|
Memórias do Instituto Oswaldo Cruz
Fundação Oswaldo Cruz, Fiocruz
ISSN: 1678-8060 EISSN: 1678-8060
Vol. 90, Num. 2, 1995, pp. 235-240
|
Memorias Instituto Oswaldo Cruz, Vol. 90(2):225-240
mar./apr. 1995
Development of a Vaccine Strategy against Human and Bovine
Schistosomiasis. Background and Update
Andre Capron^+, Gilles Riveau, Jean-Marie Grzych, Denis
Boulanger, Monique Capron, Raymond Pierce
U 167 INSERM, Institut Pasteur, 1, rue du Professeur A.
Calmette, 59019 Lille Cedex, France
Code Number:OC95047
Size of Files:
Text:32K
No associated graphics files
Schistosomiasis is a chronic and debilitating
parasitic disease that affects over 200 million people
throughout the world and causes about 500 000 deaths
annually.
Two specific characteristics of schistosome
infection are of primordial importance to the
development of a vaccine: schistosomes do not multiply
within the tissues of their definitive hosts (unlike
protozoan parasites) and a partial non-
sterilizing immunity can have a marked effect on the
incidence of pathology and on disease transmission.
Since viable eggs are the cause of disease pathology, a
reduction in worm fecundity whether or not accompanied
by a reduction in parasite burden is a sufficient goal
for vaccine induced immunity.
We originally showed that IgE antibodies played
in experimental models a pivotal role for the
development of protective immunity. These laboratory
findings have been now confirmed in human
populations.
Following the molecular cloning and expression
of a protein 28 kDa protein of Schistosoma
mansoni and its identification as a glutathion S-
transferase, immunization experiments have been
undertaken in several animal species (rats, mice,
baboons). Together with a significant reduction in
parasite burden, vaccination with Sm28 GST was recently
shown to reduce significantly parasite fecundity and egg
viability leading to a decrease in liver pathology.
Whereas IgE antibodies were shown to be correlated with
protection against infection, IgA antibodies have been
identified as one of the factors affecting egg laying
and viability. In human populations, a close association
was found between IgA antibody production to Sm28 GST
and the decrease of egg output.
The use of appropriate monoclonal antibody
probes has allowed the demonstration that the inhibition
of parasite fecundity following immunization was related
to the inhibition of enzymatic activity of the
molecule.
Epitope mapping of Sm28 GST has indicated the
prominent role of the N and C terminal domains.
Immunization with the corresponding synthetic peptides
was followed by a decrease of 70 % of parasite fecundity
and egg viability.
As a preliminary step towards phase I human trials,
vaccination experiments have been performed in cattle, a
natural model for Schistosoma bovis. Vaccination
of calves with the S. bovis GST has led to a
reduction of over 80 % of egg output and tissue egg
count.
Significant levels of protection were also
observed in goats after immunization with the
recombinant S. bovis GST. Increasing evidence of
the participation of IgA antibodies in protective
immunity has prompted us toward the development of
mucosal immunization. Preliminary results indicate that
significant levels of protection can be achieved
following oral immunization with live attenuated vectors
or liposomes.
These studies seem to represent a promising
approach towards the future development of a vaccine
strategy against one of the major human parasitic
diseases.
Key words: schistosome - vaccine - glutathione S-
transferase - IgA antibodies - parasite fecundity
Schistosomiasis, the second major parasitic disease in
the world after malaria affects at least 200 millions
people, 500 millions being exposed to the risk of
infection and is responsible for 300 to 500 000
deaths per year.
Morbidity observed in this chronic and debilitating
disease is essentially related to the remarkable female
worm fecundity, hundreds of eggs beeing laid every day
and deposited in numerous mucous membranes and tissues.
Granuloma formation around eggs, in particular in the
liver, leads to the development of severe fibrotic and
often irreversible lesions.
Although active drugs, such as Praziquantel are
available, evidence is now accumulating that, while they
can reduce the overall incidence of severe forms of the
disease, they do not prevent reinfection, have little
effect on already developped hepatosplenic
manifestations and do not significantly affect
transmission.
