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*
Division of Geographic Medicine, Case Western Reserve University School of Medicine, University Hospitals of Cleveland, Cleveland, OH 44106;
Division of Vector Borne Diseases, Ministry of Health, Nairobi, Kenya;
Kenya Medical Research Institute, Nairobi, Kenya; and
§
Veteran’s Affairs Medical Center, Cleveland, OH 44106
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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in response to
mycobacterial purified protein derivative than children of
helminth-infected mothers (p < 0.01). This
relationship was restricted to purified protein derivative because
maternal infection status did not correlate with filarial Ag-driven
IL-2, IFN-, IL-4, or IL-5 responses by children. Prospective studies
initiated at birth showed that helminth-specific T cell immunity
acquired in utero is maintained until at least 10–14 mo of age in the
absence of infection with either Wuchereria bancrofti or
Schistosoma haematobium. Purified protein
derivative-driven T cell IFN- production evaluated 10–14 mo after
BCG vaccination was 26-fold higher for infants who were not sensitized
to filariae or schistosomes in utero relative to subjects who
experienced prenatal sensitization (p < 0.01).
These data indicate that helminth-specific immune responses acquired
during gestation persist into childhood and that this prenatal
sensitization biases T cell immunity induced by BCG vaccination away
from type 1 IFN- responses associated with protection against
mycobacterial infection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Studies of experimental animals have shown that the immune environment
established by prior sensitization to helminths influences immunity to
unrelated Ags. Following immunization with sperm whale myoglobin, mice
with preexisting Schistosoma mansoni infection develop
Ag-specific T cells that produce IL-4, whereas T cells from uninfected
animals generate relatively more IFN- and IL-2 (4). With respect to
the impact of helminthiases on the host response to intracellular
pathogens, resistance against viral infections that is dependent on
cytokines such as IFN- is compromised in mice with schistosomiasis
(5). Although the interaction between heminthic and mycobacterial
infections in experimental animals has not been studied, mice immunized
with PPD following the induction of strong type 2 responses by the
filarial parasite Brugia malayi develop T cell cytokine
responses that are skewed away from the type 1 and toward the type 2
pattern. Simultaneous immunization of naive animals with helminth and
mycobacterial Ags does not diminish IFN- or enhance type 2 cytokine
responses to PPD (6).
Observations by others and us indicate that newborns whose mothers have
schistosomiasis or bancroftian filariasis during pregnancy are
frequently sensitized to these helminths in utero (7, 8, 9, 10, 11). Consistent
with the propensity of worms to induce allergic responses, cord blood
lymphocytes (CBL) from newborns of helminth-infected mothers produce
IL-4, IL-5, and IgE as well as IFN- (10, 11). The present study
tests the hypothesis that in utero sensitization to helminths
establishes immunologic memory that persists into childhood and biases
the T cell cytokine response induced by BCG vaccination. Two approaches
were taken to examine this interaction in residents of rural Kenya,
where BCG is administered at birth and filariasis and schistosomiasis
are endemic. First, in a cross-sectional study, PPD- and filarial
Ag-driven cytokine responses by PBMC from 2- to 10-year-old children
living in villages where bancroftian filariasis is endemic were
evaluated and compared according to the filarial infection status of
their mothers. Second, in a prospective study initiated at birth, the
patterns of helminth- and PPD-driven cytokine responses by 10- to
14-mo-old infants without or with documented in utero sensitization to
Wuchereria bancrofti and Schistosoma haematobium
were compared.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Thirty-three mother-child pairs living in two villages, Darigube and Eshu, participated. W. bancrofti infection is endemic and S. haematobium prevalence is low in these villages (6.3% of 150 15- to 40-year-old women had S. haematobium eggs in a single urine sample). S. mansoni is not transmitted in the study area. According to the presence of nocturnal microfilaremia and filarial antigenemia (see below), 16 children had mothers who were not infected and 17 had mothers with filariasis. None of the women were passing S. haematobium eggs in their urine or S. mansoni eggs in their feces.
