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Blood, Vol. 95 No. 9 (May 1), 2000:
pp. 2754-2759
PERSPECTIVE
The primacy of the gastrointestinal tract as a target organ of
acute graft-versus-host disease: rationale for the use of cytokine
shields in allogeneic bone marrow transplantation
Geoffrey R. Hill and
James L. M. Ferrara
From the Mater Medical Research Institute, Brisbane, Australia, and
the Departments of Internal Medicine and Pediatrics, Division of
Hematology and Oncology, University of Michigan Cancer Center,
MI.
 |
Abstract |
Acute graft-versus-host disease (GVHD), the major complication of
allogeneic bone marrow transplantation (BMT), limits the application of
this curative but toxic therapy. Studies of inflammatory pathways
involved in GVHD in animals have shown that the gastrointestinal (GI) tract plays a major role in the amplification of
systemic disease. Damage to the GI tract increases the translocation of inflammatory stimuli such as endotoxin, which promotes further inflammation and additional GI tract damage. The GI tract is therefore critical to the propagation of the "cytokine storm"
characteristic of acute GVHD. Experimental approaches to the prevention
of GVHD include reducing the damage to the GI tract by fortification of the GI mucosal barrier through novel "cytokine shields" such as IL-11 or keratinocyte growth factor. Such strategies have reduced GVHD
while preserving a graft-versus-leukemia effect in animal models, and
they now deserve formal testing in carefully designed clinical trials.
(Blood. 2000;95:2754-2759)
© 2000 by The American Society of Hematology.
| |
Introduction |
Allogeneic bone marrow transplantation (BMT) remains
the treatment of choice for a number of malignant conditions.
Graft-versus-host disease (GVHD), the primary complication of
allogeneic BMT, remains the major limitation to this therapeutic
approach. Donor T cells are critical in the induction of acute GVHD
because depletion of T cells from the bone marrow graft effectively
prevents GVHD but also results in an increase in leukemic
relapse.1 Although there is a fundamental requirement for
donor T cells in GVHD, the process still occurs in the absence of the
T-cell cytotoxicity pathways (perforin, FasL, granzyme).2,3
This anomaly has forced investigators to reconsider the traditional
T-cell-restricted paradigms of GVHD pathophysiology.
| |
Primacy of the gastrointestinal tract as a GVHD target organ |
Increasing evidence in experimental and clinical BMT settings
suggests that damage to the gastrointestinal (GI) tract during acute
GVHD plays a major pathophysiologic role in the amplification of
systemic disease. Endotoxin or lipopolysaccharide (LPS) is a
constituent of normal bowel flora known to play an important role in
GVHD pathogenesis. Early animal studies showed that death after BMT was
prevented if mice were given antibiotics to decontaminate the gut;
normalization of the gut flora at or before day 20 abrogated this
effect.4 In the clinical setting, gram-negative gut
decontamination has also been shown to reduce GVHD.5,6
Furthermore, the intensity of this decontamination has recently
been demonstrated to be an important predictor of GVHD
severity.7,8
Lipopolysaccharide is a potent stimulator of inflammatory cytokine
production, such as tumor necrosis factor (TNF)- , IL-1, and IL-12,
which are important mediators of clinical9-11 and
experimental GVHD.12-14 The production of TNF- by
monocytes and macrophages is transduced by 2 signals.15 The
first is a priming signal that may be provided by interferon
(IFN)- 15 and radiation.13 The second is a
triggering signal provided by bacterial products such as
LPS.15 Other bacterial products, such as CpG DNA repeats, in the GI tract lumen have also been shown to have potent
immuno-stimulatory properties and to induce strong Th1
responses.16 Furthermore, microbial superantigens may
activate B cells by direct stimulation of major histocompatibility
complex (MHC) class II molecules.17 During GVHD, the
IFN- produced by donor T cells renders monocytes and macrophages
extremely sensitive to endogenous LPS.18 Further support
for the role of LPS in GVHD comes from a recent study comparing donor
monocytes and macrophages that were genetically sensitive (ie, normal)
or resistant to the effects of LPS for their ability to induce
GVHD.19 The donor mouse strains were otherwise identical,
and, in particular, their T-cell responses to host alloantigens were
equivalent. Allogeneic BMT recipients of LPS-resistant bone marrow
demonstrated significantly less TNF- production and reduced GVHD
than recipients of LPS-sensitive bone marrow. Significantly, the
reduced production of TNF- in recipients of LPS-resistant marrow was
associated with reduced GVHD of the GI tract. The causality of the
association was demonstrated by the systemic neutralization of TNF-,
which reduced GVHD of the GI tract and lessened the severity of overall disease.
