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-Dependent Effector Mechanisms
*
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and
Biomedical Research Institute, Rockville, MD 20852
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-dependent mechanism, while humoral
immunity has been shown to contribute to challenge rejection in
multiply (three times) immunized mice. To better understand the
respective contribution of the B lymphocyte- and IFN--dependent
effector arms in host resistance, we compared vaccine-induced immunity
in B cell-deficient (µMT) and IFN- knockout (GKO) animals.
Unexpectedly, after a single vaccination, B cell knockout (KO) mice
displayed reduced protection against challenge infection, although they
developed a normal IFN--dominated cytokine response. This defect in
resistance was equivalent to that displayed by GKO animals. Moreover,
whereas two additional vaccinations significantly increased the level
of immunity in wild-type mice, the protection in B cell KO animals
remained unchanged. In contrast, multiple vaccination resulted in
increased but, nevertheless, defective resistance in GKO mice. Since
FcR KO mice, which lack functional FcRI, FcRIII, and Fc
RI,
show no defects in vaccine-induced resistance after immunization either
one or three times, the B cell-dependent mechanism of protection
involved does not appear to require FcR signaling. Together, these
findings indicate that effective vaccination against schistosomes
depends on the simultaneous induction of both humoral and cell-mediated
immunity, a conclusion that may explain the limited success of most
subunit vaccine protocols designed to preferentially induce either B
cell- or IFN--dependent protective mechanisms. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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An important animal model used in the study of schistosome immunity
involves the induction of resistance by attenuated vaccination with
irradiated infective forms (cercariae) (3, 4). After a single
immunization with this vaccine, mice are able to eliminate 60–80% of
the worms that ordinarily develop from challenge infection. The
protection induced is thought to primarily involve a cell-mediated
immune mechanism, since it is dependent on CD4+ T
lymphocytes (5, 6) and IFN- (7, 8, 9) and correlates with macrophage
activation (10, 11) and nitric oxide production (12, 13). Furthermore,
vaccine-induced resistance in this model has been shown to be
independent of IL-4 (7, 14), eosinophils (7), mast cells (15), IgE (7, 15, 16), and complement (17). Although anti-µ treatment before
vaccination completely abolishes protection (17), the
interpretation of this finding is unclear, since the same procedure
also results in defects in T cell responsiveness (18, 19). Furthermore,
a role for Ab in parasite rejection after a single vaccination has been
largely disregarded, since resistance is not transferred to naive
recipients with sera from animals immunized by this protocol (20, 21).
While multiple immunization with irradiated cercariae causes a small increase in protection (22, 23), the mechanism involved appears to be qualitatively different from that displayed by animals vaccinated once. Thus, in multiply vaccinated mice, depletion of CD4+ cells after vaccination fails to diminish protection (5), and IgG Ab from these animals successfully transfers resistance to naive donors (21). Moreover, while mice vaccinated once display a dominant Th1 cytokine expression profile, multiple vaccination results in a shift to a response pattern dominated by Th2 cytokines (23).
In the present study, we have reexamined the role of humoral immunity
in the protection induced by irradiated cercariae by assessing the
resistance of µMT mice (24) following single vs multiple vaccination.
These animals, generated by deletion of the transmembrane exon of the
Ig µ-chain, fail to develop mature B cells and detectable Ab but
appear to generate normal T cell responses (25, 26, 27, 28). They therefore
allow a definitive and quantitative evaluation of the contribution of B
cell-dependent humoral mechanisms to host resistance. Interestingly and
unexpectedly, based on previous evidence implicating primarily
cell-mediated immunity, we observed a major effect of B cell deficiency
on the resistance to challenge developed following single immunization
with irradiated cercariae. The mechanism involved does not require FcR
signaling and functions together with the IFN--dependent pathway of
resistance previously described (7, 8, 9). Together, our findings indicate
that optimal immunization against Schistosoma mansoni
requires the simultaneous induction of both humoral and
cell-mediated effector arms. This conclusion may explain the poor
efficacy of most experimental vaccination protocols designed to
preferentially stimulate either B cell- or IFN--dependent protective
mechanisms.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B cell-deficient µMT mice originally derived on a 129 x
C57BL/6 background (24) were backcrossed to C57BL/6 for seven
generations and then intercrossed to generate homozygous B cell
knockout (KO)2 animals. The
mice were both bred and maintained at the animal facility of the
National Institute of Allergy and Infectious Diseases, which is
accredited by the American Association for the Accreditation of
Laboratory Animal Care. To rule out possible effects of 129 background
genes, most experiments were repeated using µMT mice backcrossed to
the C57BL/10 background for 12 generations. The latter B cell-deficient
and C57BL/10 control mice were shipped from a specific pathogen-free
animal facility at Taconic Farms (Germantown, NY). The µMT mice on
the C57BL/6 and C57BL/10 backgrounds gave indistinguishable results in
all the assays performed. Mice genetically deleted for the FcR
-subunit were derived as previously described (29) and backcrossed
for 12 generations to C57BL/6J. Breeding stock of mice with a targeted
disruption of the IFN- gene backcrossed for seven generations on the
C57BL/6 background (30, 31) were maintained at Taconic Farms. Age
(8–12 wk)- and sex-matched wild-type (wt) C57BL/6 mice purchased from
Charles River Laboratories (Wilmington, MA), The Jackson Laboratory
(Bar Harbor, ME), or Taconic Farms were used as B cell-, FcR-, and
IFN--sufficient controls, respectively.