Unlike protozoan parasites, schistosomes, as
metazoans, do not replicate in their vertebrate hosts.
It is agreed, on the basis of experimental and
epidemiological studies, that a significant but partial
reduction, estimated around 60 percent, of the worm
burden following infection would considerably reduce
pathology and affect parasite transmission.
Recent epidemiological studies (Butterworth et al.
1985, Hagan et al. 1991) have now clearly established
that protective immunity in chronically exposed human
population is slowly built up and begins to be expressed
after the age of puberty. Children, who get infected, as
soon as they can walk, will know before they reach
adolescence a long period of susceptibility to multiple
reinfections and will represent both privileged targets
for the development of the disease and major actors of
transmission.
It therefore appears that a vaccine strategy which
could lead to the anticipated induction of effector
mechanisms reducing the level of reinfection and ideally
parasite fecundity would deeply affect the incidence of
pathological manifestations as well as the parasite
transmission potentialities.
On the basis of these general principles, our
strategy has aimed, in a first phase, at the
identification of effector and regulatory mechanisms of
the immune response to schistosomes in experimental
models and in human populations.
EFFECTOR AND REGULATORY MECHANISMS
Extensive studies performed in our laboratory have
attempted to a detailed analysis of the humoral
components and of the cellular partners involved in
in vitro killing of target schistosome larvae,
namely schistosomula. Using the rat as a model system in
parallel with cytotoxicity assays in humans and in
primates, we identified novel ADCC mechanisms involving
proinflammatory cell populations (macrophages,
eosinophils and platelets) as cellular partners and
unusual antibody isotypes such as IgE or a subclass of
IgG with anaphylactic properties, like rat IgG2a in the
particular case of eosinophils (Capron et al. 1987).
These observations of IgE dependent cell mediated
killing, which could be confirmed in human
schistosomiasis and in primates (Joseph et al. 1978,
Capron et al. 1984) remained however limited at this
stage to in vitro experiments thus raising the
problem of their in vivo relevance. Indeed the
essential question brought by these in vitro ADCC
mechanisms was related to the implication, so far
unsuspected, of anaphylactic antibody isotypes and
specially IgE in the mechanisms of protection against
metazoan parasites. The production of monoclonal
antischistosome antibodies of the rat IgE and IgG2a
isotype led to the demonstration of their high
protective capacity by passive transfer (Grzych et al.
1982, Verwaerde et al. 1987). Together with the
diminished protection passively conferred by IgE
depleted immune rat serum and abrogation of immunity
after anti m and anti e antibody treatment of neonate
rats (Bazin et al. 1980, Kigoni et al. 1986), evidence
was then accumulated that IgE, at least in rats, could
have a more beneficial function than being mainly
involved in deleterious allergic manifestations. The
relevance of these experimental findings to human
immunity to schistosomes have been very recently
confirmed by three independent immunoepidemiological
studies which have brought convergent evidence for a
protective role of IgE antibody in human infection.
Studying the rate of reinfection after treatment in a
community exposed to Schistosoma haematobium
infection in the Gambia, Hagan et al. (1991) have
demonstrated a positive correlation between the specific
IgE antibody response to worm antigens and the acquired
resistance to reinfection. Multiple regression analysis
show in particular that the risk of reinfection is ten
times more likely when IgE antibodies are absent or in
the lowest quintile. Similar findings have been made by
Dunne et al. (1992) in a community exposed to
S. mansoni infection as well as by Rihet et al.
in Brazil (1991). Without excluding the possibility of
the participation of additional mechanisms, as
mentionned later in this review, specific IgE antibody
response appears therefore as a strong correlate of
protective immunity in humans, confirming the views we
have expressed for many years regarding the unsuspected
functions of this class of antibody (Capron & Dessaint
1985, Capron et al. 1987).
