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Infection and Immunity, July 1999, p. 3424-3429, Vol. 67, No. 7
U.S. Army Medical Research Unit-Kenya and
Kenya Medical Research Institute, Kisumu,
Kenya,1 and Walter Reed Army
Institute of Research, Washington, D.C.2
Received 12 January 1999/Returned for modification 23 February
1999/Accepted 14 April 1999
The design of an effective vaccine against Plasmodium
falciparum, the most deadly malaria parasite of humans, requires
a careful definition of the epitopes and the immune responses involved
in protection. Liver-stage antigen 1 (LSA-1) is specifically expressed during the hepatic stage of P. falciparum and elicits
cellular and humoral immune responses in naturally exposed individuals. We report here that interleukin-10 (IL-10) production in response to
LSA-1 predicts resistance to P. falciparum after
eradication therapy. Resistance was not related to gamma interferon or
tumor necrosis factor alpha production. This is the first report that human IL-10 responses are associated with resistance after eradication therapy, and our findings support the inclusion of LSA-1 in a vaccine
against malaria.
Falciparum malaria kills over 1 million individuals in sub-Saharan Africa each year, and the
development of an effective malaria vaccine remains a public health
priority. Plasmodium falciparum is inoculated by mosquitoes
into the human bloodstream as a motile sporozoite that requires
development within hepatocytes prior to infecting erythrocytes.
Although severe disease occurs during the erythrocytic phase of
infection, a protective vaccine could limit parasite growth at any
stage of development.
Because cytotoxic T lymphocytes (CTLs) and gamma interferon (IFN- Human residents of areas where malaria is holoendemic develop naturally
acquired resistance to malarial infection, and this resistance serves
as a model for vaccine development. Because P. falciparum
can cause frequent infections, and ongoing infection can bias
measurements of immune responses (23), cross-sectional studies have a limited ability to define responses that predict protection. Therefore, we conducted a prospective study, defining the
reappearance of parasitemia after eradication therapy in a cohort of
naturally exposed volunteers, to examine the protective role of
naturally acquired anti-LSA-1 responses. Understanding the relationship
between these responses and resistance to parasitemia can guide the
rational design of an LSA-1-based vaccine.
During two consecutive transmission seasons, we eradicated detectable
parasitemia in volunteers, measured cellular immune responses against
LSA-1 recombinant proteins, and analyzed how well these responses
predicted subsequent parasitemia. In both seasons, interleukin-10
(IL-10) responses to LSA-1, but not IFN- Study site and cohort description.
The study site in western
Kenya was 10 km north of Lake Victoria, in the adjoining villages of
Wangarot, Riwa Ojelo, and Waringa, Rarieda Division, Nyanza Province.
The entomological inoculation rate in this area can exceed 300 infectious bites per person per year (2, 3). Details of this
study site and the measures of parasitemia in this cohort in
consecutive transmission seasons will be presented elsewhere
(20). This study was conducted according to a protocol
approved by ethical review boards of both the Walter Reed Army
Institute of Research and the Kenya Medical Research Institute. All
volunteers gave signed informed consent prior to entry into the study.
0019-9567/99/$04.00+0
Interleukin-10 Responses to Liver-Stage Antigen 1 Predict Human Resistance to Plasmodium falciparum
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
)
can kill liver-stage malaria parasites in animal models (26, 28,
31, 32, 34), human vaccines designed to control the liver-stage
of P. falciparum have focused on eliciting similar responses. Liver-stage antigen 1 (LSA-1) (15), a 200-kDa
antigen that accumulates as flocculent material in the parasitophorous vacuole of infected hepatocytes (17), is a leading candidate for inclusion in a P. falciparum vaccine. LSA-1 contains
several B- and T-cell epitopes that are immunogenic during the course of natural infection (12), and it stimulates CTLs and
IFN- in naturally exposed individuals (12, 16). A
specific LSA-1 peptide that associates with HLA-B53 elicits CTL
responses (16), and HLA-B53 has been associated with
naturally acquired resistance to severe malaria in some but not all
studies (9, 16).
or tumor necrosis factor
alpha (TNF-
) responses, were significantly associated with reduced
measures of parasitemia. This is the first study to suggest IL-10 is
involved in resistance after eradication therapy, and our results
support efforts to develop a malaria vaccine based on LSA-1.