Cercariae of the Puerto Rican (National Medical Research Institute, Rockville, MD) strain of S. mansoni were obtained from infected Biomphalaria glabrata snails (Biomedical Research Institute, Rockville, MD). Soluble worm Ag preparation (SWAP) was prepared from homogenized adult parasites as previously described (32).
Immunizations and challenge infections
S. mansoni cercariae were attenuated by
-irradiation from a 137Cs source (50 krad). Mice were
vaccinated by immersing their tails for 30 min in water containing 500
irradiated cercaria. In animals receiving multiple immunizations,
exposures to irradiated cercariae were repeated at 4- to 5-wk
intervals. Vaccinated and age- and sex-matched controls were challenged
with 120 viable cercariae percutaneously on the abdominal skin (33) at
4–5 wk after the last vaccination, a time at which they are known to
display high levels of immunity. In some experiments, vaccinated mice
were treated i.p. 2 days before and on days 3, 7, 10, 14, 21, 28, and
35 after the challenge infection with 1 mg (in 0.5 ml of PBS) of either
a neutralizing mAb against IFN- (XMG1, 34 or a control mAb
(GL113 directed against Escherichia coli ß-galactosidase).
The degree of protective immunity was measured by adult worm recovery
after portal perfusion at 6 wk postchallenge (33). The level of
resistance for vaccinated mice was calculated from the worm burdens
using the following formula: percentage resistance = (control worm
recovery - vaccinated worm recovery)/control worm recovery
x 100. The statistical significance of differences in worm burden
between animal groups was evaluated using Student’s two-tailed
t test.
Pulmonary histopathology
Both lungs were inflated by injection with Bouin-Hollande fixative and processed routinely (35). The size and cell composition of the inflammatory foci were determined in histological sections stained by Wright’s Giemsa stain. The diameters of lesions were measured with an ocular micrometer, and the volume of each focus was calculated assuming a spherical shape.
Measurement of circulating schistosome-specific Ab and IgE levels
Mice were bled by orbital puncture on day 28 after the final vaccination, and sera were prepared from individual mice. Schistosome-specific Ab were determined in a specific ELISA as previously described (35). Briefly, Immunolon 4 (Dynatech Laboratories, Chantilly, VA) microtiter plates were coated overnight at 4°C with SWAP (1 µg/well) in 0.2 M sodium carbonate-bicarbonate buffer, pH 9.4. Plates were blocked with 200 µl/well of 5% nonfat dried milk/0.05% Tween 20 in PBS for 90 min at 37°C. Pools of sera obtained by mixing equal volumes of serum from each animal (n = 10) within the group were tested in threefold serial dilutions starting with a 1/30 dilution in 1% BSA/PBS/Tween. Plates were incubated at 4°C overnight, washed, and then incubated with peroxidase-conjugated rabbit anti-mouse IgM or IgG (Zymed Laboratories, San Francisco, CA) according to the manufacturer’s instructions. Wells were washed, and 100 µl/well of (2.2'-azino-di[3-ethyl-benzthiazoline sulfonate] (ABTS):H2O2 one-step substrate (Kirkegaard & Perry Laboratories, Gaithersburg, MD) was added. After development at room temperature, absorbance was read at 415 nm using an ELISA Reader (Molecular Devices, Menlo Park, CA).
Total serum IgE was measured by a specific ELISA (PharMingen, San Diego, CA) and was quantified by reference to a known IgE standard (PharMingen).