Among the various mechanisms that regulate the
expression of protective immunity, one stems from
isotypic regulation itself. Evidence for the selective
production of defined antibody classes during the course
of experimental schistosome infection in rats raised
questions about the functions of other isotypes shown
not to be directly implied in killing pathways. The
decrease in immunity observed at certain periods of the
infection in rats indeed is not related to a sharp
decrease in antibody production but is concomitant with
the appearance of non anaphylactic IgG subclasses. A
representative IgG2c monoclonal antibody was shown to
inhibit the capacity of an IgG2a monoclonal antibody
both to induce eosinophil dependent killing of
schistosomula and to confer passive protection in
vivo (Grzych et al. 1984). The concept of blocking
antibody was supported by the observation that this
IgG2c monoclonal antibody can inhibit the recognition by
the protective IgG2a monoclonal antibody of the
carbohydrate moiety of a major surface glycoprotein of
schistosomula described as gp 38 (Grzych et al.
1984).
The possibility that a similar phenomenon might be
important in humans infected by S. mansoni was
first indicated by the observation that susceptibility
to reinfection after treatment of school children is
significantly correlated with the presence of high
levels of antibodies that inhibit the binding to the
major gp38 schistosomulum surface antigen of the
protective monoclonal IgG2a antibody. In addition, IgM
and IgG2 antibodies isolated from the sera of various
individuals directly block the eosinophil-dependent
killing of schistosomula mediated by IgG antibodies from
the same sera. IgM antibodies with specificity for
schistosomulum surface antigens are present in higher
levels in the young susceptible children than in the
older, resistant subjects (Khalife et al. 1986,
Butterworth et al. 1987). More recently, analysing the
isotypes of antibodies to a recombinant protective
protein (Sm28 GST) and its derived synthetic peptides,
we found a significant correlation between
susceptibility to reinfection to S. mansoni in
humans and increased production of IgG4 antibodies to
Sm28 and its defined B cell epitopes (Auriault et al.
1990). Consistently, in the framework of their studies,
Hagan et al. (1991), and Dunne et al. (1992) have also
shown a clear correlation between IgG4 antibody response
to schistosome antigens and increased susceptibility to
reinfection. More strikingly Dessein et al. (personal
communication) have shown in Brazil that the association
of low levels of IgE antibodies to S. mansoni
with high IgG4 levels resulted in an increase of over
100-fold in susceptibility to reinfection. The main
message from these studies is that in human
schistosomiasis blocking antibodies are important
components of the clinical expression of acquired
resistance at its early stages, and afterwards clinical
expression of immunity is positively correlated to the
presence of detectable IgE antibody response to
schistosomes. Such indications are obviously in the
heart ot the design of defined antischistosome
vaccines.
STRATEGY TOWARD VACCINE: BACKGROUND
On the basis of these concepts, we have developped
during the last five years extensive investigations
aiming at the identification and the molecular
characterization of potentially protective antigens
against schistosomiasis. The genes encoding several
S. mansoni proteins have now been cloned in our
laboratory, among which one of them initially named P28
(Balloul et al. 1987a) appears as a promising vaccine
candidate. After its successful cloning in collaboration
with Transgene, P28 was identified as a glutathion
S.transferase (GST) (Taylor et al. 1988) and distinct in
its molecular structure of a GST recently cloned from a
S. japonicum cDNA library (Davern et al. 1987).
Sm 28 GST has been expressed in various vectors,
including Escherichia coli, Saccharomyces
cerevisiae, and the Vaccinia virus. Vaccination
experiments performed with the highly purified native
protein indicated a level of protection close to 70 % in
rats, 50 % in the mouse and in hamsters (Balloul et al.
1987b). Immunization performed with the recombinant
protein in the presence of aluminium hydroxyde confirmed
the initial results and led to a mean protection of over
50 % in rats and 40 % in mice (Balloul et al. 1987b).
Several vaccination experiments were undertaken in
baboons and a very significant protection up to 80 %
could be obtained in some animals. However a large
degree of individual variation was noticed and the mean
protection observed was 42 % (Boulanger et al. 1991).
During these preliminary experiments, our attention
was drawn to the existence, even in the very partially
protected animals, of a significant decrease in the size
and the volume of egg granulomas in the liver, whereas a
mean reduction of 68 % of fecal egg output per female
worm and per day was noticed. Similar observations were
made in the monkey Patas patas immunized against
S. haematobium infection. A dramatic decrease of
urinary bladder lesions studied by ultrasound tomography
during a period of eight months was observed in
immunized animals compared to controls. More strikingly,
eggs collected from vaccinated monkeys showed a marked
decrease (85 %) in their hatching capacity and in the
viability and infectivity (58 %) of the miracidia
(Boulanger et al. 1991).
