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CUTTING EDGE |
*
McMaster University, Hamilton, Ontario, Canada;
INSERM Unite 131, Hôpital Antoine Béclère, Clamart, France;
Amgen Institute, Princess Margaret Hospital, University of Toronto, and
Multiorgan Transplant Group, The Toronto Hospital, University of Toronto, Toronto, Canada
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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(which activates NK cells) or
IFN-
(which activates macrophages). TNF- + -IFN
coadministration aborted >80% of the embryos whether or not NK cells
or macrophages had been depleted or estradiol + progesterone was
injected to correct potential reduction in ovarian function by
cytokines. The cytokines also aborted IRF1+/+ C57BL/6 but not IRF1-/-
females pregnant by IRF1+/+ DBA/2. Both spontaneous and
cytokine-boosted abortions in CBA x DBA/2 were blocked by Ab to
fgl2 prothombinase expressed by cytokine-stimulated vascular
endothelial cells and monocytes; in vivo Ab depletion of granulocytes
also prevented TNF- + IFN--induced abortions. Cytokine-triggered
thrombotic/inflammatory processes in maternal uteroplacental blood
vessels causes abortion. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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and IFN- play an important role in
abortions, as their administration increases the abortion rate and
specific antagonists decrease the abortion rate (7, 8, 9, 10). It has been
proposed that macrophage-derived TNF- stimulates NK cells to produce
-IFN, which further activates the macrophages, as occurs in the
early defense response to infectious agents (1, 11). There are other
potential sources of TNF- and IFN-, and systemic Th1-type
responses may cause abortions via augmenting levels of such cytokines
(12); IL-2 may also cause abortions by contributing to NK-macrophage
activation at the fetomaternal interface (7). Pregnancy tends to bias T
cell responses along a Th2 pathway, and alloimmunization against the
paternal H-2d Ag also shifts the intracellular cytokine
phenotype of 
T cells in the uterus away from Th1 and toward
Th2 (13, 14).
The mechanism by which the implanted embryo is killed is unknown. The
current paradigm holds that the fetal trophoblast cells, which form the
interface between the embryo and maternal tissues, are damaged or
killed (1). Trophoblast is not susceptible to lysis by TNF-, NK
cells, or macrophages, but may be killed by cytokine-activated NK cells
(i.e., LAKs)5 and may undergo
apoptosis in response to TNF- and IFN- in vitro (1, 15).
Haddad et al. (16) have recently suggested macrophage-derived nitric
oxide may mediate lethality and that the role of NK cells is to produce
-IFN to activate the macrophages. This makes sense because LAK
generation requires IL-2, a cytokine not detected in decidua of
DBA/2-mated CBA/J mice, and administration of aminoguanidine, an
inhibitor of inducible nitric oxide synthase, prevented abortions in
this system (16). On the other hand, IL-12 may substitute for IL-2 in
generating LAKs from NK cell precursors, and nitric oxide, a short
range mediator, may act primarily by increasing the local cytotoxic
activity of TNF- (17, 18). Aminoguanidine also impairs polyamine
metabolism and interferes with macrophage activation (19). Further, an
i.p. injection of anti-asialoGM1 Ab after day 8.5, when abortions
have already begun to occur, stopped further embryo deaths (3); one
would not expect production of NO by activated macrophages to be
arrested so quickly, and the data suggest direct NK cell-mediated
killing.
We have directly tested the role of cytokines TNF- and IFN- and
of NK cells and macrophages in causing abortions, using in vivo cell
depletion techniques and mice deficient in the response to IFN. We show
that neither NK cells nor macrophages are required for abortions, that
the cytokines act on the mother and not on embryonic trophoblast, and
that the embryos die from ischemia due to activation of vascular
endothelial cell procoagulant, which causes thrombosis and
inflammation. This appears similar to the mechanism whereby TNF-
causes ischemic necrosis of nonantigenic tumors (20).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Inbred mice of strains CBA/J and DBA/2 were obtained from Iffa Credo, l’Arbresle, France. C57BL/6J and DBA/2 mice were obtained from The Jackson Laboratory, Bar Harbor, ME. C57BL/6 mice with knockout of the IFN response element, IRF-1, were generated as previously described (21) and bred in at the Ontario Cancer Institute, Toronto, Canada. CBA/J mice were maintained in the Paris colony under conventional open-top wire cage conditions with food and water ad libitum and a 12-h light-dark cycle. Mice in the Toronto colony were maintained in a barrier facility. Female CBA/J, C57BL/6, or C57BL/6 IRF-/- mice were mated by overnight cohabitation with a DBA/2 (IRF1+/+) male, and the morning of sighting a vaginal plug was defined as day 0.5 of pregnancy.