MATERIALS AND METHODS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
Blood collection and processing. In each season, volunteers donated 10 ml of blood into heparinized tubes 2 weeks after treatment with quinine and doxycycline. Peripheral blood mononuclear cells (PBMCs) were separated by Ficoll-Hypaque (Sigma) density centrifugation, resuspended in 10% dimethyl sulfoxide in fetal bovine serum, and cryopreserved in temperature-controlled freezing boxes, followed by long-term storage in liquid nitrogen. Thawed PBMCs had an average viability of greater than 90% as determined by trypan blue exclusion, and 96% of samples in the first season responded to phytohemagglutinin stimulation with a stimulation index of >5. Sufficient PBMCs for analysis were obtained on 141 of 173 volunteers in the first season and 120 of 143 volunteers in the second season.
Clinical laboratory. Hemograms were performed on heparinized blood, using a Coulter cell counter model T-890 (Coulter Corp., Hialeah, Fla.). ABO blood group and hemoglobin phenotype were determined on 154 volunteers with commercially available reagents (Sigma, St. Louis, Mo.).
Antigens. Two recombinant LSA-1 polypeptides were expressed with a thioredoxin fusion partner. The LSA-1 N-terminal polypeptide (LSA N) contained amino acids 28 to 150, and the C-terminal polypeptide (LSA C) contained amino acids 1630 to 1909, based on the sequence of LSA-1 from parasite strain NF-54 (36). These recombinant proteins flank the central repeat region of LSA-1. Fusion proteins were purified by metal chelate chromatography. Thioredoxin alone was purified under identical conditions and used as the negative control for all assays. LSA N and LSA C were used at a concentration of 10 µg/ml, and thioredoxin was used at an equivalent molar concentration. All assays were performed with a single lot of each recombinant protein. Recombinant proteins were greater than 95% pure as determined by Coomassie blue staining of sodium dodecyl sulfate-polyacrylamide gels. Lipopolysaccharide in the LSA C preparation was measured to be less than 100 endotoxin units/mg of protein by the gel clot Limulus amebocyte lysate method.
Lymphocyte assays.
PBMCs were thawed, washed twice in RPMI
1640, and resuspended in RPMI 1640 supplemented with 10% human AB
serum at 0.5 × 106/ml. PBMCs were used at 50,000 cells per well in round-bottom microtiter plates. Stimulants were added
to a final volume of 200 µl. Cells were incubated for 5 days in a
humidified incubator at 37°C and 5% CO2. On day 5, 125-µl samples of cell-free culture supernatant were harvested from
each well and stored at 
70°C for subsequent cytokine analyses.
Cytokine assays.
Cytokine analyses on culture supernatants
were performed in duplicate on 50-µl samples by sandwich
enzyme-linked immunosorbent assay (ELISA). Paired antibodies and
standards for IFN- (MabTech, Nacka, Sweden), TNF- (Genzyme,
Cambridge, Mass.), and IL-10 (PharMingen, San Diego, Calif.) were used
as previously described (13). Standard curves for each
cytokine were linear to at least 10 pg/ml. To calculate the
LSA-1-specific cytokine response, the background cytokine concentration
measured in thioredoxin-stimulated wells was subtracted from the
cytokine concentration measured in wells stimulated with LSA N or LSA C.
Statistical analyses. We examined relationships between anti-LSA-1 cytokine responses and resistance to parasitemia. Measures of parasitemia included time to reappearance of parasitemia, mean parasitemia, and frequency of detectable parasitemia. Time to reappearance of parasitemia was examined with Kaplan-Meier models (group differences evaluated with log rank test) and Cox proportional hazards models. Mean parasitemia and frequency of parasitemia were evaluated with Pearson's correlation analysis and Student's two-tailed t test.
Immunologic data were analyzed dichotomously (Kaplan-Meier and Student's two-tailed t test) or continuously (Cox and Pearson's analyses), as appropriate for each statistical test. Cytokine responses were dichotomized as detectable (
10 pg/ml) or
undetectable (<10 pg/ml), based on the sensitivity of our ELISA. When
analyzed as continuous data, cytokine responses, mean parasitemia, and frequency of parasitemia required loge
transformation [ln(value+1)] to obtain normal distributions.
Potential confounding of immunologic variables by age, ABO blood group,
or hemoglobin phenotype was explored with contingency table analyses,
analysis of variance and multivariate linear regression where appropriate.