The use of appropriate monoclonal antibody probes
to Sm 28 GST epitopes has recently allowed to relate the
antifecundity effect observed after immunization to the
inhibition of expression of the GST enzymatic activity
of Sm 28 GST. Indeed results obtained both in
vitro and in vivo indicate that a monoclonal
antibody which inhibits the enzymatic activity confers,
with a significant protection against challenge, a
dramatic reduction in egg laying and egg viability
whereas, in contrast, another protective monoclonal
antibody which does not inhibit the enzymatic activity
confers protection in reducing worm burden but has no
effect on egg production and viability (Xu et al.
1991).
The mapping of the major epitopes of the molecule
has led to the identification of the major role played
by the N and C terminal domains in the expression of the
enzymatic activity. The construction of corresponding
synthetic peptides has allowed, after immunization, to
decrease by 70 % parasite fecundity and egg viability.
In this context the C. terminal epitope (190-211)
appears of particular interest for the optimization of
an anti parasite fecundity vaccine. In parallel, an
immunodominant epitope associated with protection
against challenge in experimental models and acquired
resistance in human population has been identified. The
immunization with an octameric construction of the
corresponding peptide (115-131) has led to significant
degree of protection in rats (Wolowczuk et al. 1991).
The study of the immunological mechanisms,
underlying the inhibition of parasite fecundity and of
egg viability has revealed the existence of an
unsuspected mechanism related to the neutralising
activity of IgA antibodies.
Recent studies performed in human populations have
revealed a close association between the production of
IgA antibodies to Sm 28 GST, their neutralising activity
of the enzymatic function of the molecule and the age
dependent decrease in the egg output observed in human
population in parallel with acquisition of immunity
(Grzych et al. 1993). Monoclonal IgA antibodies have
been raised in mice immunized with rSm28 GST and their
epitopic specificity has been determined. Passive
transfer of IgA mAb recognizing the central domain (AA
115-131) of Sm28 GST induced up to 90 % protection.
Passive transfer of IgA mAb directed against the
enzymatic site of the molecule (AA 10-43 or AA 190-211)
induced a reduction in the number of tissue eggs (45 %)
without effect on worm burden.
It therefore appears that in terms of vaccine
strategy against schistosomiasis immunization with Sm 28
GST, might achieve two complementary goals in human
population: a) A partial but significant reduction of
the worm population resulting from infection or
reinfection; b) A significant reduction of pathological
consequences by a marked decrease in parasite fecundity
and egg viability, this effect affecting directly
transmission potentialities of the disease.
It also appears, both from the study of
experimental models and of human populations that at
least two distinct immunological mechanisms, for which
the cellular components remain to be defined, may
account for these two effects. For the first, IgE
antibodies appear as a major humoral component of
acquired resistance to reinfection whereas for the
other, IgA antibodies appear as a major humoral factor
affecting parasite fecundity and its pathological
consequences. As it could be expected immunity to such
complex organisms as schistosomes is obviously
multifactorial in nature and there is no a priori reason
to think that successful immunization against this
pathogen can be achieved though the elicitation of a
single effector mechanism.
UPDATE AND PERSPECTIVES
The relevance of our observations to vaccine strategy
has been recently confirmed by vaccination experiments
performed in Sudan against cattle schistosomiasis due to
S. bovis. This model was chosen because of many
common features with human infection by S.
mansoni.
In collaboration with A. Bushara and M. Taylor
(Bushara et al. 1993), we could show that immunization
of calves with S. bovis GST results in a dramatic
reduction in egg production and tissue egg count (over
80 %) and acquisition of resistance to a lethal
infection. These results confirmed in a natural host
that the major effect of immunization with schistosome
GST is to very significantly reduce parasite fecundity.