Treatment of the mice
Pregnant CBA/J mice were depleted of NK cells by i.p. injection
of 0.2 ml rabbit IgG anti-asialoGM1 Ab (Nordic, Tebu, St. Quentin
les yvelines, France) on day 6.5 of gestation; PBS was used as a
control as it has been previously shown to be equivalent to nonimmune
rabbit IgG (1). Macrophage depletion was performed by i.p. injection of
100 mg/kg silicon dioxide (Sigma, St. Louis, MO) twice a week for 4 wk
before mating, as described in (22). Affinity-purified rabbit IgG
neutralizing Ab to mouse procoagulant (fgl2 prothombinase) was prepared
as previously described (23, 24); the mice were given an i.p. injection
of 0.2 ml of a 1/50 dilution of a 5.5 mg/ml preparation of
anti-fgl2 or control rabbit Ab each day beginning on day 3.5 of
gestation. Hormonal support of pregnancy sufficient to replace ovarian
function was provided in some experiments by injecting 6.7 ng of
17
-estradiol + 1 mg progesterone (Sigma) in 0.1 ml oil i.m.
daily beginning on day 4.5 of gestation (25). One hundred micrograms of
rat monoclonal IgG2b anti-mouse granulocyte Ab RB6-8C5 (PharMingen,
San Diego, CA) (26) or isotype control was injected i.p. on day 6.5 of
pregnancy. TNF- (Ref. 7 and R&D Systems, Minneapolis, MN), 1000 or
2000 U, and/or murine rIFN- (Ref. 7 and R&D Systems), 1000 U, was
injected i.p. on day 7.5 of pregnancy. In some experiments, rIL-10 was
used as described (9). On day 13.5 of pregnancy, the mice were killed
and the number of resorbing and healthy embryos was counted. In some
experiments, the uteri were snap frozen, 5-µm sections were cut, and
the tissues were stained with rat monoclonal F4/80 Ab (Caltag, Tebu
Nordic) to macrophages. Briefly, tissue sections were incubated with a
1/30 dilution of F4/80 in PBS for 30 min, and binding was detected
using peroxidase-streptavidin with biotin-labeled anti-rat IgG2b
second Ab (Serotec, Kidlington, Oxford, U.K.) (27).
Statistics
Four to ten mated mice per treatment group were used. The
significance of differences in the pooled resorption rate was tested by
2 or Fisher’s exact test where appropriate.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Experiment 1, Table I
, shows that
i.p. injection of TNF- boosted the abortion rate of DBA/2-mated
CBA/J mice in a dose-dependent manner. If the mice had received
anti-asialoGM1 Ab treatment, the background rate of abortion
decreased, as expected (1, 3, 7), and TNF- no longer had a
significant effect. These data supported the model TNF- 
NK
activated NK kill embryo. To ensure adequate levels of endogenous
macrophage-derived TNF-, we repeated the experiment and added
IFN-. Experiment 2 shows that IFN- alone boosted the abortion
rate in PBS-pretreated mice to the level achieved with TNF-, and
addition of TNF- had no significant supplementary effect. In NK
cell-depleted mice, IFN- failed to boost abortions. This suggested
that the model IFN- macrophages activated to produce NO
embryo death was not correct. However, when IFN- and TNF- were
administered together, >80% of the implanted embryos aborted. This
suggested an obligatory synergy/codependence; in NK cell-depleted mice,
TNF- does not work because the NK cell source of IFN- has been
eliminated, and IFN- fails because macrophages dependent on NK
cell-derived IFN- have stopped producing TNF-, and the i.p.