Analyses were performed with blood smears taken over the entire season
of follow-up (raw data) or with only those blood smears taken before
first treatment with Fansidar (adjusted data). Analyses of both
adjusted and raw data yielded similar results; therefore, only results
for the adjusted data are presented here.
All analyses were performed with StatView version 5.0 on Macintosh computers.
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RESULTS |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Parasitemia reappeared after eradication treatment in most volunteers during both seasons. In the first season, 33% of volunteers had P. falciparum present on the blood smear prior to eradication treatment. Of the 173 volunteers included for analysis during the first season, parasitemia reappeared in 50% within 13 weeks (Kaplan-Meier estimate) and reappeared in a total of 101 volunteers by the end of the season.
In the second season, 53% of volunteers had P. falciparum present on the blood smear prior to eradication treatment. Of the 143 volunteers included for analysis, parasitemia reappeared in 50% within 6 weeks (Kaplan-Meier estimate) and reappeared in a total of 135 volunteers by the end of the season. The absence of parasitemia during the first season did not predict the absence of parasitemia during the second season (contingency table analysis, P = NS [not significant]).IL-10 responses to LSA C predicted resistance to malaria in the
first season.
LSA-1 recombinant proteins frequently elicited
cytokine responses from naturally exposed individuals (Table
1). IFN-, TNF-, and IL-10 were
detected in 60, 62, and 61%, respectively, of samples stimulated with
LSA N and in 57, 71, and 24%, respectively, of samples stimulated with
LSA C. All assays were performed on PBMCs collected 2 weeks after
eradication of malaria. TNF- responses were significantly lower
among donors who were infected prior to eradication treatment
(Student's t test, P = 0.02); no other cytokine measurements were related to the presence or absence of
parasitemia prior to eradication (P = NS). By Pearson's
analysis, IFN- levels correlated mildly with TNF- levels after
stimulation with both LSA N (r = 0.273, P = 0.001)
and LSA C (r = 0.366, P < 0.001). IL-10 levels
correlated weakly with IFN- levels after stimulation with LSA N
(r = 0.180, P = 0.03) but not after stimulation with LSA C (P = NS).
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0.211, P = 0.01), and lower frequency of
parasitemia (Pearson's analysis, r = 0.176, P = 0.04). These relationships remained statistically significant
after accounting for age, ABO blood group and hemoglobin phenotype. No
other cytokine measurements, including IL-10 responses to LSA N, were
related to resistance (P = NS).
Similar relationships were observed when IL-10 responses to LSA C were
analyzed as a dichotomous variable (detectable versus undetectable) in
Kaplan-Meier analysis of time to reappearance of parasitemia and
Student's t tests on mean parasitemia and frequency of
parasitemia. Individuals who produced detectable IL-10 in response to
LSA C had significantly longer times to reappearance of parasitemia (P = 0.05), 58% lower mean parasitemia (P = 0.03), and 37% lower frequency of parasitemia (P = 0.1) (Fig. 1 and
2). When individuals were dichotomized on
the basis of other cytokine measurements, measures of parasitemia did
not significantly differ between groups.
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IL-10 responses to LSA N predicted resistance to malaria in the
second season.
During the second season, IFN-, TNF-, and
IL-10 were detected in 19, 31, and 43%, respectively, of samples
stimulated with LSA N and in 14, 63, and 27%, respectively, of samples
stimulated with LSA C (Table 1). None of the cytokine responses
measured during the first season significantly correlated with the same responses during the second season (Pearson's analysis, P =
NS). The proportion of volunteers who produced detectable IL-10 to LSA
C remained stable from the first to the second season, while the
frequency of other cytokine responses decreased substantially (Table
1). Assays were performed on PBMCs collected 2 weeks after eradication
of malaria; none of the cytokine measurements were associated with the
presence or absence of parasitemia prior to eradication (Student's
t test, P = NS for all cytokine measurements). By
Pearson's analysis, IFN- levels correlated mildly with IL-10 levels
after stimulation with LSA C (r = 0.249, P = 0.008); no other correlations between cytokine levels were
observed (P = NS).
0.233, P = 0.01)
and mean parasitemia (r = 0.252, P = 0.007).
