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and TNF-
Associated with Pregnancy Outcomes1
*
U.S. Army Medical Research Unit, Kenya Medical Research Institute, Kisumu, Kenya; and the
Nyanza Provincial Medical Office and the
New Nyanza Provincial General Hospital, Ministry of Health, Kisumu, Kenya
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-2 were absent in placentas not exposed to malaria but
present in a large proportion of placentas from a holoendemic area.
TNF-
and TGF-ß concentrations were significantly higher, and IL-10
concentrations significantly lower, in placentas from the holoendemic
area. Among primigravidas, placental TNF- concentrations were
significantly higher in the presence of severe maternal anemia, and
both IFN- and TNF- were significantly elevated when a low birth
weight, rather than normal weight, infant was delivered. We conclude
that maternal malaria decreases IL-10 concentrations and elicits
IFN-, IL-2, and TNF- in the placenta, shifting the balance toward
type 1 cytokines. This is the first demonstration that these placental
cytokine changes are associated with poor pregnancy outcomes in humans. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Pregnant women are at increased risk of malaria infection because the parasite is able to adhere to the trophoblastic villous epithelium (1) and sequester in the placenta (2, 3). Sequestration in the placenta relies on parasite adhesion to chondroitin sulfate A (CSA) (1), a molecule that may not be accessible to the parasite in other tissue beds (4-6), and parasites that bind CSA do not commonly infect a host who is not pregnant (1, 7). Therefore, primigravidas have had little or no immunologic experience with the CSA-binding parasite and are most susceptible to infection; protection develops over successive pregnancies (2, 3). While P. falciparum commonly causes anemia in the mother (8, 9), the frequency of other complications depends on a woman’s pre-exisiting immunity to malaria. Women in high transmission (and therefore high immunity) areas are typically asymptomatic (2); among women with incomplete immunity, severe syndromes, such as cerebral malaria and pulmonary edema, frequently occur (10, 11, 12).
Maternal malaria is associated with poor fetal outcomes. Stillbirths, abortions, and LBW result from infection in areas of low transmission (2, 13), and in holoendemic (high transmission) areas, malaria contributes substantially to the high incidence of LBW babies born to primigravidas (2, 3, 14). LBW infants are at higher risk to die early in life (15); because the immediate cause of these deaths is often not malaria, the overall impact of maternal malaria is underestimated. Although the relationship between maternal malaria and poor fetal outcomes is recognized, the basis for the association is unclear. P. falciparum can be found in the cord blood of up to 16% of infants born to infected mothers (16, 17, 18) but rarely establishes a circulating congenital infection (16, 19), suggesting that the parasite elicits fetal pathology through other mediators.
Pregnancy is an event of immunologic tolerance, whereby a woman accepts the implantation of the fetal allograft in her uterus (20). Murine studies suggest a bias toward type 2 responses and away from type 1 responses during successful pregnancy (20, 21, 22); studies in humans have not been adequate to resolve this issue (21, 22). Type 2 cytokines feature prominently in the mouse placenta (20, 23, 24), and type 2 cytokines (25, 26) and TGF-ß (26) appear in the human placenta, possibly to promote implantation (26) and inhibit inflammatory responses (20, 26). Infections thought to require a type 1 response for protection, such as tuberculosis, listeriosis, toxoplasmosis, malaria, and leishmaniasis, are more severe during human pregnancy (27); similarly, pregnancy compromises protective type 1 responses known to confer resistance to leishmaniasis in mice (28).
In rodent models of pregnancy, interventions that increase
concentrations of type 1 cytokines and TNF- induce stillbirths,
abortions, and maternal anemia (29, 30). In humans, TNF- is
frequently increased during severe malaria syndromes other than
maternal malaria, and elevated concentrations of this inflammatory
mediator are associated with mortality (31). No data exist regarding
the cytokine changes that result from placental malaria in humans or
the effect that these may have on fetus and mother.