injected cytokine does not stimulate TNF- production quickly enough
for both cytokines to be present simultaneously. A direct NK or
macrophage killing mechanism seemed an unlikely explanation for
abortions. To further test this idea, we repeated the experiment using
macrophage-depleted mice. Experiment 3 shows that macrophage depletion
reduced the abortion rate. It can be seen that macrophage depletion had
no significant effect on the 80% abortion rate produced by injecting
TNF- + IFN-. Tissue staining for F4/80+
macrophages confirmed that the silica treatment had been effective and
the cytokine treatment did not cause a macrophage infiltration (data
not shown). TNF- + IFN- may act synergistically to suppress
production of essential gestational hormones by the ovary (28), and
such an inhibition could cause abortions (4, 25). However, ovarian
failure should have caused 100% abortions (4). Further, when we gave
hormone replacement therapy as described in Materials and
Methods (25), there was no effect on either the background rate of
abortion or the high rate of abortion produced by 2000 U TNF- + 1000
U IFN- (35/41, 86%, n = 5, control group vs 37/45,
82%, n = 5, cytokine-treated group; not statistically
different).
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TNF- and IFN- act synergistically to induce
apoptosis in human trophoblast cell cultures (15). The results
shown in Table I
could be explained by a direct apoptotic action on
trophoblast. However, the cytokine CSF-1 is present in vivo, which may
abrogate the apoptotic effects of TNF- and IFN- (15, 29). To test
for a direct effect on trophoblast in mice, we mated
IFN--unresponsive IRF1-/- females (21, 30) to DBA/2 (+/+) males so
that fetal trophoblasts express IRF1 but maternal tissues do not. The
IRF1 knockout gene was on the C57BL/6 rather than the CBA/J background;
C57BL/6 mice have low spontaneous abortion rates and lack the NK/
T cell infiltrate seen in CBA/J mice (14). Nevertheless, as shown in
Table II, C57BL6 x DBA/2
pregnancies aborted dramatically when the cytokine treatment was given.
This validated the conclusion drawn from Table I that an NK
cell/macrophage infiltrate in decidua was not necessary for cytokines
to trigger abortions, supporting the hypothesis that the role of the
NK/ T cell infiltrate, which only occurs in response to
CBA/J x DBA/2F1 trophoblast, is to enhance the levels of IFN-
and TNF- required to trigger abortion. By contrast, pregnant
IRF-/- females had low background abortion rates and were completely
resistant to TNF- + IFN-. These data suggested that the cytokines
might be acting on the mother in the CBA/J x DBA/2 model and not
on trophoblast to induce abortions.
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Since neither macrophages nor NK cells seemed necessary for
TNF- + IFN- to act, the most logical target appeared to be the
maternal uterine vascular endothelium. These cytokines stimulate
surface expression of procoagulant (fgl2 prothombinase, which is
distinct from tissue factor); clotting initiated by fgl2 or tissue
factor is known to lead to ischemic damage in a variety of inflammatory
disease models such as hepatitis and endotoxic shock (23, 24, 31).
Table III shows the effect of treatment
of pregnant CBA/J x DBA/2 mice with Ab to fgl2. The background
rate of abortion was reduced to 4%, similar to the frequency of
chromosome abnormalities in mouse embryos (32). Further, the high
abortion rate induced by TNF- + IFN- was almost completely
prevented.
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+ IFN--activated endothelial cells (33). Nitric
oxide, a mediator implicated in abortions in CBA x DBA/2, and
IL-1, an additional cytokine participating in these abortions, also
contributes to granulocyte endothelial cell damage (8, 16, 33).
Thrombin is known to activate endothelial cells to release IL-8, and
IL-8 promotes infiltration of granulocytes, which digest tissues (5, 33, 34). To determine whether granulocytes contributed to abortions as
predicted, we injected pregnant mice with a monoclonal
anti-granulocyte Ab that is known to block granulocyte-mediated
tumor rejection in vivo (26). As shown in Table IV, anti-granulocyte Ab partially
reduced the spontaneous abortion rate and significantly abrogated the
effect of TNF- + IFN-. As a control, a significant reduction in
the spontaneous abortion rate similar to that achieved with
anti-fgl2 was confirmed using rIL-10 as described (9). A similar
result was obtained with anti-granulocyte Ab in a second experiment
(which did not include rIL-10) and combined with the data in Table IV,
the control spontaneous abortion rate of 30% (resorptions/total
implants = 29/96) was significantly reduced to 13% (11/87)
(p < 0.01, by 2), TNF- +
IFN- boosted abortions to 87% (77/89) (p <
0.001) and anti-granulocyte Ab reduced the latter to 13%
(13/98)(p < 0.001). The partial effect of
anti-granulocyte Ab (reduction of abortion rate to 12–16%) could
reflect a contributory but non-obligatory role of these cells for
abortion or an incomplete cell depletion in vivo by the dose of Ab
used.