They also open feasible perspectives for a veterinary
vaccine against schistosomiasis in a near future and
allow to consider the acceptability of Phase I trials in
human populations. In more recent experiments,
immunization of goats with the recombinant GST from
S. bovis (rSb28 GST) in presence of complete
Freund adjuvant resulted in a significant reduction in
the worm burden (48 %). Individual levels of protection
could reach up to 80 %. Unlike the controls, the
immunized animals did not experience weight loss during
the acute phase of infection. However, schistosome
fecundity was not affected by that protocol (Boulanger
et al., submitted). These results while confirming the
vaccine potential of the S. bovis recombinant GST
against veterinary schistosomiasis also clearly
illustrate the striking differences in the result of
immunization between distinct animal species.
At the same time, the molecular cloning and the
full sequence of the chromosomal gene of Sm28 GST
(McNair et al. 1993), together with the recent
crystallisation of the Sm28 GST (Trottein et al. 1992)
allows the study of its 3D molecular structure and new
approaches toward molecular design of an optimal
vaccine.
The recent cloning in our laboratory of the GST
from S. haematobium and S. bovis (Trottein
et al. 1992) has allowed a comparative analysis of the
GST sequences of the various schistosome species.
Although overall predicted aminoacid sequences
identities are above 90 % between the species, crucial
differences exist compared to defined Sm28 GST epitopes.
Notably, a single base change determining an aminoacid
substitution, leads to the non-recognition of Sh28 GST
by antibodies directed against the protective epitope
115-131 of the S. mansoni protein.
In contrast, the demonstration of the high degree
of conservation of the C terminal domain among the
various species of schistosomes (Trottein et al. 1992)
opens the possibility that a cross-specific anti-
fecundity vaccine might be achieved.
Recent experiments, in P. patas monkeys,
appear to support this hypothesis (Boulanger et al.,
submitted). Indeed, whilst heterologous immunization of
these monkeys with the recombinant Sm28 GST did reduce
the number of worms after experimental infection with a
human strain of S. haematobium urine and fecal
egg excretions were significantly reduced during one
year of observation respectively by 46 and 53 per
cent.
The demonstration of the so far unsuspected
function of IgA antibodies in schistosomiasis and their
potential role in protective immunity has paved the way
to new possibilities of immunization strategies through
mucosal routes. Several approaches have now been
deviced.
Assessment of muramy dipeptide (MDP) to enhance
specific secretory immune response has been undertaken.
Administration of this immunostimulant product by oral
route during systemic immunization with Sm28 GST
enhanced the production of specific secretory IgA. These
antibodies were shown to be effective in inhibiting
enzymatic activity of the recombinant protein. In these
experiments, anti-Sm28 GST secretory IgA production was
correlated with the protective activity (60 %) against
challenge infection in the mouse model.
Several models of synthetic vectors including
liposomes have been investigated for their capacity to
optimize mucosal response against the recombinant Sm28
GST. Preliminary experiments using oral administration
indicated that liposome associated Sm28 GST was able to
elicit a strong specific mucosal IgA response associated
with a significant reduction in the worm burden (53 %)
in the mouse.
One of the most appealing possibilities for the
development of the new mucosal vaccines appear to rely
in modified or attenuated live vectors which can be used
to express genes encoding the candidate vaccine protein.
A first model has been developed in collaboration with
the laboratory of C. Hormaeche at Cambridge University
(U.K.).
Recombinant Aro-A Salmonella typhimurium
expressing the Sm28 GST as a fusion protein with the C
fragment of tetanous toxin (Tet-C) has been used to
immunize Balb/C mice by both i.v. and oral route. Both
procedures gave an equally strong humoral response. A
marked secretory IgA response to Sm28 GST was detected
after oral administration and a significant reduction in
the worm burden (48 %) was observed.
Taken altogether, these preliminary results
indicate at least the feasibility of a novel and
attractive approach towards oral immunization against a
systemic parasitic disease.
From experimental models to human populations, from
the bench to endemic areas, studies performed during the
last 15 years have revealed at the level of effector
mechanisms of immunity, immunoregulation and
pathogenesis, novel modalities, the interest of which
extend far beyond the field of schistosomiasis (Capron &
Dessaint 1992 , Capron 1992). These studies seem
presently to represent a promising approach towards the
possible immunological control of one of the major human
parasitic disease through the identification not only of
potentially protective antigens but also of the
components of the immune response which vaccination
should aim at inducing.