Prospective study of infants from birth to 10–14 mo of age
Twenty-five newborns delivered in the facilities of Msambweni Hospital in 1996 and 1997 were enrolled. CBL responses to filarial Ag (B. malayi adult worm extract, BmA) and S. haematobium adult worm Ag (SWAP), and the helminth infection status of mothers were evaluated as described below. Patients who attend Msambweni Hospital come from a wide area of Coast Province that includes villages where both bancroftian filariasis and schistosomiasis haematobia are endemic.
BCG vaccination
The study subjects were vaccinated with BCG (Staten Serum Institute, Copenhagen, Denmark) at birth in accordance with the policy of the Kenya Ministry of Health. BCG vaccination of 2-to 10-year-old children was inferred from health records and by the presence of a typical scar on the upper arm. In the case of newborns, administration of BCG within 24 h of birth was observed by the investigators and confirmed by the presence of a scar at 10–14 mo of age.
Informed consent and ethical approval
Verbal informed consent for participation of children and newborns was obtained from their mothers. Ethical approval was secured from the Kenya Ministry of Health and Human Investigation Institutional Review Board at University Hospitals of Cleveland, Case Western Reserve University.
Parasitologic determinations
To diagnose S. haematobium infection, 10 ml of urine was passed through a polycarbonate membrane (Nuclepore, Pleasanton, CA) and examined microscopically for ova. Stool samples were examined for intestinal helminth eggs (hookworm, Trichuris trichiuria, Ascaris, S. mansoni) using standard techniques. W. bancrofti infection status was evaluated by determination of microfilaremia using the Nuclepore filtration method (12) and measurement of circulating filarial Ag by an ELISA based on the mAb Og4C3 (13). The ELISA was performed and scored as positive for infection according to the manufacturer’s instructions (TropBiomed, Townsville, Australia).
Ags and mitogens
BmA and SWAP were prepared as described (14, 15). The preparations contained <0.5 ng/ml endotoxin (5- to 50-fold less than that required for LPS stimulation of cytokine production by human lymphocytes) (16). PPD was purchased from Evans Medical Institute (Leatherhead, Surrey, U.K.).
Isolation of PBMC and culture conditions for in vitro cytokine production
Depending on the age and size of the child, 2–15 ml of blood
was obtained by venipuncture. PBMC were separated from heparinized cord
or venous blood by density gradient centrifugation on Ficoll-Hypaque
and resuspended in RPMI 1640 supplemented with 10% FCS, 4 mM
L-glutamine, 25 mM HEPES, and 80 µg/ml gentamicin
(BioWhittaker, Walkersville, MD) (C-RPMI). PBMC were incubated at
2 x 106 cells/ml in C-RPMI in a total volume of 1 ml.
Media alone, SWAP (50 µg/ml), BmA (10 µg/ml), PPD (1:200 dilution),
or PMA (50 ng/ml) plus ionomycin (1 µg/ml; Calbiochem, La Jolla, CA)
were added to duplicate cultures. Cells were incubated at 37°C in 5%
CO2. Supernatants were collected at 36 h (for IL-2 and
IL-4 detection) and 72 h (for IL-5 and IFN- measurement) and
immediately frozen at -70°C for subsequent measurement of cytokine
production.
Cytokine and Ig ELISAs
Cytokine levels in culture supernatants were measured by ELISA
and expressed in pg/ml by interpolation from standard curves based on
recombinant lymphokines using Abs and methods as described (17).
Monoclonal Abs for capture and biotinylated Abs, respectively, for
detection of each cytokine were: IL-5, TRFK5 and 5D10 (PharMingen, San
Diego, CA); IL-4, 8D and 25D2 (PharMingen); IFN-, M-700 and M-701
(Endogen, Cambridge, MA); and IL-10, 18551D and 18652D (PharMingen).
The limits of detection were 18 pg/ml for IL-5, 16 pg/ml for IL-4, 10
pg/ml for IFN-, and 16 pg/ml for IL-10. Polyclonal IgE and BmA- and
SWAP-specific IgE and IgG4 Abs were quantified as described (14, 18, 19).