In this study, we examined cytokine concentrations in placentas
collected from Kenyan parturients presenting for delivery at urban
hospitals. We show that type 1 cytokines are absent and type 2
cytokines are present in normal placentas at parturition. Exposure to
malaria elicits TNF-, IFN-, and IL-2 in the placenta, and these
cytokine changes are associated with poor pregnancy outcomes among
primigravidas.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Nine hundred thirty volunteers were recruited at New Nyanza Provincial General Hospital, Kisumu, Kenya, between April 1995 and August 1996, and forty-nine volunteers at Kenyatta National Hospital, Nairobi, Kenya, during November 1996. All parturients 18 years and older were asked to participate in the study and gave signed informed consent after receiving a study explanation form and oral explanation from a nurse in their native language. Women involved in other research studies and women delivering in Nairobi who had traveled to endemic areas during pregnancy were excluded. This study was approved by the ethical committees of Walter Reed Army Institute of Research, Kenya Medical Research Institute and Kenyatta National Hospital, Nairobi.
Clinical data
Infants and placentas were weighed immediately after delivery. A medical history of the pregnancy was obtained from parturients using a standard questionnaire. Peripheral blood samples were collected by venipuncture from women after delivery. Cord blood samples were obtained by manual compression of the umbilical cord. After removal of the umbilical cord and fetal membranes, placental blood samples were obtained by compressing fresh tissue in a tissue grinder. Hemoglobin (hgb) concentrations were determined on a Coulter cell counter, model T-890 (Coulter Corp., Hialeah, FL); samples were categorized as severely anemic for hgb <7 g/100 ml, mildly anemic for hgb 7 to 10 g/100 ml, and normal for hgb >10 g/100 ml. Peripheral and placental parasitemias at the time of delivery were determined by microscopic examination of Giemsa-stained blood smears. Placental blood smears were examined for the presence of either pigment within macrophages (as a sign of parasite death) or parasites, or both, to define the stage of infection: no infection (no parasites, no pigment); early infection (parasites, no pigment); late infection (parasites and pigment); resolved infection (pigment, no parasites).
Cytokine assays
Serum cytokine concentrations were measured by the sandwich
ELISA method (32). The following Abs were used: IFN-, mAb 1-D1K and
mAb 7-b6-1-biotin (MABTECH, Nacka, Sweden); TNF-, mAb, and
polyclonal Ab (Genzyme, Cambridge, MA); IL-2, IL-4, and IL-6, DuoSet
kits (Genzyme); IL-10, mAb JES3–9D7, and mAb JES-12G8-biotin
(PharMingen, San Diego, CA); TGF-ß1, ELISA system (Promega, Madison,
WI). Detection limits for cytokines were: IFN-, TNF-, and IL-10,
10 pg/ml; IL-2, IL-4, and IL-6, 50 pg/ml; TGF-ß1, 30 pg/ml.
Assays were performed on all samples collected in Nairobi (n = 49), and on a representative number of randomly chosen samples collected in Kisumu.
Statistical analyses
Differences between groups were analyzed by nonparametric methods (Mann-Whitney or Kruskal-Wallis). Proportions were compared by contingency table analysis. Correlations were examined by Spearman rank test. Tied p values are given. The significance limit was chosen at p = 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Type 2 cytokines predominate in a normal mouse placenta (20, 23, 24); data concerning the cytokine bias in human placentas are
incomplete (21, 22). To define the effect of malaria, we compared
placental concentrations of TNF-, IFN-, IL-2, IL-4, IL-6, IL-10,
and TGF-ß1 among exposed women with concentrations among unexposed
women. Only aparasitemic women were included in this analysis.
"Exposed" women were recruited in Kisumu, Kenya, a
malaria-holoendemic area where the incidence of infection among male
residents can exceed 90% over 4 mo (P. E. Duffy, unpublished
data). "Unexposed" women were recruited in Nairobi, where
transmission is sporadic.
The proportions of samples with detectable TGF-ß1, IL-4, and IL-6
were similar in the two groups (Table I
).