Additional evidence for the importance of GI tract integrity during
GVHD comes from studies of the effect of BMT conditioning on GVHD
severity after allogeneic BMT. Clinical studies first suggested a
correlation between GVHD severity and radiation dose (less than 1200 versus more than 1200 cGy)20,21 and more severe GVHD after
conditioning regimens that included radiation therapy than those that
included only chemotherapy.22 The increased incidence of
conditioning-related toxicity has also been associated with GVHD
incidence.23 However, these studies demonstrated an inverse
correlation between conditioning intensity and compliance with
immunosuppression prophylaxis, which might partially account for the
increase in GVHD. Indeed, only 1 of these studies identified increased
radiation intensity as an independent risk factor for GVHD,20 and there was no demonstrable association with
severe disease (grades 2 to 4). By contrast, the association of
increased GVHD with dose reductions in cyclosporine was maintained
throughout all GVHD grades. Using clinical data alone, it has
thus been difficult to separate the influence of conditioning intensity
and suppression of T-cell function on subsequent GVHD severity.
We have recently examined this issue in murine BMT models in which
these variables could be tightly controlled. These studies demonstrated
an increase in GVHD severity in several donor-recipient strain
combinations, after intensification of the conditioning regimen, by
increasing the total body irradiation (TBI) dose from 900 cGy to 1300 cGy. Synergistic damage to the GI tract was caused by increased TBI and
allogeneic donor cells, permitting increased translocation of LPS to
the systemic circulation. In vitro, LPS triggered the most TNF-
secretion in macrophages taken from animals with the worst GI tract
damage. Neutralization of TNF- eliminated deaths from GVHD. Thus,
the higher TBI dose increased gut damage after allogeneic BMT, causing
higher systemic levels of inflammatory cytokines and more severe
GVHD.13 High levels of inflammatory cytokines may
perpetuate GVHD because TNF- has been shown to be directly toxic to
the GI tract during GVHD in other experimental systems.19,24,25
The addition of cyclophosphamide (Cy) to TBI also increased damage to
the GI tract and the subsequent incidences of mortality and morbidity
related to GVHD.14 After Cy/TBI conditioning, neutralization of IL-1 with a hamster antibody to the IL-1 receptor significantly reduced serum LPS levels and GVHD deaths, whereas neutralization of TNF- did not. Although the expansion of donor T
cells on day 13 after BMT was increased after Cy/TBI than with Cy or
TBI alone, cytotoxic T lymphocyte (CTL) function was not different
between groups. Taken together, these studies confirm that
increasing the dose of TBI or combining TBI with cyclophosphamide increases the severity of GVHD. Importantly, the pathophysiologic mechanisms involved in this increase in GVHD appear to be focused on GI
tract damage and subsequent amplification of the inflammatory effectors
of GVHD rather than on the effects on donor T cells.