Cell proliferation and cytokine assays
Single-cell suspensions of spleens, in which RBC were lysed by osmotic treatment, and lung-associated (mediastinal) lymph node (LN) cell suspensions were prepared as a pool from four or five animals per group. All in vitro assays involved culturing of cells in RPMI 1640 supplemented with 10% FCS, 2 mM glutamine, 100 U/ml penicillin, 100 µg/ml streptomycin, 25 mM HEPES, 1 mM sodium pyruvate, nonessential amino acids, and 50 µM 2-ME at 37°C in 5% CO2.
Proliferative responses to SWAP were assayed at day 22 after vaccination by exposing pooled splenocyte suspensions (2.5 x 106/ml) from B cell KO and wt animals (n = 5) to graded concentrations of the Ag in 200 µl in 96-well flat-bottom microtiter plates. After 48 h of incubation, [3H]TdR (0.5 µCi/well, New England Nuclear, Boston, MA; sp. act., 2 Ci/mmol) was added, and incorporation of the isotope was measured 18 h later. The stimulation index was calculated as the ratio between the [3H]TdR incorporated in the presence and absence of SWAP.
To measure cytokine secretion, mediastinal LN cells (3 x
106/ml) were cultured in 24-well plates in 1-ml volumes and
exposed to medium alone, Con A (5 µg/ml), or SWAP (50 µg/ml) for
72 h. IFN-, IL-5, and IL-10 were measured in culture
supernatants by specific sandwich ELISA (36, 37). Cytokine levels were
calculated by reference to standard curves prepared with known amounts
of recombinant cytokine. IL-4 was assayed in culture supernatants using
the IL-4-dependent cell line CT.4S as previously described (38, 39).
Proliferation of CT.4S cells was quantified by measuring
[3H]TdR incorporation, and the amount of cytokine in
supernatant was determined by comparison with proliferation induced by
known amounts of rIL-4 (Genzyme, Cambridge, MA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To formally address the role of B cells in the protection induced
by single vaccination with attenuated larvae, we analyzed the
resistance to percutaneous challenge infection of B cell-deficient vs
genetically matched wt control animals immunized with 500 irradiated
cercaria of S. mansoni. As shown previously (40), the worm
recoveries were quantitatively indistinguishable from nonvaccinated
control wt and KO mice (p > 0.9), confirming
that neither B cells nor Ab influence the development of S.
mansoni during primary infection (Fig. 1
). In contrast, vaccine-induced
protection was substantially impaired in the absence of B cells.
Although B cell-deficient mice developed statistically significant
levels of protection, in all five experiments performed, the worm
recoveries from vaccinated µMT mice were significantly increased in
comparison with those from simultaneously vaccinated B cell-sufficient
animals (Fig. 1). The level of protection induced in B cell KO mice was
on average only 60% of that observed in wt animals.
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To determine whether the reduced protection in B cell KO mice is
associated with aberrant cellular immunity, we compared T
cell-associated responses in vaccinated wt and KO mice. Histological
examination of the lungs from the two groups of mice failed to reveal
any significant difference in either the size of inflammatory foci or
their eosinophil composition (Fig. 2). In
addition, splenocytes isolated at day 22 postvaccination from KO mice
mounted comparable if not slightly increased proliferative responses to
a SWAP over a wide dose range (Fig. 3).
Finally, lung-associated draining LN from both groups of animals were
found to display comparable lymphokine secretion profiles in response
to SWAP (Fig. 4). In particular, IFN-,
a cytokine known to play an important role in the effector mechanism of
vaccine-induced resistance (7, 8, 9), was expressed at similar levels by
cells from wt and B cell-deficient mice. Furthermore, in the case of
the Th2 cytokines previously shown to down-regulate macrophage
anti-parasitic activity (41), some increase in IL-4, but not in
IL-10, was detected in the cultures from vaccinated KO animals. In
addition, the number of activated CD4+CD44+
cells (which represent the major fraction of Ag-reactive T lymphocytes
in LN (42)) was determined to be comparable in the wt and KO cell
preparations (data not shown). In the case of Con A responses, B
cell-deficient mice displayed increased production of all four
cytokines assayed, perhaps reflecting the increased overall percentage
of T cells in the cultures from these animals.