While placental concentrations of IL-4 and IL-6 were also similar among
the groups (Fig. 1, B and
C), the placental concentration of TGF-ß1 was
significantly lower in unexposed women (Fig. 1A).
IL-10 was detected more frequently (Table I) and was measured at a
significantly higher concentration (Fig. 1D) in
placentas from unexposed women.
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were not detected in any samples from
unexposed women but were detected in 38.3 and 42%, respectively, of
samples from exposed, uninfected women (Table I
; Fig. 2, A and B),
both highly significant differences. TNF- was also detected more
frequently (Table I) and at a significantly higher concentration (Fig. 2C) in placental samples obtained from these exposed
women.
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Systemic malaria infection elicits an array of immune responses
(33). Exposure to malaria during pregnancy elicits type 1 cytokines in
the placenta, altering the cytokine balance observed in unexposed women
(Figs. 1 and 2), and we questioned whether active infection predictably
altered the cytokine profile. We stratified women in a holoendemic area
(Kisumu, Kenya) by the presence or absence of parasites in their
placentas at the time of delivery. Type 2 cytokines (IL-4, IL-6, and
IL-10) in the placenta did not significantly differ on the basis of
infection or parity (Fig. 3). Among
multigravidas, but not other women, placental TGF-ß1 concentrations
were significantly higher during infection (Fig. 3A).
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, IFN-, and IL-2 are soluble mediators of the
cellular response, and we analyzed placental concentrations of these
cytokines with regard to infection and gravidity. TNF-
concentrations did not differ between gravid groups but did vary within
groups on the basis of infection. Among primigravid and multigravid
women, TNF- concentrations were significantly higher when the
placenta was parasitized (Fig. 4A); the elevation of
TNF- was not significant among secundigravid women. Like TNF-,
IL-2 concentrations did not differ among gravid groups. IL-2
concentrations were higher during infection in all groups, although
these elevations (compared with uninfected samples) were not
significant (Fig. 4B).
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were significantly higher
in primigravidas than other groups (p = 0.01,
Kruskal-Wallis). Within gravid groups, multigravid women had
significantly elevated concentrations of IFN- in association with
infection while primigravid women had decreased concentrations (Fig. 4C). We defined the stage of infection at the time of
delivery (no infection, early infection, late infection, or resolved
infection) and compared IFN- concentrations between different stages
(Fig. 4D). In multigravidas, IFN- concentrations
were significantly elevated during early infections compared with other
stages of infection; among primigravidas, the elevation of IFN- did
not differ significantly between stages. The significant elevation of
IFN- in uninfected placentas of primigravidas
(p = 0.02, compared with similar placentas from
other gravid groups) may indicate a sustained pattern of cytokine
secretion after infection or may indicate the cumulative effect of more
frequent (2, 3) or more chronic infections.
IFN- and TNF- are associated with poor pregnancy outcomes
among primigravidas
Placental concentrations of IFN- and TNF- were significantly
higher in primigravidas delivering LBW babies than in those delivering
normal birth weight (NBW) babies (Fig. 5,
A and B). The elevation of IFN- among
primigravidas in the absence of infection (Fig. 4D)
was specifically associated with LBW babies: among uninfected
primigravidas, IFN- concentrations were significantly higher with
the birth of a LBW rather than a NBW infant (p
= 0.0075, Mann-Whitney), a difference not seen among infected
primigravidas or other groups. Because small placentas are associated
with LBW babies and often reflect a general growth disturbance, we also
examined the relationship between cytokine concentrations and placental
weight. Among primigravidas, but not other women, deliveries
characterized by low placental weight (LPW), compared with normal
placental weight (NPW), had significantly higher concentrations of
IFN- and TNF- (Fig. 5, C and D).