| |
Rationale for shielding the gastrointestinal tract |
These studies suggest that the GI tract is not only a major target
organ of GVHD but is a critical amplifier of systemic GVHD severity. We
have previously suggested that acute GVHD pathophysiology can be
conceptualized in 3 sequential phases (Figure
1).26 In phase 1, the
conditioning regimen (irradiation, chemotherapy, or both) leads to
damage to and activation of host tissue by release of the inflammatory
cytokines TNF- and IL-1. These cytokines can increase the expression
of MHC antigens and adhesion molecules on host antigen-presenting
cells, enhancing the recognition of host MHC and minor
histocompatibility antigens by mature donor T cells. Donor T-cell
activation in phase 2 is characterized by the proliferation of Th1 T
cells and the secretion of IL-2 and IFN-. IL-2 and IFN- induce
further T-cell expansion, CTL- and NK-cell responses, and prime
additional mononuclear phagocytes to produce IL-1 and TNF-. Effector
functions of mononuclear phagocytes (phase 3) are triggered by the
secondary signal provided by bacterial products such as LPS. Damage to
the intestinal mucosa in phase 1 and by cytolytic effectors activated
in phase 2 allows translocation of LPS from the intestinal lumen to the
circulation. Subsequently, LPS may stimulate additional cytokine
production by gut-associated lymphocytes and macrophages in the GI
tract and by keratinocytes, dermal fibroblasts, and macrophages within
the skin. This mechanism may amplify local tissue injury and further
promote an inflammatory response that, together with the CTL and NK
component, leads to target tissue destruction in the BMT host. Damage
to the GI tract in phase 3 increases LPS release, stimulating further
cytokine production and causing additional GI tract damage. Thus the GI tract is critical to propagating the "cytokine storm"
characteristic of acute GVHD.
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| Fig 1.
The immunopathophysiology of GVHD.
Schematic representation of central role of GI tract damage during
GVHD. In phase 1, the conditioning regimen (irradiation, chemotherapy,
or both) leads to the damage and activation of host tissues, especially
the intestinal mucosa. This allows the translocation of LPS from the
intestinal lumen to the circulation, stimulating the secretion of the
inflammatory cytokines TNF- and IL-1 from host tissues, particularly
macrophages. These cytokines increase the expression of MHC antigens
and adhesion molecules on host tissues, enhancing the recognition of
MHC and minor histocompatibility antigens by mature donor T cells.
Donor T-cell activation in phase 2 is characterized by the
proliferation of Th1 T cells in the presence of IL-12 and the secretion
of IL-2 and IFN-. IL-2 and IFN- induce further T-cell expansion
and CTL and NK cell responses, and they activate mononuclear
phagocytes. The CTL and NK effectors damage tissue by
perforin/granzyme, FasL, and TNF-. In phase 3, effector functions of
activated mononuclear phagocytes are triggered by the secondary signal
provided by LPS and other immuno-stimulatory molecules that leak
through the intestinal mucosa damaged during phases 1 and 2. This
damage results in the amplification of local tissue injury, and it
further promotes an inflammatory response. Damage to the GI tract in
this phase, principally by inflammatory cytokines, amplifies LPS
release and leads to the "cytokine storm" characteristic of
severe acute GVHD. Double lines show the points at which KGF and IL-11
both interrupt this process, whereas single lines reflect interruption
by IL-11 only. IL-11, but not KGF, promotes type 2 donor T-cell
differentiation and inhibits IFN- secretion. Neither IL-11 nor KGF
impairs CTL or NK function, thereby preserving GVL effects. The
reduction in GI tract damage by these "cytokine shields"
prevents systemic LPS translocation and reduces inflammatory cytokine
production, culminating in reduced GI tract damage and subsequent death
from GVHD.
|
|
Although cytokines clearly play important roles in incidences of
morbidity and mortality related to systemic GVHD, their relative importance as mediators of damage in GVHD target organs is less well
established. The unusual cluster of GVHD target organs (skin, gut, and
liver) is inadequately explained by the systemic release of cytokines.