Statistics
Results are expressed as the mean ± SEM using
log-transformed data unless otherwise stated. Log-transformation of
cytokine levels produced a normal distribution of the data. Thus, a
comparison of means of between the two independent populations was
examined by the Student’s t test. We also compared
differences between populations using the nonparametric Mann-Whitney U
test. All comparisons were also statistically significant using this
test except for PPD-driven IL-5 production by infants born to
infected vs noninfected mothers in Fig. 1
b. The frequencies of
responses among different groups were compared using Fisher’s exact
test. Spearman’s rank correlation was used to test for correlation
between ordered data.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Because observations made in some endemic areas suggest that
maternal filarial infection leads to tolerization to filarial Ags in
offspring (20, 21, 22), the relationship between maternal W.
bancrofti infection and childhood infection status and filarial
(BmA)-driven cytokine responses was first examined. Maternal infection
status did not correlate with BmA-driven IFN- or IL-5 production by
children. PBMC from 12 of 16 children of uninfected mothers made
IFN- compared with 9 of 17 children of W.
bancrofti-infected mothers (p > 0.10;
Fig. 1
a). The geometric mean levels of BmA-driven IFN-
and IL-5 production by children in each group were also similar. Of
note, filarial Ag-driven IL-5 production was significantly greater than
IFN- production (e.g., children of filarial-infected mothers
produced 160 pg/ml of IL-5 and 32 pg/ml of IFN-; p
< 0.01).
In contrast to BmA-driven responses, PPD-specific cytokine production
differed according to the filarial infection status of the child’s
mother (Fig. 1b). PBMC from 15 of 16 children (94%) of
uninfected mothers made IFN- when stimulated with PPD compared with
8 of 14 children (57%) of infected mothers (p
= 0.03). Moreover, the mean level of PPD-driven IFN- produced by
PBMC from children in the former group was 10-fold higher than the
latter (p < 0.01). With respect to PPD-driven
IL-5, the frequency of responses was similar for PBMC from children in
both groups (50% and 57%, respectively). However, among children
whose PBMC did produce IL-5 when stimulated with PPD, those from
mothers with W. bancrofti infection generated significantly
higher amounts of this cytokine (means of 211 pg/ml vs 82 pg/ml,
p = 0.03). PPD-driven IFN- and IL-5 or IL-10
production were not inversely correlated (data not shown), suggesting
that cross-regulation of type 1 and type 2 cytokine production was not
occurring in vitro (23).
Young children in these filarial endemic communities rapidly became infected with filariasis as determined by the presence of filarial antigenemia. None of the 2-year-old children studied were infected. Overall, 10 of the 37 children (27%) between 2–10 years old (median, 6 years) were infected. There was no association between the filarial infection status of mothers and children (25% of children of uninfected mothers had filarial antigenemia compared with 36% of children of infected mothers; p > 0.05).
Prospective study: acquisition of filarial or schistosome infection between birth and 10–14 mo of age
To determine whether infants were infected with W. bancrofti or S. haematobium between birth and 10–14 mo of age, blood was examined for the presence of filarial Ag and urine was evaluated for schistosome eggs at both time points. None of the subjects were infected with either parasite by these criteria. One infant had hookworm ova in her stool at 14 mo of age.
Two additional examinations were performed to determine whether the
infants acquired W. bancrofti or S. haematobium
infection during the course of the study. First, the levels of
parasite-specific IgE at birth (i.e., in cord blood) and at 10–14 mo
of age were compared. BmA-specific IgE decreased in 21 of 25 cases and
increased in only 4 paired samples, although these increases were
<4-fold (Fig. 2). Similar results were
obtained for SWAP-specific IgE, although none increased with age (data
not shown). The lack of increase in BmA- and SWAP-specific IgE was not
due to an inability to generate this Ig isotype because the level of
polyclonal IgE increased 2- to >100-fold during this time interval in
all of the subjects (Fig. 2). Second, BmA- and SWAP-specific IgG4 Abs
at 10–14 mo of age were measured. None of the subjects had
parasite-specific Abs of this IgG subclass (IgG4 Abs in cord blood were
not evaluated because these are primarily of maternal origin). In
aggregate, these data indicate that none of the subjects were infected
with W. bancrofti or S. haematobium between birth
and 10–14 mo of age.
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Similar to earlier observations of a different group of infants
delivered at the same hospital (10), 12 of the 25 newborns in the
current study were sensitized to S. haematobium and/or
W. bancrofti in utero (i.e., their CBL produced IL-2,
IFN-, IL-4, and/or IL-5 when stimulated with BmA or SWAP; Table I). Newborns whose mothers had filariasis
or schistosomiais were more likely to have helminth Ag-driven CBL
cytokine responses than those whose mothers were not infected with
either parasite (75% vs 23%, respectively; p <
0.03).