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concentrations (Fig. 6) and significantly smaller infants
(p = 0.01, Mann-Whitney, severe anemia vs no
anemia) occurred in association with maternal anemia. Because TNF-
and anemia might both contribute to LBW, we stratified the data from
primigravidas: anemia was associated with significantly smaller babies
when TNF- was detected in the placenta (p <
0.05, Kruskal-Wallis), but not if TNF- was not detected; conversely,
detection of TNF- in the placenta was associated with significantly
smaller babies in anemic (p < 0.05,
Mann-Whitney) but not in normal women. In sum, TNF- concentrations
are related to anemia in primigravid women, and both appear to
contribute to the development of LBW infants.
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, 
= 0.096; IFN-, = 0.49; IL-4, = 0.18),
suggesting a marginal effect of fetal blood on overall cytokine
measurements. Further, cord cytokine concentrations had no significant
association with pregnancy outcomes. Therefore, the presence of fetal
blood would tend to reduce the significance of associations between
placental cytokine concentrations and outcomes, and our analyses may
understate the relationship between placental cytokine concentrations
in maternal blood and pregnancy outcomes. Peripheral cytokine concentrations do not predict pregnancy outcomes
Peripheral and placental concentrations of cytokines correlated to
varying degrees (TNF-, = 0.081, n = 285;
IFN-, = 0.5, n = 173; IL-4, = 0.3,
n = 143: Spearman rank correlation). Frequently,
TNF- was detected in the placenta but not in the peripheral
circulation; less commonly, TNF- was detected in the periphery but
not in the placenta (Fig. 7A). IFN- and IL-4
followed patterns similar to that of TNF- (data not shown).
Peripheral TNF- concentrations were significantly higher among
multigravid women than among other women (p =
0.03, Kruskal Wallis) but did not significantly differ on the basis of
infection (Fig. 7B). Peripheral concentrations of
IFN- (data not shown) or TNF- (Fig. 7C) were
not elevated in association with LBW infants. The relationship between
peripheral TNF- and anemia was more complicated (Fig. 7D): primigravidas with mild anemia had significantly
decreased concentrations; secundigravidas with mild anemia had
significantly increased concentrations; concentrations did not differ
between groups with severe anemia and normal hgb counts. Thus, despite
the strong relationship between placental cytokines and pregnancy
outcomes, peripheral cytokine concentrations were not associated with
either LBW or severe anemia among primigravidas.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study, exposure to malaria altered the balance of placental
cytokines. In placentas from Nairobi, type 2 cytokines (IL-4, IL-6, and
IL-10) predominated, and type 1 cytokines (IFN- and IL-2) were
absent. These data support the idea that successful pregnancy in humans
is accompanied by a bias away from type 1 cytokines and toward type 2
cytokines (27). Samples from malaria-exposed women were markedly
different: pro-inflammatory cytokines like TNF-, IFN-, and IL-2
appeared in abundance; IL-10 concentrations were decreased (possibly
down-regulated by type 1 cytokines); and TGF-ß1 concentrations were
increased. In studies of mice, IL-10 and the inflammatory cytokines
play counter-regulatory roles in the placenta (23, 36), a finding
consistent with our observations. Conversely, placental concentrations
of the anti-inflammatory cytokine TGF-ß1 were higher among women
exposed to malaria in this study. The uterine epithelium and placental
trophoblasts are known to be sources of TGF-ß during pregnancy (26).
Increases in TGF-ß may have occurred in response to the appearance of
inflammatory cytokines, perhaps to ameliorate immune-mediated damage to
the fetoplacental unit.
TNF- is believed to have a role in parturition (37), which may
explain our detection of this cytokine in some placentas donated by
unexposed women. However, exposure to malaria was associated with
significant elevations of placental TNF- (Fig. 2C). Further, type 1 cytokines (IFN- and IL-2)
appeared only in women exposed to malaria. TNF- and IL-2
concentrations were always higher during infection (Fig. 4, A and B), but the pattern of IFN-
secretion was not similarly uniform (Fig. 4, C and
D): compared with other groups, primigravidas had
elevated concentrations of IFN- at all stages of infection; among
multigravidas, IFN- was elevated during early infection, but not at
other stages of infection.