For example, intravenous infusion of TNF- and IL-1 does not cause
the lymphomononuclear cell infiltration of liver and skin observed in
GVHD. Furthermore, the absence of GVHD toxicity in other visceral
organs, such as the kidney, argues against circulating cytokines as the
sole cause of tissue-specific damage. The infiltrates seen in GVHD
target organs are generally thought to contain T cells responding to
alloantigens on host tissues. As mentioned above, LPS leakage through
skin or mucosa may act as an adjuvant to the antigens expressed in
these tissues, attracting and activating alloreactive donor T cells. A
second possibility is that tissue-specific neoantigens are expressed at
these sites as the result of ongoing inflammation. Such inflammation
may alter ligands for homing receptors on T cells (eg, selectins) that
enables them to traffic into specific tissues.
It is clear in murine systems that cytolytic T-lymphocyte effectors
contribute to GVHD. The application of knock-out technology and the
identification of pertinent mutant mice have provided important tools
for dissecting effector mechanisms. Three cytolytic pathways have been
identified as important to GVHD: the perforin/granzyme B pathway, the
Fas/FasL pathway, and direct cytokine-mediated injury. Donor cells from
perforin-deficient and granzyme B-deficient knock-out mice can mediate
lethal GVHD, but the onset of clinical manifestations is significantly
delayed.27,28 Similarly, when mutant mice deficient in FasL
(gld) are used as donors, GVHD occurs in an attenuated
fashion.3 When FasL-deficient mice are crossed with those
having perforin or granzyme B knock-outs, the use of lymphocytes from
these donors further diminishes but does not abrogate
GVHD.27 Interestingly, the Fas pathway is important in the
development of hepatic and cutaneous GVHD.24
GVHD histopathology in the GI tract has been described in 3 phases.29 The early phases of GI tract changes have been
described in animal models that do not use chemotherapy or radiation to condition the host; therefore, direct comparisons to clinical GVHD
after BMT are not possible. This initial proliferative phase results in
increased crypt cell mitotic activity, crypt lengthening, and
intraepithelial lymphocytes. In experimental systems, this phase seems
to be linked to IFN- production,30 which increases MHC
class II expression and gut permeability by altering tight junction
integrity31 and may modulate crypt stem-cell
turnover.29 The histologic features of the GI tract in
clinical GVHD and experimental GVHD after myeloablative conditioning
are consistent with the destructive and atrophic phases, characterized
by villus blunting, lamina propria inflammation, crypt destruction
(with crypt stem-cell loss), and mucosal atrophy. These features can be
induced in animals by the administration of exogenous cytokines,
including TNF-32 and IL-1.33 Furthermore,
the inhibition of IFN-,34 TNF-,25 IL-1,33 or nitric oxide35 can reduce GI tract
histopathology in animals with GVHD. In contrast, CTL effectors do not
appear to play a dominant role in experimental GVHD of the GI
tract,3,13,14,19,24,36 despite the ability of
intraepithelial lymphocytes to induce Fas-mediated apoptosis of host
type tumor cells.37 It is clear, when these findings are
considered in aggregate, that cytokines and cellular effectors combine
to produce specific target organ damage and systemic toxicity of acute GVHD.
The experimental studies referenced above used novel cytokine
antagonists and transgenic/knock-out mice. As yet, it has not been
possible to confirm the extent to which the principals derived from
these studies apply to humans. The histologic features of end-stage
intestinal GVHD are similar in animals and humans.29 The
diarrhea characteristic of GVHD may occur because of a number of
mechanisms, including enterocyte damage and epithelial disaccharidase deficiency with an excess of luminal sugars and osmotic water loss, an
increase in the proportion of immature enterocytes with subsequent
enzyme deficiency and impaired water transport, and protein and water
exudation through a hyperpermeable epithelium. In the large intestine,
damage to colonic enterocytes also impairs water
reabsorption.29
Increasing the intensity of the conditioning regimen in murine models
of GVHD to the levels used clinically amplifies GVHD of the GI tract.
This increase in gut injury and LPS leak is a common proximal pathway
for the dysregulation of inflammatory cytokines after allogeneic BMT.