Higher levels of IL-10 in response to LSA N correlated with lower mean
parasitemia and lower frequency of parasitemia. IL-10 responses to LSA
C were not related to measures of parasitemia during the second season (in contrast to the first season), nor were other cytokine measurements related (P = NS).
Similar results were obtained when IL-10 responses to LSA N were
analyzed as a dichotomous variable (detectable versus undetectable) in
Student's t tests on mean parasitemia and frequency of
parasitemia. Individuals who produced detectable IL-10 in response to
LSA N had 52% lower mean parasitemia (P = 0.01) and
26% lower frequency of parasitemia (P = 0.008) (Fig.
3). Measures of parasitemia did not
differ when individuals were dichotomized based on any of the other
cytokine measurements (P = NS).
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DISCUSSION |
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Abstract
Introduction
Materials and Methods
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Discussion
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We report that measures of parasitemia after eradication therapy are significantly reduced in individuals who produce IL-10 in response to a liver-stage-specific antigen. Individuals who produced IL-10 in response to LSA C in the first season (low transmission) had a 58% reduction in mean parasitemia and a 37% reduction in frequency of detectable parasitemia compared to nonresponders. In the second (high-transmission) season, IL-10 production in response to LSA N was associated with similar reductions in parasitemia. Because IL-10 responses to LSA-1 are associated with naturally acquired resistance, a vaccine that elicits these responses may enhance protection in humans.
Earlier studies have examined the development of immune responses that
could arrest parasite development in the liver. Human studies have
identified low levels of CTL activity in naturally exposed populations
(1, 10, 16, 22) and in irradiated sporozoite-immunized
volunteers (24, 33). Other studies indicate that antibody,
proliferative, cytokine, and CTL responses to LSA-1 peptides are
detectable in naturally exposed individuals (8, 11, 12).
Connelly et al. reported that in an area of Papua New Guinea where
malaria is holoendemic, 10 of 11 individuals with two negative blood
smears (obtained 6 months apart) produced detectable IFN- in
response to an LSA-1 peptide, while only 9 of 27 individuals with one
or two positive blood smears produced detectable IFN- in response to
this peptide (8). No association was found between blood
smear status and IFN- responses to two other LSA-1 peptides.
We did not observe a relationship between IFN- or TNF- responses
and measures of parasitemia. Previous animal data support a paradigm
whereby CTL and IFN- responses are principal mediators of
pre-erythrocytic immunity (26, 28, 31, 32, 34), and Connelly
et al. have reported that IFN- production in response to an LSA-1
peptide is associated with the absence of parasitemia (8).
IFN- and TNF- responses were high in our cohort but failed to
predict reductions in parasitemia; we did not examine CTL responses.
Possibly, CTL and IFN- responses are essential components of
pre-erythrocytic immunity in humans but are ubiquitous at the site of
infected hepatocytes in chronically exposed individuals and therefore
no longer differentiate susceptible and resistant phenotypes.
IL-10, TNF-, and IFN- are cross-regulatory cytokines. Whereas
TNF- can contribute to the induction of IL-10 release in vivo
(30), IL-10 inhibits the release of proinflammatory
cytokines, including TNF-, by human monocytes and neutrophils, and
inhibits IFN- secretion by Th1 lymphocytes (reviewed in reference
21). Levels of TNF- are elevated in patients with
malaria, and these elevations are associated with severe disease
(14). IL-10 levels are also high during symptomatic malaria
(25) but may be only slightly elevated in individuals with
asymptomatic parasitemia (18). We did not identify
significant relationships between IL-10 and TNF- responses in the
same season. However, IL-10 and TNF- responses were all greater
during the high-transmission season than during the low-transmission
season (Table 1), possibly reflecting the increased exposure to malaria.
Assessing immunity against liver-stage parasites is problematic. Hepatic tissue is generally inaccessible to direct evaluation, relatively few antigens specific to this stage have been defined, and PBMCs can only indirectly reflect the responses occurring at the site of the infected hepatocyte. Given these limitations, we believe that the design of our study has distinct advantages to identify immune responses associated with resistance. Cytokine measurements were determined after infection was eradicated, avoiding confounding of immune responses by active infection, and IL-10 responses were unrelated to pretreatment parasitemia in both seasons. Cytokine measurements were made immediately before the collection of parasitemia data, temporally supporting a cause (immune response)-and-effect (reduced parasitemia) relationship. Thus, our cytokine measurements were performed in the absence of ongoing infection, were unrelated to recent infection, and were timed to support a causal relationship with resistance.