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during challenge infection abolishes the
residual protection in µMT mice vaccinated once
Although vaccinated µMT mice show decreased resistance to
challenge, they nevertheless are significantly protected. To determine
whether this residual protection is due to a cell-mediated mechanism,
vaccinated B cell KO mice were injected with neutralizing
anti-IFN- mAb during challenge infection. In agreement with
previously published data from our laboratory (7), this treatment was
found to cause only a partial (35%) reduction of protective immunity
in wt mice (Fig. 5, left).
However, parallel administration of anti-IFN- mAb to B
cell-deficient mice reduced the residual protection in these animals to
insignificant levels based on comparison of worm burdens with those
from nonvaccinated controls (Fig. 5). These results argue that the
IFN--induced response in vaccinated B cell-deficient mice is
functional and is likely to explain the partial protective immunity
displayed by these animals.
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Multiple vaccination with irradiated cercariae is known to both
increase the level of protection and result in the emergence of Ab that
can transfer resistance to naive mice (21, 22, 23). To formally evaluate
the contribution of this humoral component, we assessed vaccine-induced
resistance in wt and B cell KO animals immunized one time vs three
times. As expected, multiple vaccination resulted in a further decrease
in challenge worm recovery in B cell-sufficient control mice in
comparison with animals vaccinated once (mean recoveries, 57.1 ±
11.5, 17.2 ± 7.2, and 8.8 ± 4.0 for nonvaccinated,
once-vaccinated, and three times-vaccinated group; Fig. 6). In contrast, the worm burdens in
challenged B cell-deficient animals vaccinated once and three times
were indistinguishable and were still significantly higher than in
once-immunized wt mice (Fig. 6). These results confirm the critical
role of B cells in the protective immunity developed by multiply
vaccinated animals and further demonstrate that the non-B
cell-dependent component that operates in animals immunized once is not
enhanced by repeated vaccine exposure.
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The above results on vaccination against S. mansoni in
µMT mice pointed to an important role for B cell-dependent responses
in protective immunity. To determine whether FcR-dependent Ab mediated
interactions are required for the effector mechanism of resistance, we
analyzed levels of protection displayed by once- or three
times-vaccinated FcR -chain KO animals. These mice possess a normal
B cell compartment, but due to the deletion of the gene encoding the
common FcR -chain, they fail to express FcRI, FcRIII, and
FcRI, the major cell surface receptors involved in positive
Ab/Fc-mediated triggering. As shown in Fig. 7, these animals developed resistance to
challenge that was indistinguishable from simultaneously vaccinated wt
mice regardless of the number of immunizations (one or three) received.
This observation, that animals that fail to express FcRI, FcRIII,
and FcRI display normal protective immunity, strongly argues against
involvement of FcR signaling by Ab belonging to the Ig isotypes (IgG1,
IgG2a, IgG2b, and IgE but not IgG3) known to be induced with the
attenuated vaccine (35).
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-deficient animals immunized three
times despite the induction of unimpaired Ab responses
Although IFN--dependent mechanisms clearly play a role in the
protective immunity induced by a single vaccination, their possible
contribution to the effector mechanisms of resistance has never been
formally assessed in mice immunized three times in which a
strong B cell-dependent component clearly exists, as demonstrated by
the present as well as previous studies. This analysis was performed by
measuring vaccine-induced resistance in animals with a targeted
disruption of the IFN- gene (GKO mice). As expected, GKO animals
immunized once displayed significantly reduced protection with respect
to simultaneously vaccinated wt controls (Fig. 8). The reduction observed (30%) due to
IFN- deficiency was similar to that (40%) resulting from B cell
deficiency (Fig. 1
).
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-dependent functions in the
protection induced by this protocol. Nevertheless, the GKO mice
vaccinated three times clearly displayed more resistance than did those
immunized once (63% vs 46%, respectively). This observation is in
direct contrast with the results obtained in B cell-deficient mice, in
which three-time vaccination failed to augment protection. To determine
whether the reduced vaccine-induced resistance of GKO mice may itself
be due to an effect on B cell function, SWAP-specific Ab titers were
compared in KO and wt animals 4 wk after single immunization or the
last of three multiple immunizations (Fig. 9). Although Ab levels were clearly
augmented in mice vaccinated three times vs those vaccinated once, no
major differences in either IgM or IgG titers were observed between GKO
and wt animals.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The possible contribution of B cells to protective immunity induced by
single vaccination with attenuated cercariae has previously been
ignored because of the low schistosome-specific Ab titers stimulated by
this protocol as well as the failure of sera from vaccinated mice to
transfer resistance to naive recipients (20). Instead, a role for
IFN--dependent cell-mediated immunity was established based on both
in vitro killing experiments and cytokine depletion or cytokine
receptor KO studies (7, 8, 9, 12). Nevertheless, treatment with
anti-µ antisera was shown to effectively deplete vaccine-induced
protection (17), although the interpretation of the latter finding was
complicated by the observation of altered T-cell responsiveness in the
B cell-depleted animals (18, 19). The availability of B cell KO animals
has enabled us to formally re-evaluate this issue in a more defined
experimental system.