Primigravid women are at particular risk to deliver LBW babies, and
maternal anemia, most commonly seen in primigravidas, increases that
risk (35). In Kisumu, primigravid women delivered significantly smaller
babies than other women did (p < 0.05, data
not shown), and maternal age did not account for these differences.
Elevations of TNF- and IFN- were both significantly associated
with LBW and LPW in primigravid women. The association of elevated
IFN- and LBW was strongest in aparasitemic primigravidas, suggesting
that the sustained elevation of IFN- after resolution of infection
may be particularly harmful. Rodent models of pregnancy provide
findings consistent with our own: administration of IFN- and TNF-
(29, 30, 38), or increases in these cytokines that occur during
infection of C57BL/6 mice with Leishmania major (39), are
associated with impaired development and fetal loss. In particular, the
sustained administration of low doses of IFN- to pregnant rodents,
which may approximate the pattern of IFN- secretion in
malaria-exposed primigravidas (Fig. 4D), increases
fetal abortion and decreases fetal weight (30). Malaria, like other
infections that activate macrophages, potentiates the abortifacient
effects of TNF- in mice (40).
For the mother, anemia is the commonest consequence of maternal
malaria. Anemia frequently results from malaria infection in other
populations and is an important cause of death among small children in
holoendemic areas (41, 42). Among subjects in this study, placental
TNF- concentrations were significantly higher among primigravidas
with severe anemia compared with other primigravidas (Fig. 6). Anemia
places the mother at risk for mortality (9) and is an independent risk
factor for poor fetal outcomes (9, 35, 43).
The shift to a type 1 immune response and elevation of TNF- were
associated with adverse pregnancy outcomes among our primigravid
subjects. Elevated serum TNF- has been associated with severe
nonmaternal malaria (31), as have specific alleles of the TNF-
promoter region (44). While these earlier findings suggested that
TNF- up-regulation of downstream immune mediators, like nitric
oxide, might contribute to syndromes such as cerebral malaria (45),
subsequent work has not consistently supported this hypothesis (46). In
rodent models of malaria, TNF- can be associated with survival or
death, depending on which tissues express the cytokine, and the point
in the course of infection when concentrations peak (47).
Human studies generally measure peripheral concentrations of
soluble mediators, which may not correlate with concentrations in
inflamed tissues. Here, peripheral concentrations of TNF-, IFN-,
and IL-4 correlated with placental concentrations to varying degrees,
from minimal to moderate. The correlations between peripheral and
placental concentrations suggest that immune responses occurring in the
placenta can influence the systemic profile of cytokines, but this
influence can vary according to the cytokine of interest. We were
unable to identify significant associations between peripheral cytokine
concentrations and clinical outcomes. Perhaps because cytokine effects
are local, our measurements within the placenta were best able to
describe the relationship between the immune response and fetal
outcomes. The strong relationship in primigravidas between severe
maternal anemia and placental TNF-, but not peripheral TNF-, was
unexpected. TNF- is known to inhibit erythropoiesis in mice, in part
by suppressing erythropoietin-induced erythroid cell formation (48),
and the human trophoblast was recently identified as an extrarenal site
for the expression of erythropoietin (49). Although the role of
placental erythropoietin in erythropoiesis remains undefined, its
production may be suppressed by placental TNF- (50), with maternal
anemia as a potential consequence. Alternatively, maternal anemia and
placental TNF- may both be related to another variable, such as the
frequency or chronicity of infection, but are not causally related to
each other.
Parasites infecting the placenta have a unique adhesive phenotype (1). Women may have limited immunologic experience with this subpopulation until their first pregnancy, making primigravidas relatively naive, and therefore more susceptible to malaria. In a holoendemic area, malaria exposure altered the placental cytokine profile, shifting the balance in favor of a type 1 environment. Although P. falciparum may initiate the events leading to disease and death in the mother and her newborn, other mediators, such as placental cytokines, may play a critical role in pathophysiology.