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. Peak cytokine response is shown to
either Ag. Four infants responded to both Ags at birth. The responses
to schistosome and filarial Ags were combined because either helminth
infection stimulates an allergic-type immune response capable of
biasing the immune response to BCG vaccination. Four of the 13 infants
(38%) whose CBL responses indicated they were not sensitized to either
helminth at birth had BmA- or SWAP-driven responses at 10–14 mo. PBMC
from these four individuals made IFN- and two also made IL-5. Two
subjects (numbers 170 and 226) had mothers with filarial or schistosome
infection. Subject 226 also had elevated SWAP-specific IgE in his cord
blood (13.7 ng/ml vs <0.8 ng/ml for cord blood from 20 North American
controls), suggesting that he was sensitized to S.
haematobium at birth despite the lack of a detectable
helminth-driven CBL response. In contrast to subjects who lacked
evidence of prenatal sensitization, 10 of 12 (83%) newborns whose CBL
produced one or more cytokines when stimulated with BmA or SWAP
retained Ag-specific lymphocyte responses at 10–14 mo of age
(p < 0.05; Table I). Notably, nine of these
infants had mothers with elevated parasite-specific IgG4 Abs, i.e.,
suggesting that some mothers were infected during the time of the
child’s gestation. The two subjects in whom T cell responses were not
detectable at 10–14 mo of age (numbers 64 and 65) had helminth-driven
IL-2 responses at birth. With respect to the 10 infants who retained
helminth Ag-specific responses, type 2 cytokines increased with age in
all cases. The levels of IFN- and IL-2 production did not show a
consistent trend with increasing age. In utero sensitization to helminths and PPD-driven cytokine responses at 10–14 mo of age
PBMC from all 13 infants whose CBL responses indicated they were
not sensitized to W. bancrofti or S. haematobium
at birth produced PPD-driven IFN- at 10–14 mo of age (Fig. 3a). Cells from four of these
infants also produced IL-5 in response to PPD. Two of the latter
subjects (numbers 226 and 170) had evidence of in utero sensitization
to helminths (see Table I). Cytokine responses by infants whose CBL
demonstrated they were sensitized to the helminths in utero showed a
different pattern of responses. The mean level of IFN- produced by
this group was only 3.8% of that of infants who were not sensitized in
utero (respective means of 88 pg/ml and 2270 pg/ml; p
< 0.01). PBMC from three subjects in the helminth-sensitized group did
not produce IFN- when stimulated with PPD. With respect to IL-5,
PBMC from 9 of 12 infants sensitized to helminths at birth generated
IL-5 (p < 0.01 compared with the unsensitized
group).
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b. Infants whose CBL showed a
dominant type 2 response to helminth Ags (ratio of type 1:type 2
response, <1.0) had PBMC that produced relatively little or no IFN-
when stimulated with PPD. In contrast, PBMC from infants whose CBL
produced exclusively or relatively more IFN- or IL-2 in response to
SWAP or BmA generated greater amounts of PPD-driven IFN-.
PPD-driven cytokine responses by CBL were also evaluated. Twenty-two of
the 25 CBL preparations did not produce IFN-, IL-2, IL-4, or IL-5
when stimulated with PPD; three samples produced one or more of the
cytokines. These responses did not correlate with PPD-driven cytokine
production reevaluated 10–14 mo later.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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50% of newborns examined in
this area of Kenya, that immunologic memory to the helminths persists
during infancy, and that this prenatal sensitization is associated with
diminution of type 1 immunity induced by BCG vaccination. The
observations of filarial and schistosome-specific immunity in infants
and children are notable in several respects. First, helminth
Ag-specific T cell responses demonstrable at birth (i.e., by
measurement of CBL cytokine production) persist for at least 10–14 mo,
even in the absence of boosting afforded by infection. This finding
supports the notion that immunologic memory established by priming of
prenatal T cells with Ags that pregnant women encounter through
infection or vaccination (24, 25, 26, 27, 28) is long-lived, and that T or B cell
responses detected in cord blood preparations are not due to maternal
lymphocytes that have passed into the fetal circulation. Second, the
lack of evidence for acquisition of W. bancrofti or S.