As discussed above, recent work has confirmed that GVHD of the GI tract
is principally mediated by inflammatory cytokines. From this
perspective, it should be possible to interrupt the process of GI tract
damage at a number of steps. First, attempts to eradicate or
significantly reduce the load of gram-negative organisms from the GI
tract are current practice in a number of transplant centers.
Unfortunately, endotoxemia has been noted to be common after BMT even
with gut decontamination; it occurs in association with biochemical
parameters of gut damage.38 Although gut decontamination
can reduce clinical GVHD,5,7 the effect is at best partial.
It has not been shown to benefit the recipients of unrelated donor BMT,
who are in the greatest need for improved GVHD
prophylaxis.8 Inhibition of systemic LPS with neutralizing
proteins is under investigation in experimental GVHD models. However,
the success of this approach assumes that LPS is the only or primary
immuno-stimulatory constituent of the GI tract lumen that amplifies
GVHD. There are numerous additional putative immuno-stimulatory
molecules, such as soluble peptidoglycan, lipoteichoic
acid,39 bacterial DNA,40 and heat-shock
proteins,41 suggesting that neutralization of LPS alone may
be only partially successful in preventing GVHD.
Reductions in the doses of chemoradiotherapy to condition BMT
recipients should also reduce GVHD, as demonstrated in experimental models.13,14 This reduction is the result of reduced
priming of mononuclear cells by lower TBI doses and of subsequent
reductions in TNF- production.13 It is also likely that
low TBI doses fail to sensitize the GI tract to secondary damage by
inflammatory cytokines. The use of non-myeloablative conditioning
should therefore also reduce GI tract damage after allogeneic BMT. The
activation of donor T cells is enhanced by inflammatory
cytokines,42 and a temporal separation of the inflammatory
milieu induced by conditioning (which is thought to be self-limited)
and donor lymphocyte infusions may interrupt the cytokine cascade that
damages the GI tract and increases systemic GVHD.12,43
Much of the therapeutic potential of allogeneic BMT relates to the
graft-versus-leukemia (GVL) effect, which is mediated by the cytotoxic
pathways of donor T and NK cells, including perforin/granzyme and
Fas/FasL.44 In experimental GVHD models, the absence of perforin in donor T cells results in an almost complete loss of GVL,45-47 whereas the absence of FasL does not diminish GVL
effects.47 Inhibition of inflammatory cytokine production
after BMT might offer an approach to separate GVHD and GVL. However,
TNF- may not be an ideal target because the p55 TNF- receptor is
critical for donor CTL activity after BMT and contributes to the GVL
effect.14 GVL effects are also diminished when TNF- is
neutralized in experimental models of GVHD.47 IL-1 may be a
more attractive target for neutralization because the inhibition of
IL-1 does not inhibit CTL generation or the GVL effect.14
Neutralization of inflammatory cytokines must therefore be approached
on an individual basis with respect to the potential to separate GVHD
and GVL.
| |
Cytokine shields: interleukin-11 and keratinocyte growth factor |
An alternative approach to prevent GI tract damage during
allogeneic BMT may permit the exploitation of intensive
conditioning as an antileukemic modality without requiring T-cell
depletion. This approach involves strengthening the GI mucosal barrier
before BMT conditioning to prevent the entry of immunostimulatory
molecules from the GI tract lumen into the circulation. Because direct
shielding of the GI tract from TBI is not feasible, this effort relies
on pharmacologic agents that provide a "cytokine shield" to
reduce mucosal sensitivity to radiation, chemotherapy, or both. This approach is attractive because it blocks inflammatory cytokine dysregulation before the initiation of the cascade. In addition, by
acting as indirect cytokine antagonists, these shields would not impede
the physiological functions of cytokines in cellular differentiation
(as might be the case with complete neutralization of TNF- and
IL-1). Two growth factors, IL-11 and KGF, have recently shown
particular promise as cytokine shields.
