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Antimicrobial Agents and Chemotherapy, June 2000, p. 1494-1498, Vol. 44, No. 6
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Activity of the Novel Immunomodulatory Compound
Tucaresol against Experimental Visceral Leishmaniasis
Aden C.
Smith,1
Vanessa
Yardley,1
John
Rhodes,2 and
Simon L.
Croft1,*
Department of Infectious and Tropical
Diseases, London School of Hygiene and Tropical Medicine, London WC1E
7HT,1 and Glaxo Wellcome Research and
Development, Medicines Research Centre, Stevenage, Herts SG1
2NY,2 United Kingdom
Received 28 December 1999/Returned for modification 7 February
2000/Accepted 6 March 2000
 |
ABSTRACT |
Tucaresol, a novel immunomodulator, was inactive against
Leishmania donovani amastigotes in both peritoneal and bone
marrow macrophages in vitro at concentrations between 100 and 1 µM,
with toxicity to macrophages and parasites at 300 µM. However,
against L. donovani in BALB/c mice at doses between 80 and
1.25 mg/kg of body weight administered once daily by the oral route
during days 7 to 11 of infection, an optimal dose of 5 mg/kg produced a
43.8 to 62.4% suppression of liver amastigotes, with significantly reduced activity at the extremes of the dose range. This response was
not related to levels of infection. No interaction with the standard
pentavalent antimonial sodium stibogluconate (Pentostam) was observed
during this period of infection. The optimum dose of 5 mg/kg was
ineffective when administered during the first week of infection and
was most effective against the liver infection when administered during
weeks 2 to 3 of infection (42.3 to 46.8% inhibition) and against the
splenic infection when administered during week 6 of infection (59.5%
inhibition). The optimum dose of tucaresol against L. donovani in C57BL/6 mice was 5 mg/kg, which produced a 40.8 to
48.7% suppression of liver amastigotes when administered in a range of
80 to 1.25 mg/kg during days 7 to 11 of infection. The drug had no
activity against L. donovani infections in C.B-17
scid mice when the same regimen was used.
| |
INTRODUCTION |
Leishmaniasis is a complex of
diseases with visceral, cutaneous, and mucocutaneous pathologies caused
by up to 15 different species of the protozoan parasite
Leishmania. The visceral form of the disease, caused by
Leishmania donovani, Leishmania infantum, or
Leishmania chagasi, can be potentially fatal if untreated. Visceral leishmaniasis (VL) is found in tropical and subtropical regions of the world and has a worldwide incidence of up to 500,000 cases (5; World Health Organization, Communicable
Diseases Surveillance and Response [CSR]: Leishmaniasis Control
[http://www.who.int/emc/diseases/leish/leisepidat.html]). Coinfections with L. infantum and human immunodeficiency
virus (HIV) have been a growing problem in Mediterranean countries and have indicated that this parasite is also an opportunist
(3). The current recommended drugs for the therapy of VL
remain the pentavalent antimonials, sodium stibogluconate (Pentostam)
and meglumine antimoniate (Glucantime) (9), which have been
in clinical use for leishmaniasis for over 50 years. Other recommended drugs include amphotericin B, together with lipid formulations of this
polyene antibiotic, and the aminoglycoside aminosidine (paromomycin)
(9, 10). All the recommended drugs require parenteral
administration and have other limitations that include cost, toxicity,
variable efficacy, or restricted supplies. There is no effective
treatment for immunosuppressed patients with L. infantum-HIV
coinfection (3, 22).
In the search for new drugs for the treatment of leishmaniasis there
has been a major emphasis on biochemical and molecular targets, for
example, trypanothione reductase and cysteine proteases, and the
identification of inhibitors by rational design or empirical screening
(8, 39). The ability of Leishmania parasites to establish an infection in humans is dependent upon the adaptation of
parasites to survive and multiply in the phagosomal compartment of
macrophages as well as upon the development of host immunosuppression (12). The fine balance of this host-parasite interaction has suggested that immunostimulation is another rational approach to the
treatment of leishmaniasis. The effects of immunomodulators on both VL
and cutaneous leishmaniasis have been studied, either alone or in
combination with chemotherapeutic drugs. These studies have included
the endogenous biologicals gamma interferon (IFN-
) (38)
and granulocyte-macrophage colony-stimulating factor (7) in
both experimental and clinical leishmaniasis and interleukin 12 (IL-12)
(30) in experimental leishmaniasis, the bacterial and fungal
derivatives muramyl dipeptide (2), trehalose dimycolate (19), and glucan (6), and the synthetic compounds
levamisole (23), lipoidal amine CP-46,665-1 (1),
cimetidine (20), tuftsin (18, 24),
polyinosinic-polycytidylic acid (11), and imiquimod
(14).
Tucaresol, an orally bioavailable immunopotentiatory drug, has been
shown to enhance T-helper-cell activity, with the induction of
increased IL-2 and IFN- levels in mice and humans (17,
36). The compound probably acts through the formation of a Schiff
base on CD4+ T-cell surface amines which provides a
costimulatory signal between antigen-presenting cells, such as
macrophages, and T cells. Convergence of the tucaresol-mediated
costimulatory signaling with T-cell receptor signaling occurs at the
level of the mitogen-activated protein kinase ERK2 (16).