References
Auriault C, Gras-Masse H, Pierce RJ, Butterworth AE,
Wolowczuk I, Capron M, Ouma JH, Balloul JM, Khalife J,
Neyrinck JL, Tartar A, Koech D, Capron A 1990. Antibody
response of Schistosoma mansoni infected human
subjects to the recombinant P28 glutathione S-
transferase and to synthetic peptides. J Clin
Microbiol 28: 1918-1924.
Balloul JM, Grzych JM, Pierce RJ, Capron A 1987a. A
purified 28,000 dalton protein from Schistosoma
mansoni worms protects rats and mice against
experimental schistosomiasis. J Immunol 138:
3448-3453.
Balloul JM, Sondermeyer P, Dreyer D, Capron M, Grzych
JM, Pierce RJ, Carvallo D, Lecocq JP, Capron A 1987b.
Molecular cloning of a protective antigen against
schistosomiasis. Nature 326: 149-153.
Bazin H, Capron A, Capron M, Joseph M, Dessaint JP,
Pauwels R 1980. Effect of neonatal injection of anti-m
antibodies on immunity to schistosomes (S.
mansoni) in the rat. J Immunol 124: 2373-
2377.
Boulanger D, Reid GD, Sturrock RF, Wolowczuk I, Balloul
JM, Grezel D, Pierce RJ, Otieno MF, Guerret S, Grimaud
JA, Butterworth AE, Capron A 1991. Dual expression of
protection against experimental schistosomiasis mansoni
in mice and baboons immunized with the recombinant Sm28
GST. Parasite Immunol 13: 473-490.
Bushara HO, Bashir MEN, Malik KHE, Mukhtar MM, Trottein
F, Capron A, Taylor MG 1993. Suppression of S.
bovis egg production in cattle by vaccination with
either glutathione S-transferase or keyhole limpet
haemocyanin. Parasite Immunol 15: 383-390.
Butterworth AE, Bensted-Smith R, Capron A, Dalton PR,
Dunne DW, Grzych JM, Kariuki HC Khalife J, Koech D,
Mugambi M, Ouma JH, Siongok JK, Sturrock RF 1987.
Immunity in human schistosomiasis mansoni: prevention by
blocking antibodies of the expression of immunity in
young children. Parasitology 94: 281-300
Butterworth AE, Capron M, Cordingley JS, Dalton PR,
Dunne DW, Kariuki H, Kimani G, Koech D, Mugambi M., Ouma
JH, Prentice MA, Richardson BA, Arap TK, Sturrock RF,
Taylor DW 1985. Immunity after treatment of human
schistosomiasis mansoni. II. Identification of
resistance individuals, and analysis of their immune
responses. Trans R Soc Med Trop 79: 393-408
Capron A 1992. Immunity to schistosomes. Current
Opinion in Immunology 4: 419- 424.
Capron A, Dessaint JP 1985. Effector and regulatory
mechanisms in immunity to schistosomes: a heuristic
view. Ann Rev Immunol 3: 455-476
Capron A, Dessaint JP 1992. Immunologic aspects of
schistosomiasis. Ann Rev Med 43: 209-218.
Capron A, Dessaint JP, Capron M, Ouma JH, Butterworth AE
1987. Immunity to Schistosomes: progress toward vaccine.
Science 238: 1065-1072.
Capron M, Spiegelberg HL, Prin L, Bennich H, Butterworth
AE, Pierce RJ, Ouaissi MA, Capron A 1984. Role of IgE
receptors in effector function of human eosinophils.
J Immunol 232: 462-468.
Davern KM, Tiu W, Morahan G, Wright MD, Garcia EG,
Mitchell GF 1987. Responses in mice to Sj26, glutathione
S-transferase of Schistosoma japonica worms.
Immunol Cell Biol 65: 473-482.