| |
Interleukin-11 |
IL-11, a member of the IL-6 cytokine family, is produced by a
variety of tissues, including the central nervous system, thymus, lung,
bone, skin, and connective tissue, and has pleiotropic
effects.48 IL-11 stimulates megakaryopoiesis and
accelerates neutrophil recovery after myelosuppressive
therapy.49-51 In addition, IL-11 has potent anti-inflammatory effects by virtue of its ability to inhibit nuclear
translocation of nuclear factor- B
(NF-B).52,53 Preclinical studies have
demonstrated the efficacy of IL-11 in treating inflammatory disorders,
among them oxygen- and radiation-induced lung damage,54,55 inflammatory bowel disease,56 and sepsis.57 In
addition, IL-11 down-regulates IL-12 production by
macrophages,58 which suggests that IL-11 may also modulate
T-cell-mediated inflammation. Significantly, IL-11 has direct
protective effects on the GI tract epithelium in models of injury by
chemotherapy and radiation,59-63 surgery,64,65 and ischemia.66 Small bowel crypt recovery is improved
through the protection of clonogenic crypt cells,60
reductions in apoptosis,62 and increases in cellular
mitotic index.59,64,65 These studies confirmed that IL-11
has trophic effects on mucosal epithelium and suggested that continuing
therapy with IL-11 after BMT conditioning would not impair mucosal
healing. Of interest was the observation that maximum crypt protection
occurred if IL-11 treatment was begun before irradiation and was
continued for 3 days.60
In experimental studies examining the possible use of IL-11 as a
cytokine shield to prevent GVHD, IL-11 administration was begun 2 days
before conditioning and was continued for 7 to 14 days after BMT. When
used in this fashion, IL-11 almost completely prevented GVHD of the
small bowel, and it reduced serum endotoxin levels after BMT by 80%.
Treatment with IL-11 also reduced TNF- serum levels and suppressed
TNF- secretion by macrophages to LPS stimulation in vitro. Donor CTL
responses to host antigens were not affected by IL-11. Surprisingly,
IL-11 administration polarized the donor T-cell cytokine responses to
host antigen after BMT with a 2-fold reduction in IFN- and IL-2
secretion and a 10-fold increase in IL-4. This polarization of T-cell
responses was associated with reduced IFN- serum levels and
decreased IL-12 production in mixed lymphocyte cultures. Therefore,
IL-11 inhibits GVHD pathophysiology at multiple steps
(Figure 1), enabling IL-11 to dramatically reduce GVHD
mortality and morbidity rates after allogeneic BMT.67 The
10-day schedule of IL-11 treatment, beginning just before BMT, also
provides long-term protection of the GI tract and improved immune
reconstitution.67 Further studies showed that IL-11 spared
donor CTL/NK function and preserved a GVL effect that was mediated by
perforin, improving long-term leukemia-free survival.45
These data confirm the ability of IL-11 to separate GVHD and GVL in
experimental animal studies.
| |
Keratinocyte growth factor |
A member of the fibroblast growth factor family FGF-7, KGF shows
specificity for epithelial tissues that express its receptors, including gut epithelial cells, hepatocytes,68 skin
keratinocytes,69 alveolar type 2 cells,70
mammary epithelium,71 and urothelium.72 In
early studies, KGF administration before autologous BMT dramatically protected the gut epithelium from injury by lethal
chemoradiotherapy.73 This protection appears to result from
a potent trophic effect on intestinal epithelium68 and from
improved survival of crypt stem cells,74 perhaps through
reduced oxidative damage (nonselenium glutathione
peroxidase)75 and enhanced DNA repair (DNA polymerase-, - , and - ).76
In 2 recent studies, investigators have examined the effect of human
recombinant KGF on experimental GVHD.77,78 When KGF was
given before conditioning only, it reduced the mortality rate and GVHD
target organ histopathology.78 When KGF was
administered from 3 days before to 7 days after BMT, it abolished GVHD
of the GI tract and further improved survival.77 As
expected, this improvement was associated with a reduction in serum LPS
and TNF- levels. Therapy with KGF also preserved donor T-cell
responses (CTL activity, proliferation, and IL-2 production) to host
antigens and significantly improved leukemia-free survival
and when a lethal dose of P815 leukemia was given at the
time of BMT (42% vs 4%; P < .001).77 KGF has
a favorable clinical toxicity profile,79 and its
administration, like that of IL-11, thus offers a novel approach to the
separation of GVL effects from GVHD (Figure 1).