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production) and to injection of TNF-. There were no signs of
systemic illness noted in our cytokine-treated mice. It is unknown why
the vascular supply to the embryo is so sensitive, but teleologically,
autoamputation via ischemia provides a primitive mechanism for
preserving the function of those organs required for survival during
times of stress. An obligatory synergy of TNF- and IFN-, which we
noted in our mice after in vivo depletion of asialoGM1+
cells or of macrophages, has been shown for lethality in endotoxic
shock (35). Further support for the idea that more than one cytokine
must be present to abort the embryo has been provided by a study of
TNF- in CBA/H mice in which concomitant infection was necessary
(36); one may suggest that the role of infection is to increase the
production of other cytokines needed to deliver the termination signal
to the uterine vasculature. An obligatory synergy in induction of
premature parturition has also been reported (37). Concerning
protection against abortion, TGF-2-producing
cells in the uterine lining appear to be important (14, 38).
TGF-1 protects the endothelium from granulocyte-mediated
reperfusion injury (39). However, it is unclear whether
TGF-1 and/or TGF-2 explain why 15 to 20%
of implants survive TNF- + IFN- or whether another mechanism is
involved. TGF-2 and IL-10 may prevent abortions in the
CBA/J x DBA/2 model by acting on NK cells, macrophages, and other
potential sources of Th1-type cytokines rather than by altering the
endothelium (9, 14).
An increase in activated blood CD56+16+ NK
cells in uterine endometrium/decidua, Th1 cytokine responses to
trophoblast, and a deficiency of TGF-2-producing
nonclassical CD56+16- decidual NK/ cells
has been reported in approximately 50% of women with recurrent
spontaneous abortions (40, 41, 42, 43, 44, 45). In humans, in contrast to the mouse,
approximately one-half of recurrent abortions may be attributed to
chromosome anomalies in fetal trophoblast, and NK/ T cells would
not be expected to have a role in the mechanism of such losses in
contrast to the abortion of chromosomally normal embryos (45).
Interestingly, Kohut et al. (46) have recently reported that women who
are more likely to abort chromosomally normal embryos show more marked
histologic evidence of thrombosis and inflammation (villitis and
vasculitis). Vascular injury, rather than direct NK/macrophage
cytotoxicity on fetal trophoblast, may explain abortion of normal
embryos in both mice and humans. Prothombin activation at endothelial
and trophoblast cell surfaces may also occur in abortions due to
antiphospholipid Abs (47); therefore, coagulation triggered by
different initiators may represent a final common pathway for pregnancy
termination.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. David A. Clark, Department of Medicine, 3V39 McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada. E-mail address: clarkd{at}fhs.csu.McMaster.ca
3 Current address: Department of Obstetrics and Gynaecology, Julius Maximilians University, Würzburg, Germany.
4 Current address: Max-Planck-Institute for Biology of Infection, Berlin, Germany.
5 Abbreviation used in this paper: LAK, lymphokine-activated killer (cells).
Received for publication September 4, 1997. Accepted for publication November 6, 1997.
