treatment of thalassemia by the creation of mixed
chimerism.120-122 A selective advantage for donor
erythropoiesis based on a survival advantage for donor
erythroid-committed progenitors due to ineffective host erythropoiesis
and/or the relative half-life of mature donor and recipient red blood
cells may exist. Clinical observations on mixed chimerism after
postnatal BMT for -thalassemia123,124 and
SCD115 support the presence of a selective advantage for donor-derived erythropoiesis. In addition, in -thalassemia there is
evidence that second transplants using minimally myeloablative regimens
can augment the presence of minimal chimerism.97
| |
DISEASES THAT ARE UNLIKELY TO BENEFIT FROM IUHSCTx |
This category of diseases would include hematologic disorders not cured
by postnatal BMT, diseases that have no selective advantage and require
near-complete hematopoietic replacement to effect a cure, and diseases
that have central nervous system (CNS) manifestations requiring
large-scale CNS repopulation for prevention of the clinical disease.
At the present time, most metabolic storage diseases would fall into
this category. In some storage diseases there has been no benefit or
improvement in the CNS manifestations after BMT (ie, Sanfilippo and
Hunter syndromes) and there is no rationale for IUHSCTx.125
Those storage diseases that have been corrected by postnatal BMT such
as Gaucher's disease126 or Maroteaux-Lamy syndrome127 (minimal CNS involvement) require higher levels
of donor cell engraftment than are currently attainable by IUHSCTx, but
could be candidate disorders for prenatal tolerance induction if no
matched donor is available. Another group are those in which BMT has
corrected the peripheral manifestations of the disease and arrested the
neurologic deterioration, but not reversed preexisting neurologic
injury, ie, adrenoleukodystrophy and Hurler's
disease.125,128 In these diseases the neurologic injury may
begin before birth. The primary question is whether donor HSC-derived
microglial elements would populate the CNS providing the necessary
metabolic correction within the blood-brain barrier. In a sheep model
of Ceroid-Lipofuscinosis, IUHSCTx resulting in levels of donor cell
chimerism of approximately 10% in peripheral blood failed to affect
the clinical course of the disease.129 Maturation of the
blood brain barrier restricts access to the CNS of transplanted cells
or the deficient enzyme. Although there is good evidence for origin of
CNS glial cells from BM, the timing of their differentiation and
migration to the CNS is unclear and probably quite
early.130 Thus, even with relatively high levels of
systemic engraftment, there may be inadequate enzyme production within
the CNS to effect a cure. At the present time, it would seem that this
group of diseases is the least biologically attractive group for
IUHSCTx. In the future, new approaches such as CNS-directed gene
therapy, or cellular therapy131 using CNS "stem
cells" or "mesenchymal stem cells" in combination with
IUHSCTx, can be envisioned.
| |
ETHICAL CONSIDERATIONS OF THE FETUS AS A PATIENT |
Because of the experimental nature of IUHSCTx and considerations unique
to fetal therapy in general, it is essential to develop an ethical
framework for nondirective counseling of patients and families.
Fortunately, the ethical framework for the field of fetal therapy has
been relatively well developed.132 The concept of the fetus
as a patient, and when a fetus has independent moral status, has been
rationally addressed by McCullough and
Chervenek.133 They argue that the previable
fetus has no independent moral status, and that all arguments to that
effect on religious, philosophic, or moral grounds are impossible to
bring to closure. Rather, the previable fetus should be considered to
have "dependent" moral status. The status of the previable fetus
is totally dependent on the mother's autonomous decisions. It follows
that only she can present the fetus as a patient for treatment.
However, because of the experimental nature of IUHSCTx, she has no
moral obligation to present her fetus for experimentation. Thus, the
moral imperative for the investigator is to respect the pivotal status
of the mother in the decision to treat her fetus. Implicit in this
moral imperative is the necessity for accurate, honest, and
nondirective counseling in the informed consent process. A key
component of counseling is to assure that the parents understand the
options, including postnatal treatment, and potential outcomes. This
requires discussion with pediatric bone marrow transplant physicians or
immunologists regarding their future child's disorder and prospects
with conventional treatment. It is inappropriate to convince a patient
who would otherwise terminate the pregnancy that an unproven,
experimental procedure (ie, IUHSCTx) is her best option.
The ethical questions in case selection are also similar in many
respects to those with other fetal therapeutic endeavors and can be
discussed in the context of benefit and risk to the subjects involved.
Determination of risk and benefit may be somewhat arbitrary and may be
influenced by a mother's experience with previous children or family
members. The assessment of benefit is complicated by variable
phenotypic expression of some genotypes, ie, it may be difficult to
predict the severity of some diseases based on known genotype and
previous family history. If risks are low, the required benefit can be
relatively small and a wider spectrum of candidate diseases could be
treated. If, on the other hand, risk is high, then the required
expectation of benefit should be high and only a few diseases would be
reasonable candidates. Until wider experience is gained with IUHSCTx,
this risk-to-benefit analysis will remain imperfect, but at the present
time the risks appear small relative to the potential benefits.
Therefore, it seems premature to make absolute statements about
appropriate candidate diseases for prenatal therapy, although
application should be based on rational expectation of success based on
a thorough understanding of the field. Further insights into the biology of prenatal transplantation will undoubtedly yield more successful therapeutic strategies based on IUHSCTx in the future.
| |
FOOTNOTES |
Submitted February 4, 1999; accepted June 23, 1999.
Supported in part by Public Health Service Grants No. HL 52954 (A.W.F.), HL49042-04 (E.D.Z.), HL48378 (E.D.Z.), DK51427 (E.D.Z.), and
HL52955 (E.D.Z.); funds from the Ruth and Tristam C. Colket Jr. Chair
in Pediatric Surgery; and by the G. Harold and Leila Y. Mather's
Charitable Foundation.
Address reprint requests to Alan W. Flake, MD, Department of Surgery,
Children's Hospital of Philadelphia, Abramson Pediatric Research
Center, Room 1102D, 34th St and Civic Center Blvd, Philadelphia, PA
19104; e-mail: flake{at}emailchop.edu.
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P. A. Taylor, R. T. McElmurry, C. J. Lees, D. E. Harrison, and B. R. Blazar
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[Abstract]
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N. D. Tran, C. D. Porada, G. Almeida-Porada, H. A. Glimp, W. F. Anderson, and E. D. Zanjani
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June 1, 2001;
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3417 - 3423.
[Abstract]
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M. L. Casal and J. H. Wolfe
In utero transplantation of fetal liver cells in the mucopolysaccharidosis type VII mouse results in low-level chimerism, but overexpression of {beta}-glucuronidase can delay onset of clinical signs
Blood,
March 15, 2001;
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[Abstract]
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W. C. Mentzer and Y. W. Kan
Prospects for Research in Hematologic Disorders: Sickle Cell Disease and Thalassemia
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[Abstract]
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L. Gallacher, B. Murdoch, D. Wu, F. Karanu, F. Fellows, and M. Bhatia
Identification of novel circulating human embryonic blood stem cells
Blood,
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[Abstract]
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M. C. Renda, E. Fecarotta, A. Maggio, F. Dieli, G. Sireci, A. Salerno, L. Markling, M. Westgren, G. Damiani, C. Jakil, et al.
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TOP
INTRODUCTION
"NATURAL" HEMATOPOIETIC...