| |
Summary |
Insights into the pathophysiology of GVHD have confirmed a central
role of GI tract damage in this process and have predicted for the success of novel approaches to preventing GVHD in
experimental models. It is important to note that the majority of data
regarding our understanding of GVHD pathophysiology derive from murine
models that use inbred strains of donors and recipients with highly
defined and often limited genetic disparity compared with our own human outbred species. The experimental conditions of these BMT models were
highly controlled, and the mice spent their entire lives, from
conception to death, in specific pathogen-free conditions. Both
circumstances help to maximize the clarity of experimental results, but
they may also lead to certain distortions with respect to the more
variable clinical reality of human transplantation. It is unlikely that
the mechanisms of murine and human GVHD differ completely, but the
relative contribution of a given effector pathway to specific organ
damage may well differ between humans and mice. Certainly, the use of
intensive conditioning schedules and pharmacologic immunosuppression in
clinical BMT is in contrast to most published murine systems in which
GVHD target organ damage has been mediated primarily by T cells. Strong
evidence supports the concept that inflammatory cytokines, GI tract
damage, and LPS translocation are important mediators of clinical
GVHD.9-11 Reduced GVHD severity seen in patients
conditioned with nonmyeloablative conditioning regimens provides
further support for this assertion.80 Nevertheless, some
initial clinical studies of specific cytokine antagonists have yielded
less compelling results than the murine models predict, and the effect
of any single cytokine inhibitor may be small because of complex
interactions of multiple, potentially redundant cytokines. Clinical
testing of novel biologic response modifiers often occurs under
high-risk conditions in patients with advanced disease, and
considerable time may be required for these novel therapeutic regimens
to be introduced under more standard risk situations, in which their
true value in the prevention and treatment of GVHD can be discerned.
The preclinical data offer a compelling rationale for the testing of
agents that can protect the GI tract and that therefore may modulate
the inflammatory amplification of acute GVHD. Success in animal models
does not always predict clinical efficacy, however. Given the potential
toxicities of these agents and the severity of illness experienced by
many patients under allogeneic BMT, the use of such agents should be
tested in carefully monitored clinical protocols designed to test the
feasibility and safety of this approach and its potential efficacy. If
successful, the concept of "cytokine shields" may allow the
potent antileukemic effect of high-dose chemoradiotherapy to be used
without the induction of life-threatening GVHD and may permit
traditional allogeneic BMT to be undertaken in a patient population
that would otherwise be ineligible for this therapy.
| |
Footnotes |
Submitted August 24, 1999; accepted January 20, 2000.
Reprints: James L. M. Ferrara, Departments of Internal Medicine
and Pediatrics, University of Michigan Cancer Center, 1500 E
Medical Center Drive, Ann Arbor, MI 48109-0560; e-mail:
ferrara{at}umich.edu.