Unexpectedly, B cell-deficient animals vaccinated once displayed
significantly reduced protection equivalent to 
60%, the level
displayed by vaccinated B cell-sufficient controls. Similarly,
vaccinated IFN--deficient mice showed a comparable if not smaller
defect in protective immunity, and anti-IFN- treatment of B cell
KO animals immunized once resulted in a near-complete loss of
vaccine-induced resistance. Together these observations strongly
suggest that the protection induced by this protocol requires a
separate humoral and cell-mediated component. The results further
suggest that the depletion in resistance induced by anti-µ
treatment may indeed have been partially due to the loss in a B
cell-mediated effector function.
The nature of the B cell-dependent protective mechanism operating in
mice vaccinated once is at present unclear, although it is likely to
involve humoral Ab. The alternative hypothesis, that the requirement
for B cells reflects their function in Ag presentation, seems unlikely
given the undiminished proliferative and nondefective cytokine
responses displayed by B cell KO animals (Figs. 3 and 4). Although the
specific Ab titers present in wt mice after single immunization are
low, they are known to be boosted by the challenge infection (43) and
could reach biologically significant levels during the period of
schistosomulum attrition in the lungs. One approach for testing this
interpretation would be to transfer sera from wt mice, vaccinated once
and challenged, into vaccinated B cell KO animals to assess increased
protective immunity. Although we are currently attempting the latter
experiment, a negative result would be uninterpretable, since full
reconstitution of Ig levels in B cell KO animals may be difficult to
achieve with the volumes of sera that can be safely injected into mice.
While the isotype and Ag specificity of the Ab involved in the
effector mechanism of immunity in mice vaccinated once are at present
undefined, it is nevertheless possible to make several statements about
their functional requirements. First, based on previous studies using
IL-4- as well as IgE-deficient animals (14, 16), it is clear that Ab of
the IgE isotype are not necessary for immunity in mice, as has been
proposed for the host resistance acquired by humans (44, 45). Secondly,
since complement-deficient (C5-deficient or cobra venom factor-treated)
animals are also not defective in vaccine-induced resistance (17), the
activity of the relevant Ab is unlikely to be complement dependent.
Finally, based on our observation of normal protection in vaccinated
FcR KO mice, signaling by FcRI, FcRIII, and FcRI is not
required for Ab-dependent function. Nevertheless, while Ab-mediated
cellular triggering, such as that occurring in Ab-dependent
cell-mediated cytotoxicity (ADCC) reactions (27, 46), may not be
involved, FcR could still play a "passive" role by mediating the
adherence of the effector cells to Ab opsonized larvae. Such an effect
occurs in vitro in the enhancement by Ab of schistosomulum killing by
activated macrophages (47).
As would be predicted from previous passive transfer studies, multiply
immunized B cell-deficient mice were defective in their resistance to
challenge infection. Nevertheless, these animals still displayed
significant levels of protection equivalent to that shown by B cell KO
mice vaccinated once. The latter observation suggests that the
enhancement of resistance induced by multiple immunization is due to
boosting of the B cell-dependent effector mechanism already operating
in mice vaccinated once. Moreover, this finding argues that the
cell-mediated mechanism induced by single vaccination is still
functional after further immunization but is not enhanced in magnitude.
The observation of decreased protection in IFN--deficient vs wt
animals, both vaccinated three times, further supports a role for
cell-mediated immunity in host resistance in this model.
An important question raised by the above findings is whether the
B cell- and IFN--dependent effector components are mutually
dependent in their function. At present the data fail to support such a
scenario. Thus, in mice vaccinated either one or three times, the
effect of IFN- or B cell deficiency is always partial (<50%).