In both a high- and a low-transmission season, IL-10 production (measured 2 weeks after malaria eradication) was associated with resistance to subsequent parasitemia. Measures of parasitemia (time to reappearance of parasitemia, mean parasitemia, and frequency of parasitemia) are related and can be influenced by both pre-erythrocytic and erythrocytic immunity, making it difficult to define the point at which IL-10 responses may be involved in protection. LSA-1 is not expressed during the erythrocytic stages of the parasite and has not been shown to share cross-reactive epitopes with blood-stage parasites, suggesting that anti-LSA-1 responses are elicited during liver-stage parasite development.
We did not determine the cellular source of cytokines in our samples,
and therefore deducing a mechanism by which IL-10 augments resistance
is largely speculative. IL-10 has several immunostimulatory effects
that could participate in antiparasite effector pathways. For example,
CD8+ CTLs mediate killing of liver-stage parasites in
animal models of malaria (26, 32), and IL-10 can enhance CTL
activity. In mice, IL-10 augments IL-2-induced differentiation,
proliferation, and cytotoxicity of CD4
CD8+
cells (7). In humans, IL-10 is a chemoattractant for
CD8+ lymphocytes (19) and could recruit
CD8+ CTLs to the site of infected hepatocytes.
IL-10 could also enhance antibody-dependent cellular inhibition (ADCI)
activity against P. falciparum. ADCI is mediated by the
cooperative activity of antibodies and monocytes, resulting in arrested
parasite development (4, 5). Human IL-10 induces activated B
cells to secrete immunoglobulin (Ig) (27), particularly the
cytophilic IgG1 and IgG3 isotypes (6), and supports the retention of Fc receptors on the surface of monocytes
(29). Thus, IL-10 could enhance an ADCI effect triggered as
merozoites emerge from the ruptured hepatocyte. Separately, elevated
antibody levels could inhibit parasite growth by agglutinating the
flocculent mass of LSA-1 around merozoites emerging from ruptured
hepatocytes, as first suggested by Zhu and Hollingdale (36).
IL-10 production in response to LSA C predicted resistance in the first (low-transmission) season, while IL-10 production in response to LSA N predicted resistance in the second (high-transmission) season. Among other possibilities, the change in apparently protective epitopes may be due to naturally occurring sequence variation of LSA-1. Sequence variation in both the N and C termini of LSA-1 has been reported in parasites from this study site (35). As a consequence, the epitopes shared by recombinant LSA-1 polypeptides (used as in vitro stimulants) and naturally occurring LSA-1 (expressed by circulating parasites) can change between seasons.
Our study supports a protective role for IL-10 production in response to LSA-1. Additional investigation is required to define specific mechanisms, including antibody, CTL activity, and enhanced ADCI, involved in LSA-1-mediated protection during acute and chronic human infection. In summary, through direct association of anti-LSA-1 responses with resistance in a naturally exposed population, our study supports the inclusion of LSA-1 in multicomponent vaccines and suggests that IL-10 responses may augment resistance to P. falciparum in chronically exposed humans.
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ACKNOWLEDGMENTS |
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J.D.K. was a National Research Council fellow and an American Society of Tropical Medicine and Hygiene/Becton Dickinson fellow.
This work is published with the kind permission of the director of the Kenya Medical Research Institute.
We thank Raphael Onyango, Samuel Oduor Wangowe, and Frederick Onyango for excellent supervision of the field studies and the volunteers for their participation. Stephen Hoffman provided thoughtful discussions of pre-erythrocytic immunity, and W. Ripley Ballou, David Fidock, and Michal Fried reviewed the manuscript.
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FOOTNOTES |
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* Corresponding author. Present address: Room 2028, Immunology, Building 40, Walter Reed Army Institute of Research, 14th & Dahlia St., Washington, DC 20307-5100. Phone: (202) 782-1234 or (202) 782-0200. Fax: (202) 782-0748. E-mail: duffyp{at}wrsmtp-ccmail.army.mil.
Present address: Hospital of the University of Pennsylvania,
Department of Pathology and Laboratory Medicine, Philadelphia, PA 19104.
Editor: S. H. E. Kaufmann
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Materials and Methods
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Discussion
References
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