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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Blood,
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Control of systemic B cell-mediated autoimmune disease by nonmyeloablative conditioning and major histocompatibility complex-mismatched allogeneic bone marrow transplantation
Blood,
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S. Yada, N. Takamura, K. Inagaki-Ohara, M. K. O'Leary, C. Wasem, T. Brunner, D. R. Green, T. Lin, and M. J. Pinkoski
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C.-K. Min, Y. Maeda, K. Lowler, C. Liu, S. Clouthier, D. Lofthus, E. Weisiger, J. L. M. Ferrara, and P. Reddy
Paradoxical effects of interleukin-18 on the severity of acute graft-versus-host disease mediated by CD4+ and CD8+ T-cell subsets after experimental allogeneic bone marrow transplantation
Blood,
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[Abstract]
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G. M. Bendle, A. Holler, L.-K. Pang, S. Hsu, M. Krampera, E. Simpson, and H. J. Stauss
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T. Iwasaki
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M. P. Rettig, J. K. Ritchey, J. L. Prior, J. S. Haug, D. Piwnica-Worms, and J. F. DiPersio
Kinetics of In Vivo Elimination of Suicide Gene-Expressing T Cells Affects Engraftment, Graft-versus-Host Disease, and Graft-versus-Leukemia after Allogeneic Bone Marrow Transplantation
J. Immunol.,
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E. Holler, G. Rogler, H. Herfarth, J. Brenmoehl, P. J. Wild, J. Hahn, G. Eissner, J. Scholmerich, and R. Andreesen
Both donor and recipient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation
Blood,
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[Abstract]
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U. A. Duffner, Y. Maeda, K. R. Cooke, P. Reddy, R. Ordemann, C. Liu, J. L. M. Ferrara, and T. Teshima
Host Dendritic Cells Alone Are Sufficient to Initiate Acute Graft-versus-Host Disease
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E. S. Morris, K. P. A. MacDonald, V. Rowe, D. H. Johnson, T. Banovic, A. D. Clouston, and G. R. Hill
Donor treatment with pegylated G-CSF augments the generation of IL-10-producing regulatory T cells and promotes transplantation tolerance
Blood,
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[Abstract]
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P. Reddy, Y. Maeda, K. Hotary, C. Liu, L. L. Reznikov, C. A. Dinarello, and J. L. M. Ferrara
Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect
PNAS,
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[Abstract]
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M. Y. Mapara and M. Sykes
Tolerance and Cancer: Mechanisms of Tumor Evasion and Strategies for Breaking Tolerance
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G. C. Hildebrandt, U. A. Duffner, K. M. Olkiewicz, L. A. Corrion, N. E. Willmarth, D. L. Williams, S. G. Clouthier, C. M. Hogaboam, P. R. Reddy, B. B. Moore, et al.
A critical role for CCR2/MCP-1 interactions in the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation
Blood,
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[Abstract]
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D.-W. Kim, Y.-J. Chung, T.-G. Kim, Y.-L. Kim, and I.-H. Oh
Cotransplantation of third-party mesenchymal stromal cells can alleviate single-donor predominance and increase engraftment from double cord transplantation
Blood,
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[Abstract]
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Blood,
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J. C. Papadimitriou, C. B. Cangro, A. Lustberg, A. Khaled, J. Nogueira, A. Wiland, E. Ramos, D. K. Klassen, and C. B. Drachenberg
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M. Mielcarek, P. J. Martin, W. Leisenring, M. E. D. Flowers, D. G. Maloney, B. M. Sandmaier, M. B. Maris, and R. Storb
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P. Reddy, T. Teshima, G. Hildebrandt, D. L. Williams, C. Liu, K. R. Cooke, and J. L.M. Ferrara
Pretreatment of donors with interleukin-18 attenuates acute graft-versus-host disease via STAT6 and preserves graft-versus-leukemia effects
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P. Reddy, T. Teshima, M. Kukuruga, R. Ordemann, C. Liu, K. Lowler, and J. L.M. Ferrara
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K. R. Cooke, G. R. Hill, A. Gerbitz, L. Kobzik, T. R. Martin, J. M. Crawford, J. P. Brewer, and J. L. M. Ferrara
Hyporesponsiveness of Donor Cells to Lipopolysaccharide Stimulation Reduces the Severity of Experimental Idiopathic Pneumonia Syndrome: Potential Role for a Gut-Lung Axis of Inflammation
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V. Reddy
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Top
Abstract
Introduction