Moreover, anti-IFN- treatment was shown to abrogate the residual
resistance displayed by B cell KO mice. Together, these results argue
that the unique efficacy of the irradiated schistosome vaccine may stem
in part from its ability to simultaneously induce both B
lymphocyte-dependent and cell-mediated effector mechanisms. In this
regard, it is interesting to note that most nonliving vaccine protocols
using defined Ag usually result in significantly lower protection than
that observed with attenuated cercariae, perhaps because they result in
the induction of one but not both immune arms.
If indeed, optimal protection against schistosome infection requires
the induction of both B lymphocyte- and IFN--dependent effector
components, what strategies can be employed to promote these responses
during vaccination? One approach, which we have recently documented, is
the use of rIL-12 as an immunostimulant. This cytokine was shown to
augment immunity against S. mansoni in both the once and
three-time attenuated vaccine models, a result that correlated with
enhanced IFN- production as well as increased levels of protective
parasite-specific Ab (35, 48). Similar combined effects of IL-12 on
humoral and cell-mediated immune responses have been described in
studies using defined protein Ag (49, 50). The work reported here
suggests that immunomodulatory strategies of this type may be necessary
for achieving consistent, high levels of protection against schistosome
parasites.
Note added in proof. Since completion of this study, we performed an additional experiment in which either normal mouse sera or sera from once-vaccinated and challenged mice (35) were transferred to vaccinated B cell-deficient animals (0.5 ml sera/mouse i.v.) on days 3 and 6 after percutaneous challenge infection. Vaccinated µMT mice and those which in addition received normal mouse sera showed indistinguishable challenge recoveries (34.5 ± 3.4 (n = 8) vs 34.5 ± 11.3 (n = 10) adult worms, respectively) and displayed 30% protection when compared with the recovery from nonvaccinated control animals (49.5 ± 10.1 (n = 15)). In contrast, worm burdens were markedly reduced in the group of vaccinated µMT animals that received immune sera (11.2 ± 3.5 (n = 10)), yielding a level of protection (77%) comparable to that achieved by a single vaccination in wt mice. Importantly, the same immune sera gave only marginal protection (18%) in nonvaccinated wt recipients as reported previously (35). These results confirm that the defect in host resistance in vaccinated B cell-KO mice results from the absence of humoral Ab and support the concept that vaccine immunity involves both B cell and non-B cell-dependent mechanisms.
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Acknowledgments |
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KO mice, as well as
helpful discussion, and Drs. K. Hoffmann, S.
Gurunathan, and R. Clynes for critically reviewing the manuscript. |
Footnotes |
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2 Abbreviations used in this paper: KO, knockout; wt, wild-type; SWAP, soluble adult worm antigen preparation; LN, lymph node; GKO, IFN- knockout.
Received for publication June 2, 1998. Accepted for publication September 2, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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modifies pulmonary inflammatory responses and abrogates immunity to Schistosoma mansoni in mice vaccinated with attenuated cercariae. J. Immunol. 149:3654.[Abstract]
receptor gene exposed to the irradiated Schistosoma mansoni vaccine. Immunology 87:275.[Medline]
chain deletion results in pleiotropic effector cell defects. Cell 76:519.[Medline]
, mice develop unimpaired IL-12 responses to Toxoplasma gondii while failing to control acute infection. J. Immunol. 157:4045.[Abstract]
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M. Street, P. S. Coulson, C. Sadler, L. J. Warnock, D. McLaughlin, H. Bluethmann, and R. A. Wilson TNF Is Essential for the Cell-Mediated Protective Immunity Induced by the Radiation-Attenuated Schistosome Vaccine J. Immunol., October 15, 1999; 163(8): 4489 - 4494. [Abstract] [Full Text] [PDF]
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K. F. Hoffmann, S. L. James, A. W. Cheever, and T. A. Wynn Studies with Double Cytokine-Deficient Mice Reveal That Highly Polarized Th1- and Th2-Type Cytokine and Antibody Responses Contribute Equally to Vaccine-Induced Immunity to Schistosoma mansoni J. Immunol., July 15, 1999; 163(2): 927 - 938. [Abstract] [Full Text] [PDF]
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D. Jankovic, M. C. Kullberg, N. Noben-Trauth, P. Caspar, J. M. Ward, A. W. Cheever, W. E. Paul, and A. Sher Schistosome-Infected IL-4 Receptor Knockout (KO) Mice, in Contrast to IL-4 KO Mice, Fail to Develop Granulomatous Pathology While Maintaining the Same Lymphokine Expression Profile J. Immunol., July 1, 1999; 163(1): 337 - 342. [Abstract] [Full Text] [PDF]
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