In this study, all parities produced TNF- and type 1 cytokines in
response to malaria. In primigravidas, elevations of placental IFN-
at all stages of infection, in concert with raised concentrations of
TNF- and possibly IL-2, are associated with poor outcomes for both
mother and child. The distinct pattern of cytokines observed in
primigravidas may be the result of more frequent parasitemia or could
represent cellular responses occurring in the absence of established
acquired immunity. In either case, a vaccine against the parasite
subpopulation infecting the human placenta could offer nulligravid
women the immunologic protection enjoyed by multigravid women, averting
the cytokine responses associated with poor outcomes during first
pregnancy.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Michal Fried or Dr. Patrick Duffy at the current address: Department of Immunology, Walter Reed Army Institute of Research, Rm. 2028, Bldg. 40, 14th and Dahlia St., Washington, CD 20307-5001. E-mail address:
3 Abbreviations used in this paper: CSA, chondroitin sulfate A; LBW, low birth weight; NBW, normal birth weight; LPW, low placental weight; NPW, normal placental weight; hgb, hemoglobin.
Received for publication June 23, 1997. Accepted for publication November 11, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and tumor necrosis factor cause placental injury in the rat. Am. J. Pathol. 135:239.[Abstract]
responses and increased production of T helper 2 cytokines. J. Immunol. 156:644.[Abstract]
promoter region associated with susceptibility to cerebral malaria. Nature 371:508.[Medline]
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A. L. Suguitan Jr., D. C. Gowda, G. Fouda, L. Thuita, A. Zhou, R. Djokam, S. Metenou, R. G. F. Leke, and D. W. Taylor Lack of an Association between Antibodies to Plasmodium falciparum Glycosylphosphatidylinositols and Malaria-Associated Placental Changes in Cameroonian Women with Preterm and Full-Term Deliveries Infect. Immun., September 1, 2004; 72(9): 5267 - 5273. [Abstract] [Full Text] [PDF]
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P. A. HOLDING and P. K. KITSAO-WEKULO DESCRIBING THE BURDEN OF MALARIA ON CHILD DEVELOPMENT: WHAT SHOULD WE BE MEASURING AND HOW SHOULD WE BE MEASURING IT? Am J Trop Med Hyg, August 1, 2004; 71(2_suppl): 71 - 79. [Abstract] [Full Text] [PDF]
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S. CHAISAVANEEYAKORN, P. KONGTAWELERT, P. ANGKASEKWINAI, R. McGREADY, F. NOSTEN, and S. C. CHAIYAROJ INHIBITORY ACTIVITIES OF SULFATED PROTEOGLYCANS ON CHONDROITIN SULFATE A-MEDIATED CYTOADHERENCE OF PLASMODIUM FALCIPARUM ISOLATES FROM THAILAND Am J Trop Med Hyg, February 1, 2004; 70(2): 149 - 157. [Abstract] [Full Text] [PDF]
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A. L. SUGUITAN JR., T. J. CADIGAN, T. A. NGUYEN, A. ZHOU, R. J. I. LEKE, S. METENOU, L. THUITA, R. MEGNEKOU, J. FOGAKO, R. G. F. LEKE, et al. MALARIA-ASSOCIATED CYTOKINE CHANGES IN THE PLACENTA OF WOMEN WITH PRE-TERM DELIVERIES IN YAOUNDE, CAMEROON Am J Trop Med Hyg, December 1, 2003; 69(6): 574 - 581. [Abstract] [Full Text] [PDF]
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 V. E. Murphy, P. G. Gibson, W. B. Giles, T. Zakar, R. Smith, A. M. Bisits, C. G. Kessell, and V. L. Clifton Maternal Asthma Is Associated with Reduced Female Fetal Growth Am. J. Respir. Crit. Care Med., December 1, 2003; 168(11): 1317 - 1323. [Abstract] [Full Text] [PDF]