Dunne D, Butterworth AE, Fulford AJC, Kariuki HC,
Langley JG, Ouma JH, Capron A, Pierce RJ,
Sturrock RF 1992. Immunity after treatment of hu-
man schistosomiasis mansoni: association between
IgE antibodies to adult worm antigens and
resistance to reinfection. Eur J Immunol
22: 1483-1494.
Grzych JM, Capron M, Bazin H, Capron A 1982. In
vitro and in vivo effector function of rat
IgG2a monoclonal anti-S. mansoni antibodies. J
Immunol 129: 2739-2743.
Grzych JM, Capron M, Dissous C, Capron A 1984. Blocking
activity of rat monoclonal antibodies in experimental
schistosomiasis. J Immunol 133: 998-1004.
Grzych JM, Grezel D, Xu CB, Neyrinck JL, Capron
M, Ouma JH, Butterworth AE, Capron A 1993. IgA
antibodies to a protective antigen in human
schistosomiasis mansoni. J Immunol 150:
527-535.
Hagan P, Blumenthal UJ, Dunne D, Simpson AJG, Wilkins HA
1991. Human IgE, IgG4 and resistance to reinfection with
Schistosoma haematobium. Nature 349: 243-
245
Joseph M, Capron A, Butterworth AE, Sturrock RF, Houba V
1978. Cytotoxicity of human and baboon mononuclear
phagocytes against schistosomula in vitro:
induction by immune complexes containing IgE and
Schistosoma mansoni antigens. Clin Exp Immunol
33: 48-56.
Khalife J, Capron M, Capron A, Grzych JM, Butterworth
AE, Dunne DW, Ouma JH 1986. Immunity in human
schistosomiasis mansoni. Regulation of protective immune
mechanisms by IgM blocking antibodies. J Exp Med
164: 1626-1640.
Kigoni EP, Elsas PPX, Lenzi HL, Dessein AJ 1986. IgE
antibody and resistance to infection. II. Effect of IgE
suppression on the early and late skin reaction and
resistance of rats to Schistosoma mansoni
infection. Eur J Immunol 16: 589-595.
McNair A, Dissous C, Duvaux-Miret O, Capron A 1993.
Cloning and characterization of the gene encoding the 28
kDa glutathione S-transferase of Schistosoma
mansoni. Gene 124: 245-249.
Rihet P, Demeure CE, Bourgeois A, Prata A, Dessein AJ
1991. Evidence for an association between human
resistance to Schistosoma mansoni and high anti-
larval IgE levels. Eur J Immunol 21: 2679-
2686.
Taylor JB, Vidal A, Torpier G, Meyer DJ, Roitsch C,
Balloul JM, Southan C, Sondermeyer P, Pemble S, Lecocq
JP, Capron A, Ketterer B 1988. The glutathione
transferase activity and tissue distribution of a cloned
Mr28K protective antigen of Schistosoma mansoni. Embo
J 7: 465-472.
Trottein F, Godin C, Pierce RJ, Sellin B, Taylor M,
Gorillot I, Sampaio Silva M, Lecocq JP, Capron A 1992.
Inter-species variation of schistosome 28 kDa
glutathione S-transferases. Mol Biochem Parasitol
54: 63-72.
Verwaerde C, Joseph M, Capron M, Pierce RJ, Damonneville
M, Velge F, Auriault C, Capron A 1987. Functional
properties of a rat monoclonal IgE antibody specific for
Schistosoma mansoni protect rats against
infection. J Immunol 138: 4441-4446.
Wolowczuk I, Auriault C, Bossus M, Boulanger D, Gras-
Masse H, Mazingue C, Pierce RJ, Grezel D, Reid GD,
Tartar A, Capron A 1991. A multiple peptide construction
of the S. mansoni Sm28 GST antigen protects
Fischer rats against infection. J. Immunol. 146:
1987-1995
Xu CB, Verwaerde C, Grzych JM, Fontaine J, Capron A
1991. A monoclonal antibody blocking the Schistosoma
mansoni 28 kDa glutathione S-transferase activity
reduces female worm fecundity and egg viability. Eur
J Immunol 21: 1801-1807.
Copyright 1995 Fundacao Oswaldo Cruz (Fiocruz)
|