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J. E. Boyson, B. Rybalov, L. A. Koopman, M. Exley, S. P. Balk, F. K. Racke, F. Schatz, R. Masch, S. B. Wilson, and J. L. Strominger CD1d and invariant NKT cells at the human maternal-fetal interface PNAS, October 15, 2002; 99(21): 13741 - 13746. [Abstract] [Full Text] [PDF]
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 A. Mjihdi, M.-A. Lambot, I. J. Stewart, O. Detournay, J.-C. Noel, Y. Carlier, and C. Truyens Acute Trypanosoma cruzi Infection in Mouse Induces Infertility or Placental Parasite Invasion and Ischemic Necrosis Associated with Massive Fetal Loss Am. J. Pathol., August 1, 2002; 161(2): 673 - 680. [Abstract] [Full Text] [PDF]
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C. W. Y. Chan, M. W. C. Chan, M. Liu, L. Fung, E. H. Cole, J. L. Leibowitz, P. A. Marsden, D. A. Clark, and G. A. Levy Kinetic Analysis of a Unique Direct Prothrombinase, fgl2, and Identification of a Serine Residue Critical for the Prothrombinase Activity J. Immunol., May 15, 2002; 168(10): 5170 - 5177. [Abstract] [Full Text] [PDF]
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P. Vigano, B. Gaffuri, E. Somigliana, M. Infantino, M. Vignali, and A.M. Di Blasio Interleukin-10 is produced by human uterine natural killer cells but does not affect their production of interferon-{gamma} Mol. Hum. Reprod., October 1, 2001; 7(10): 971 - 977. [Abstract] [Full Text] [PDF]
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M. Makhseed, R. Raghupathy, F. Azizieh, A. Omu, E. Al-Shamali, and L. Ashkanani Th1 and Th2 cytokine profiles in recurrent aborters with successful pregnancy and with subsequent abortions Hum. Reprod., October 1, 2001; 16(10): 2219 - 2226. [Abstract] [Full Text] [PDF]
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 S. A. Huber, D. Graveline, W. K. Born, and R. L. O'Brien Cytokine Production by V{gamma}+-T-Cell Subsets Is an Important Factor Determining CD4+-Th-Cell Phenotype and Susceptibility of BALB/c Mice to Coxsackievirus B3-Induced Myocarditis J. Virol., July 1, 2001; 75(13): 5860 - 5869. [Abstract] [Full Text] [PDF]
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M. Yamasaki, T. Sasho, H. Moriya, M. Kanno, M. Harada, N. Kamada, E. Shimizu, T. Nakayama, and M. Taniguchi Extrathymic Development of V{{alpha}}11 T Cells in Placenta During Pregnancy and Their Possible Physiological Role J. Immunol., June 15, 2001; 166(12): 7244 - 7249. [Abstract] [Full Text] [PDF]
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D. A. Clark, J.-W. Ding, G. Yu, G. A. Levy, and R. M. Gorczynski Fgl2 prothrombinase expression in mouse trophoblast and decidua triggers abortion but may be countered by OX-2 Mol. Hum. Reprod., February 1, 2001; 7(2): 185 - 194. [Abstract] [Full Text] [PDF]
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R. L. O'Brien, X. Yin, S. A. Huber, K. Ikuta, and W. K. Born Depletion of a {gamma}{delta} T Cell Subset Can Increase Host Resistance to a Bacterial Infection J. Immunol., December 1, 2000; 165(11): 6472 - 6479. [Abstract] [Full Text] [PDF]
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M. Makhseed, R. Raghupathy, F. Azizieh, R. Farhat, N. Hassan, and A. Bandar Circulating cytokines and CD30 in normal human pregnancy and recurrent spontaneous abortions Hum. Reprod., September 1, 2000; 15(9): 2011 - 2017. [Abstract] [Full Text] [PDF]
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A. A. Ashkar, J. P. Di Santo, and B. A. Croy Interferon {gamma} Contributes to Initiation of Uterine Vascular Modification, Decidual Integrity, and Uterine Natural Killer Cell Maturation during Normal Murine Pregnancy J. Exp. Med., July 17, 2000; 192(2): 259 - 270. [Abstract] [Full Text] [PDF]
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R. Raghupathy, M. Makhseed, F. Azizieh, A. Omu, M. Gupta, and R. Farhat Cytokine production by maternal lymphocytes during normal human pregnancy and in unexplained recurrent spontaneous abortion Hum. Reprod., March 1, 2000; 15(3): 713 - 718. [Abstract] [Full Text] [PDF]
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K. Ito, M. Karasawa, T. Kawano, T. Akasaka, H. Koseki, Y. Akutsu, E. Kondo, S. Sekiya, K. Sekikawa, M. Harada, et al. Involvement of decidual Valpha 14 NKT cells in abortion PNAS, January 18, 2000; 97(2): 740 - 744. [Abstract] [Full Text] [PDF]
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R. J. Passey, E. Williams, A. M. Lichanska, C. Wells, S. Hu, C. L. Geczy, M. H. Little, and D. A. Hume A Null Mutation in the Inflammation-Associated S100 Protein S100A8 Causes Early Resorption of the Mouse Embryo J. Immunol., August 15, 1999; 163(4): 2209 - 2216. [Abstract] [Full Text] [PDF]
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P. Arck, J. Dietl, and D. Clark From the Decidual Cell Internet: Trophoblast-Recognizing T Cells Biol Reprod, February 1, 1999; 60(2): 227 - 233. [Abstract] [Full Text] [PDF]
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