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S. T. Agbor-Enoh, R. N. Achur, M. Valiyaveettil, R. Leke, D. W. Taylor, and D. C. Gowda Chondroitin Sulfate Proteoglycan Expression and Binding of Plasmodium falciparum-Infected Erythrocytes in the Human Placenta during Pregnancy Infect. Immun., May 1, 2003; 71(5): 2455 - 2461. [Abstract] [Full Text] [PDF]
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 R. N. Achur, M. Valiyaveettil, and D. C. Gowda The Low Sulfated Chondroitin Sulfate Proteoglycans of Human Placenta Have Sulfate Group-clustered Domains That Can Efficiently Bind Plasmodium falciparum-infected Erythrocytes J. Biol. Chem., March 21, 2003; 278(13): 11705 - 11713. [Abstract] [Full Text] [PDF]
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G. Xi, R. G. F. Leke, L. W. Thuita, A. Zhou, R. J. I. Leke, R. Mbu, and D. W. Taylor Congenital Exposure to Plasmodium falciparum Antigens: Prevalence and Antigenic Specificity of In Utero-Produced Antimalarial Immunoglobulin M Antibodies Infect. Immun., March 1, 2003; 71(3): 1242 - 1246. [Abstract] [Full Text] [PDF]
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E. T. Abrams, H. Brown, S. W. Chensue, G. D. H. Turner, E. Tadesse, V. M. Lema, M. E. Molyneux, R. Rochford, S. R. Meshnick, and S. J. Rogerson Host Response to Malaria During Pregnancy: Placental Monocyte Recruitment Is Associated with Elevated {beta} Chemokine Expression J. Immunol., March 1, 2003; 170(5): 2759 - 2764. [Abstract] [Full Text] [PDF]
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S. J. Rogerson, H. C. Brown, E. Pollina, E. T. Abrams, E. Tadesse, V. M. Lema, and M. E. Molyneux Placental Tumor Necrosis Factor Alpha but Not Gamma Interferon Is Associated with Placental Malaria and Low Birth Weight in Malawian Women Infect. Immun., January 1, 2003; 71(1): 267 - 270. [Abstract] [Full Text] [PDF]
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S. J. ROGERSON, E. POLLINA, A. GETACHEW, E. TADESSE, V. M. LEMA, and M. E. MOLYNEUX PLACENTAL MONOCYTE INFILTRATES IN RESPONSE TO PLASMODIUM FALCIPARUM MALARIA INFECTION AND THEIR ASSOCIATION WITH ADVERSE PREGNANCY OUTCOMES Am J Trop Med Hyg, January 1, 2003; 68(1): 115 - 119. [Abstract] [Full Text] [PDF]
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 P. Vigano, E. Somigliana, S. Mangioni, M. Vignali, M. Vignali, and A. M. Di Blasio Expression of Interleukin-10 and Its Receptor Is Up-Regulated in Early Pregnant Versus Cycling Human Endometrium J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5730 - 5736. [Abstract] [Full Text] [PDF]
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V. E. Murphy, T. Zakar, R. Smith, W. B. Giles, P. G. Gibson, and V. L. Clifton Reduced 11{beta}-Hydroxysteroid Dehydrogenase Type 2 Activity Is Associated with Decreased Birth Weight Centile in Pregnancies Complicated by Asthma J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1660 - 1668. [Abstract] [Full Text] [PDF]
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A. Perez-Diez, P. J. Spiess, N. P. Restifo, P. Matzinger, and F. M. Marincola Intensity of the Vaccine-Elicited Immune Response Determines Tumor Clearance J. Immunol., January 1, 2002; 168(1): 338 - 347. [Abstract] [Full Text] [PDF]