haematobium infection in infants <14 mo old suggests that
prenatal sensitization rather than exposure to these helminths during
childhood is important in determining the initial immune response
elicited by natural infection. It is thus possible that infants who
have been sensitized to filariae before birth may develop anamnestic
responses to the same parasite Ags following infection. We speculate
that this situation is analogous to reports demonstrating that
vaccination of pregnant women with tetanus toxoid leads to enhance Ab
responses of infants following primary immunization (26). Because the
methods used to ascertain infection status (parasitologic diagnosis,
IgG4 Abs, antigenemia) may not be sensitive enough to detect
extraordinarily light infections and do not exclude the possibility
that exposure to helminths without patent infection boosts or maintains
Ag-specific T cell responses, future studies should include
measurements of the immune response to Ags expressed exclusively by
infective-stage parasites (i.e., proteinases of W. bancrofti
third-stage larvae and S. haematobium cerceriae). However,
the fact that the majority of infants whose CBL responses indicated
that they were not sensitized in utero continue to be nonresponsive
when they are 10–14 mo old argues that the latter is unlikely. Third,
comparison of the profile of cytokine responses at birth and 10–14 mo
of age indicates that mixed as well as dominant type 2 responses
persist in infants who are sensitized in utero. Longer periods of
follow-up will be necessary to determine whether the allergic type 2
responses, which characterize Ag-specific responses by many adults,
develop during early childhood. Finally, the data described here are in
contrast to conclusions of other studies, which suggest that maternal
microfilaremia leads to immunologic tolerance and predisposes to patent
infection in children (20, 21, 22, 29). The reasons for this discrepancy
may relate to the fact that none of the studies of older children
(including the present one) ascertained maternal infection status
during pregnancy, so that this variable may have differed from that
assumed. It is also possible that the intensity of transmission during
early childhood, independent of maternal infection status, has a major
effect on the propensity to develop infection and microfilaremia later
in life. Recent observations in Papua New Guinea and India indicate
that quantification of spatial heterogeneity of transmission potential
is important in such analyses (30, 31, 32).
The other major goal of the current study was to determine whether
prenatal sensitization to filariae or schistosomes influences the
immune response to BCG in newborns and children. With respect to 2- to
10-year-old children, there was a negative correlation between maternal
infection with W. bancrofti and the ability of the child’s
T cells to make IFN- in response to PPD. This diminution in
PPD-driven type 1 responses was accompanied by increased generation of
type 2 cytokines such as IL-5. The bias in T cell cytokine responses
was limited to PPD and did not extend to the relationship between
maternal filariasis and helminth Ag-specific T cell cytokine responses.
Assuming that the infection status of the mothers was similar during
the time of their pregnancy with the children under study, the data
suggest that cytokine responses engendered by in utero sensitization to
filariae affects the qualitative nature of T cell immunity to PPD for
at least 2–10 years after BCG vaccination. Moreover, because filarial
Ag-driven cytokine responses did not correlate with maternal infection,
it is unlikely that the modulating effects of filarial infection
acquired during childhood influence in vitro T cell immunity to PPD. We
have not yet examined the interaction between filarial Ag- and
PPD-driven cytokine responses in Kenyan adults, but a report of adults
living in a filariasis endemic area of Indonesia showed that PPD-driven
IFN- responses were not diminished among individuals who had strong
type 2 (IL-4) responses to BmA (33).
Several caveats should be considered when drawing conclusions from
cross-sectional studies such as those described above. Most
importantly, this type of analysis does not ascertain directly whether
an infant has been sensitized to helminth Ags in utero. In addition,
worm infections acquired after BCG vaccination and repeated exposure to
M. tuberculosis and other mycobacteriae may influence
PPD-specific immunity during childhood. Therefore, we determined the
precise relationship between prenatal sensitization to helminths and
immunity induced by BCG in a cohort of infants vaccinated on the day of
delivery and examined at birth and 10–14 mo of age. Infants with
documented prenatal sensitization to schistosome or filarial Ags had
diminished PPD-driven type 1 responses (IFN- and/or IL-2) and
correspondingly increased type 2 responses (IL-4 and/or IL-5) relative
to age-matched subjects who were not sensitized to the helminths at
birth. The striking reduction in type 1 immunity in infants who were
sensitized in utero was not attributable to infection with W.
bancrofti, S. haematobium, or geohelminths acquired
during the first year after birth. Moreover, T cell IFN- responses
were most depressed in infants whose T cell responses at birth showed a
dominant type 2 response.
