Current Drug Targets-Immune, Endocrine & Metabolic Disorders, Volume 2, No. 3, 2002
Contents
Immune Response to Parasitic Infections
Guest Editors: Jacques Mauël / Olga Brandonisio
Immune Response to Parasitic Infections - An
Introduction Pp.193-199
O. Brandonisio and R. Spinelli
Vaccination Against Leishmania Infections Pp.201-226
J. Mauël
Prospects for A Human Toxoplasma Vaccine Pp.227-234
D.T. Bout, M.-N. Mevelec, F. Velge-Roussel, I. Dimier-Poisson and M. Lebrun
Molecular and Cellular Tools in Human Cystic
Echinococcosis Pp.235-245
A. Siracusano, E. Ortona and R. Riganò
Immunotherapy of Trypanosoma Cruzi Infections Pp.247-254
N. Chamond, N. Coatnoan and P. Minoprio
Malaria Vaccines: From the Laboratory to the
Field Pp.255-267
B. Genton and G. Corradin
The Immune Response to the Parasitic Nematode
Trichinella and the Ways to Escape it. From Experimental Studies to
Implications for Human Infection Pp.269-280
F. Bruschi
Prospects for A Schistosome Vaccine Pp.281-290
A. Capron, G.J. Riveau, P.B. Bartley and D.P. McManus
Humoral and Cellular Immunity Against
Cryptosporidium Infection
Pp.291-301
M. Angeles, G. Morales and E. Pozio
Abstracts
[Back to top] Immune Response to Parasitic Infections - An
Introduction
O. Brandonisio and R. Spinelli
Many parasitic diseases are an important cause of mortality and
morbidity in humans. The resurgence of malaria and trypanosomiasis in countries
where these diseases have been effectively controlled and the global increase
of several other parasitic diseases, such as cryptosporidiosis and trichinosis
[1] are major health problems.
The WHO Special Programme for Research and Training in Tropical
Diseases (TDR) includes seven parasitic diseases (African trypanosomiasis,
leishmaniasis, malaria, schistosomiasis, Chagas disease, lymphatic filariasis,
onchocerciasis) and one vector-borne viral disease (dengue) among ten major
infectious diseases in its current disease portfolio [2].
In spite of the great importance of these pathogens and the
considerable efforts made to develop vaccines against parasitic infections, at
present there are no licensed vaccines or immunotherapies for these human
diseases.
This is in part due to the genetic and antigenic complexity of these
organisms, and to their ability to evade the immune response, which is often
not completely efficient in parasite elimination. However, in recent years much
progress has been made in understanding the immune mechanisms controlling
parasitic infections, thus establishing the scientific background required for
the design of safe and efficient vaccines against human parasites. Moreover,
sequencing of genomes of protozoan and metazoan parasites will facilitate the
development of new drugs and vaccines [3].
This issue summarizes recent developments in immunoprophylaxis and
immunotherapy of major human protozoan diseases (malaria, leishmaniasis, Chagas
disease, toxoplasmosis and cryptosporidiosis) and helminthiasis
(schistosomiasis, trichinellosis and hydatidosis).
[Back to top] Vaccination Against Leishmania Infections
J. Mauël
Leishmaniasis, that affects millions of people worldwide, is an
infectious disease caused by the protozoan parasite Leishmania. Incidence of
the condition appears to be increasing in several parts of the world. Of the
three main presentations of the disease, i.e. cutaneous, mucocutaneous and
visceral, only the first one tends to heal spontaneously, while the other two
are considered fatal if left to run their natural course. Recovery from
leishmaniasis, whether spontaneous or drug-induced, is usually accompanied by
solid immunity against reinfection, which provides a rationale for attempting
to design vaccines against the disease. This review presents an outline of the
main immunological features
of Leishmania infections and of
the mechanisms thought
[Back to top] Prospects for A Human Toxoplasma Vaccine
D.T. Bout, M.-N. Mevelec, F. Velge-Roussel, I.