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I. O'Neil-Dunne, R. N. Achur, S. T. Agbor-Enoh, M. Valiyaveettil, R. S. Naik, C. F. Ockenhouse, A. Zhou, R. Megnekou, R. Leke, D. W. Taylor, et al. Gravidity-Dependent Production of Antibodies That Inhibit Binding of Plasmodium falciparum-Infected Erythrocytes to Placental Chondroitin Sulfate Proteoglycan during Pregnancy Infect. Immun., December 1, 2001; 69(12): 7487 - 7492. [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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 C. W. Roberts, W. Walker, and J. Alexander Sex-Associated Hormones and Immunity to Protozoan Parasites Clin. Microbiol. Rev., July 1, 2001; 14(3): 476 - 488. [Abstract] [Full Text] [PDF]
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C. H. Ricke, T. Staalsoe, K. Koram, B. D. Akanmori, E. M. Riley, T. G. Theander, and L. Hviid Plasma Antibodies from Malaria-Exposed Pregnant Women Recognize Variant Surface Antigens on Plasmodium falciparum-Infected Erythrocytes in a Parity-Dependent Manner and Block Parasite Adhesion to Chondroitin Sulfate A J. Immunol., September 15, 2000; 165(6): 3309 - 3316. [Abstract] [Full Text] [PDF]
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J. Vekemans, C. Truyens, F. Torrico, M. Solano, M.-C. Torrico, P. Rodriguez, C. Alonso-Vega, and Y. Carlier Maternal Trypanosoma cruzi Infection Upregulates Capacity of Uninfected Neonate Cells To Produce Pro- and Anti-Inflammatory Cytokines Infect. Immun., September 1, 2000; 68(9): 5430 - 5434. [Abstract] [Full Text] [PDF]
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M. T. Long and T. V. Baszler Neutralization of Maternal IL-4 Modulates Congenital Protozoal Transmission: Comparison of Innate Versus Acquired Immune Responses J. Immunol., May 1, 2000; 164(9): 4768 - 4774. [Abstract] [Full Text] [PDF]
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J. Gysin, B. Pouvelle, N. Fievet, A. Scherf, and C. Lepolard Ex Vivo Desequestration of Plasmodium falciparum-Infected Erythrocytes from Human Placenta by Chondroitin Sulfate A Infect. Immun., December 1, 1999; 67(12): 6596 - 6602. [Abstract] [Full Text] [PDF]
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B. Maubert, N. Fievet, G. Tami, M. Cot, C. Boudin, and P. Deloron Development of Antibodies against Chondroitin Sulfate A-Adherent Plasmodium falciparum in Pregnant Women Infect. Immun., October 1, 1999; 67(10): 5367 - 5371. [Abstract] [Full Text] [PDF]
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 R. F. G. Leke, R. R. Djokam, R. Mbu, R. J. Leke, J. Fogako, R. Megnekou, S. Metenou, G. Sama, Y. Zhou, T. Cadigan, et al. Detection of the Plasmodium falciparum Antigen Histidine-Rich Protein 2 in Blood of Pregnant Women: Implications for Diagnosing Placental Malaria J. Clin. Microbiol., September 1, 1999; 37(9): 2992 - 2996. [Abstract] [Full Text]
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J. D. Kurtis, D. E. Lanar, M. Opollo, and P. E. Duffy Interleukin-10 Responses to Liver-Stage Antigen 1 Predict Human Resistance to Plasmodium falciparum Infect. Immun., July 1, 1999; 67(7): 3424 - 3429. [Abstract] [Full Text] [PDF]
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N. Tsutsui and T. Kamiyama Transforming Growth Factor beta -Induced Failure of Resistance to Infection with Blood-Stage Plasmodium chabaudi in Mice Infect. Immun., May 1, 1999; 67(5): 2306 - 2311. [Abstract] [Full Text] [PDF]
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 P. Moreau, F. Adrian-Cabestre, C. Menier, V. Guiard, L. Gourand, J. Dausset, E. D. Carosella, and P. Paul IL-10 selectively induces HLA-G expression in human trophoblasts and monocytes Int. Immunol., May 1, 1999; 11(5): 803 - 811. [Abstract] [Full Text] [PDF]
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