The implication of these findings for the protective efficacy of BCG
vaccination against tuberculosis remains to be determined. Because type
1 T cell responses, particularly IFN-, enhance the capacity of
macrophages to kill M. tuberculosis and IFN- is involved
in controlling mycobacterial infections (34, 35, 36, 37), it will be
informative to determine whether IFN- or other cytokines in culture
supernatants of PPD-driven T cells from helminth-sensitized and
nonsensitized infants differentially effect the ability of macrophages
to eliminate mycobacteriae in vitro. In the broader context of public
health, the data are consistent with previous reports that adults with
preexisting schistosomiasis, filariasis, or onchocerciasis have
diminished reactions to BCG vaccination (38, 39). Because the incidence
of clinical tuberculosis is low and difficult to measure accurately,
especially in the tropics where this infectious disease is a major
public health problem, studies of BCG efficacy in children will
necessarily need to involve thousands of subjects. However, given the
fact that BCG vaccination is a major strategy for limiting morbidity
from tuberculosis in many areas of the world and control of worm
infections such as bancroftian filariasis with mass chemotherapy may be
feasible (40, 41), the design and implementation of such studies may be
warranted.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Christopher L. King, Division of Geographic Medicine, Case Western Reserve University School of Medicine, Room W137, 2109 Adelbert Road, Cleveland, OH, 44106-4983. E-mail address:
3 Abbreviations used in this paper: BCG, bacillus Calmette-Guérin; PPD, purified protein derivative of Mycobacterium tuberculosis; CBL, cord blood lymphocytes; BmA, soluble Ag preparation of Brugia malayi parasites; SWAP, soluble Ag preparation of adult Schistosoma haematobium parasites.
Received for publication September 24, 1998. Accepted for publication March 5, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guérin infection and a sibling with clinical tuberculosis. J. Clin. Invest. 100:2658.[Medline]
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J. Xainli, M. Baisor, W. Kastens, M. Bockarie, J. H. Adams, and C. L. King Age-Dependent Cellular Immune Responses to Plasmodium vivax Duffy Binding Protein in Humans J. Immunol., September 15, 2002; 169(6): 3200 - 3207. [Abstract] [Full Text] [PDF]
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 M. Yazdanbakhsh, P. G. Kremsner, and R. van Ree Allergy, Parasites, and the Hygiene Hypothesis Science, April 19, 2002; 296(5567): 490 - 494. [Abstract] [Full Text] [PDF]
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J. P. Akue and E. Devaney Transmission Intensity Affects Both Antigen-Specific and Nonspecific T-Cell Proliferative Responses in Loa loa Infection Infect. Immun., March 1, 2002; 70(3): 1475 - 1480. [Abstract] [Full Text] [PDF]
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 S. W. Chensue Molecular Machinations: Chemokine Signals in Host-Pathogen Interactions Clin. Microbiol. Rev., October 1, 2001; 14(4): 821 - 835. [Abstract] [Full Text] [PDF]
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 R. L. MILLER, G. L. CHEW, C. A. BELL, S. A. BIEDERMANN, M. AGGARWAL, P. L. KINNEY, W. Y. TSAI, R. M. WHYATT, F. P. PERERA, and J. G. FORD Prenatal Exposure, Maternal Sensitization, and Sensitization In Utero To Indoor Allergens in an Inner-City Cohort Am. J. Respir. Crit. Care Med., September 15, 2001; 164(6): 995 - 1001. [Abstract] [Full Text] [PDF]
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C. L. King, M. Connelly, M. P. Alpers, M. Bockarie, and J. W. Kazura Transmission Intensity Determines Lymphocyte Responsiveness and Cytokine Bias in Human Lymphatic Filariasis J. Immunol., June 15, 2001; 166(12): 7427 - 7436. [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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