Dimier-Poisson and M. Lebrun
Human toxoplasmosis is usually benign, but may occasionally lead to
severe or lethal damages when combined with immunosuppressive states or when
transmitted to the fetus during pregnancy. Only a vaccine could prevent these
harmful effects. The oral route is the natural portal of entry of T. gondii. A
protective immune response at the mucosal level is required to kill the
parasite as soon as it penetrates the intestinal barrier thus preventing
toxoplasma from invading the host and settling into tissues. The probable major
roles played by both CD8 T cells and antibodies, specially IgA, suggest
[Back to top] Molecular and Cellular Tools in Human Cystic
Echinococcosis
A. Siracusano, E. Ortona and R. Riganò
The latest developments in the molecular and cellular mechanisms that
underlie Echinococcus infection have renewed interest in the immunodiagnosis of
this disease and have helped in understanding the host-parasite relationship.
This review discusses current concepts on the immune response to Echinococcus
granulosus in humans, and relates these findings to diagnosis and clinical
management. The two most promising molecular tools developed for the
immunodiagnosis of cystic echinococcosis involve isolating native or
recombinant parasite antigens to detect specific serum antibodies in patients
with suspected echinococcosis and producing monoclonal antibodies to detect
parasite antigens in clinical samples. Novel drugs should be designed to
strengthen host immune responses thus combating parasitic survival. Currently,
attention has been focused on understanding T-helper lymphocyte activity; in
particular the role of Th1 and Th2 subsets in orchestrating immune responses.
The Th1/Th2 model explaining how selective immune responses -- including
cell-mediated or humoral immunity -- develop, seems promising as the rationale
for molecular tools that could lead to new therapeutic strategies.
[Back to top] Immunotherapy of Trypanosoma Cruzi Infections
N. Chamond, N. Coatnoan and P. Minoprio
The protozoan parasite Trypanosoma cruzi, causative agent of Chagas’
disease, is transmitted to man and other mammals by triatominae insects, or
‘kissing bugs’. Since its discovery in 1909, by Carlos Chagas, this parasite
has been the object of several publications in the domains of immunology, cellular
biology and of control gene organization, regulation and expression. Although
much progress has been made concerning prophylaxis of Chagas’ disease,
particularly vector eradication, additional cases of infection and disease
development still occur every day throughout the world. Whilst infection was
largely limited in the past to vector transmission in endemic areas of Latin
America, its impact has increased in terms of congenital and blood
transmission, transplants and recrudescence following immunosuppressive states.
Reports on new insect vectors adapted to the parasite and domestic animals
infected in more developed countries, emphasize the continuing worldwide public
health issue. Therapy against this parasite is limited and cure is subjected to
several criteria, such as susceptibility of the parasite strain, age of the
host and stage of the disease. The ability of Trypanosoma cruzi to induce
important and various host immune system dysfunctions makes the development of
effective vaccines a laborious and complex task. These considerations
strengthen the latent significance of Chagas’ disease and encourage the search
for new preventive procedures and the research on rational vaccines.
[Back to top] Malaria Vaccines: From the Laboratory to the
Field
B. Genton and G. Corradin
The demonstration of the i) acquired protective immunity in adults
living in endemic areas, ii) cure of malaria patients with passive transfer of
specific immunoglobulins, and iii) protection conferred by vaccination with sporozoites attenuated by
radiation, justifies the search for a malaria vaccine. Given the improbability
that a vaccine directed against a single antigen will be completely protective,
the preferred option is to combine several antigens of different stages of the
parasite in a multi-component multi-stage vaccine which is likely to protect
both the travellers and the populations living in endemic areas. Potential
manufacturing technologies include recombinant proteins, synthetic peptides and
DNA vaccines, the relevant genes encoding malaria antigens being inserted into
a plasmid or a live vector such as vaccinia or poxvirus. A number of human
trials using different antigens and technologies have been carried out in the
last ten years. Three vaccines have undergone safety and efficacy testing in
the field. SPf66, comprising a linear polymerized synthetic peptide with
several distinct epitopes, has been extensively evaluated in different
epidemiological settings. The efficacy overall was 23%, but was only 2% in
African infants, the most susceptible group. The circumsporozoite recombinant
protein fused with the antigen S of the hepatitis B virus and formulated in a
potent adjuvant (RTS,S) led to a high, but short-term, level of protection against
infection and disease in Gambian adults. The first pure asexual blood-stage
vaccine comprising three antigens of the merozoite stage (MSP1&2 and RESA,
Combination B) had an efficacy of 62% in reducing parasite density in Papua New
Guinean children. A malaria vaccine that can reduce the burden of disease in
the most affected populations is thus an achievable goal, and each trial
provides additional knowledge about mechanisms of protection as well as about
new vaccine technology.
[Back to top] The Immune Response to the Parasitic Nematode
Trichinella and the Ways to Escape it. From Experimental Studies to
Implications for Human Infection
F. Bruschi
The review describes different aspects of the host immune response to
Trichinella, not only at the intestinal level on which most of the studies have
focused until now, but also in the muscles which represent the final target of
host invasion. The role of antibodies, T cells, mast cells, eosinophils and
neutrophils, respectively, in immune reaction to this nematode is considered,
in the light of the recent data derived from experimental models, both “in
vivo” and more recently “in vitro” and when available, from clinical
observations. A section is also devoted to the principal escape mechanisms from
host immune responses, described in Trichinella, which are in part common to
other parasites, in part peculiar. Two groups of mechanisms are described:
antigen-dependent, such as anatomic seclusion, antigen stage-specificity,
shedding and renewal and molecular mimicry, and those directly affecting the
host immune response. Of the latter, some act at central level like immune
suppression, polyclonal activation and eosinophilia induction, others interfere
with effector functions as in the case of host leukocyte modification, immune
complex accumulation, blocking antibody production or complement assembly
blocking.
The antigenic composition of the different stages is the subject of
another section which has the aim to give an overview of the principal antigens
described up to now, without giving too many biochemical details, but just
illustrating the candidates for possible vaccines.
Finally, the perspectives for vaccination are described.
Most of the results described are derived from the experimental
studies, but their implications in human infection are relevant.
[Back to top] Prospects for A Schistosome Vaccine
A. Capron, G.J. Riveau, P.B. Bartley and D.P. McManus
After some 20 years experience it is generally agreed that chemotherapy
against schistosomiasis, a parasitic disease which should be considered a
consequence of a chronic infection, does have significant limitations. In
particular, chemotherapy does not affect transmission of the infection or the
high re-infection rates and so limits the success by demanding frequently
re-scheduled mass treatments. For this reason, a complementary approach that
can be integrated and could sustain chemotherapy-based control programs, i.e.
vaccination, is very much needed. The rationale is that drug treatment would
provide short-term reduction of worm burdens and vaccination, long-term
protective immune response. Vaccination can either be targeted towards the
prevention of infection or to the reduction of parasite fecundity. A reduction
in worm numbers is the “gold standard” for anti-schistosome vaccine development
but, as schistosome eggs are responsible for both pathology and transmission, a
vaccine targeted on parasite fecundity and egg viability also appears to be
entirely relevant. This review considers various aspects of anti-schistosome
protective immunity that are important in the context of vaccine development.
The current status in the development of vaccines against the African
(Schistosoma mansoni and S. haematobium) and Asian (S. japonicum) schistosomes
is then discussed as the new approaches that may improve on the efficacy of the
available vaccines and aid in the identification of new targets for immune
attack.
[Back to top] Humoral and Cellular Immunity Against Cryptosporidium Infection
M. Angeles, G. Morales and E. Pozio
Protozoans of the genus Cryptosporidium are the etiological agents of
opportunistic infections mainly of the gastrointestinal tract of animals and humans.
Young and elderly persons, those with concomitant infections, with AIDS, under
an immunosuppressive therapy, with congenital T-cell, B-cell or other effector
cell deficiencies develop persistent progressive infections of different degree
of severity related to the level of immunodepression. Both humoral and cellular
immunity play a role in the control of this infection, but the latter plays the
major role, mainly in the intestinal mucosa. However, a natural resistance to
these coccidian parasites is also involved. IgG, IgM and IgA have been detected
in serum and mucosa of humans and animals with the resolution of the infection;
but also high levels of these immunoglobulins have been detected in persons
with AIDS with chronic cryptosporidiosis. In HIV-positive persons, CD4+ T-cells
are required to prevent the establishment of the infection and IFN-γ and
CD4+ T-cells can also limit the duration and the clinical manifestations of the
infection. In persons exposed to cryptosporidial infections, it has been possible
to show the important role of IFN-γ in both the innate and acquired cell
mediated immunity. The severity of cryptosporidiosis has been also associated
with the inability to produce IFN-γ. An antibody therapy using bovine
colostrum from cows hyperimmunised with Cryptosporidium oocysts or monoclonal
antibodies against sporozoite antigens has been developed at the experimental
level mainly for persons with AIDS or with other immunodeficiencies; however,
these preparations of antibodies have shown only a limited degree of efficacy
both in animals and humans.