Tucaresol has proved effective against experimental models of
cytomegalovirus and murine colon adenocarcinoma and has been shown to
be biologically active as an immunopotentiator, favoring a Th1 response
in patients with malignant melanoma (29, 36). Tucaresol was
well tolerated at doses of 400 mg/kg of body weight in phase I and II
melanoma trials (29), and an elimination half-life of 1 week
was shown in other studies (4). The costimulatory potential
of tucaresol, as well as its ability to bias immunity toward a
cell-mediated T-helper-cell response, suggests that it could prove to
be of therapeutic benefit against chronic infectious diseases such as
VL, which is characterized by its ability to induce T-cell anergy
(26). In this study we describe the effect of tucaresol in
murine models of L. donovani infection.
(This work was presented in part at the 39th Interscience Conference on
Antimicrobial Agents and Chemotherapy, San Francisco, Calif., 26 to 29 September 1999 [S. L. Croft, A. C. Smith, V. Yardley, and J. Rhodes, Abstr. 39th Intersci. Conf. Antimicrob. Agents Chemother.,
abstr. 1854, p. 730, 1999].)
| |
MATERIALS AND METHODS |
Parasites.
L. donovani (strain MHOM/ET/67/L82) was
routinely maintained in golden hamsters (Mesocricetus
auratus; Wright's strain; Charles River Ltd., Margate, United
Kingdom) by passage every 6 to 8 weeks.
Compounds.
Tucaresol
(4-[2-formyl-3-hydroxy-phenoxymethyl]benzoic acid) (Fig.
1) and sodium stibogluconate (Pentostam)
were kindly provided by Glaxo Wellcome, Stevenage, United Kingdom.
In vitro studies.
Peritoneal exudate macrophages (PEMs) were
isolated from female CD1 mice (Charles River Ltd.) and were maintained
in 16-well Lab-tek (Nunc, Naperville, Ill.) tissue culture slides in
RPMI 1640 medium (Gibco, Paisley, United Kingdom) with 10%
heat-inactivated fetal calf serum at 37°C in a 5%
CO2-air mixture. Bone marrow macrophages (BMMs) were
derived from 8- to 10-week-old female BALB/c mice (Charles River Ltd.)
as described previously (28). Briefly, bone marrow cells
were eluted from the femur and were cultured for 8 days in Dulbecco
modified Eagle medium with GlutaMAX I (Gibco) supplemented with 20%
heat-inactivated fetal calf serum, 100 U of penicillin per ml, 100 µg
of streptomycin per ml, and 10% L-cell-conditioned medium as a source
of colony-stimulating factor 1. Macrophages were rested for 2 days in
the absence of colony-stimulating factor 1 before use in experiments.
L. donovani amastigotes were isolated from an infected
hamster spleen and were used to infect the macrophage cultures at a
ratio of 10 amastigotes to 1 macrophage. Infected cultures were
maintained in medium containing test compounds in either a three- or
fivefold dilution series, with quadruplicate cultures at each
concentration, for 5 days (35). Medium was replaced once
with fresh medium containing drug on day 3. After the 5-day exposure,
the slides were methanol fixed and Giemsa stained and the proportion of
infected macrophages was determined in each chamber. The 50 and 90%
effective doses (ED50s and ED90s, respectively)
were determined by sigmoidal regression analysis with Xlfit
software for Microsoft Excel.
In vivo studies.
Female BALB/c mice (Charles River Ltd.),
C57BL/6 mice (Charles River Ltd.), and C.B-17 scid mice
(from a breeding colony at the London School of Hygiene and Tropical
Medicine) were infected intravenously, via the lateral tail vein, with
2 × 107 L. donovani amastigotes freshly
isolated from the spleen of an infected hamster, followed by random
sorting into groups of five. In initial and drug combination
experiments, mice were dosed by the oral route once per day from days 7 to 11 of infection. In the time course studies separate groups of five
mice were dosed for 5 consecutive days on either days 1 to 5, 7 to 11, 14 to 18, 21 to 25, 28 to 32, 35 to 40, 42 to 46, 49 to 53, or 56 to 60 of infection. Sodium stibogluconate, used either as a standard drug or
in combination with tucaresol, was administered subcutaneously once a
day for 5 consecutive days. In all regimens described, the mice were
killed 3 days after the completion of treatment, livers and spleens
were removed and weighed, and impression smears were prepared from a
cut surface. Smears were methanol fixed and Giemsa stained (BDH, Poole,
United Kingdom). Drug activity was determined by comparing the number
of amastigotes per 500 liver cells or spleen cells times the organ
weight (in milligrams) in mice from the treated and untreated groups.
Data represent the mean ± standard error of the mean (SEM), with
differences between values analyzed by a two-tailed Student's
t test. ED50s were determined by sigmoidal
regression analysis with Xlfit software for Microsoft Excel.
All studies were conducted by procedures approved under the United
Kingdom Home Office Animals (Scientific Procedures) Act
of
1986.
| |
RESULTS |
In vitro.
Tucaresol had no activity against L. donovani amastigotes in BMMs at 30 to 1 µM or in PEMs in the
range of 100 to 1 µM but was toxic to both PEMs and parasites at 300 µM. In the same studies the standard drug sodium stibogluconate had
an ED50 of 4.8 to 5.3 µg of SbV per ml and an
ED90 of 11.3 to 13.4 µg of SbV per ml for
parasites in PEMs, in line with previously reported results with this
model (35).
In vivo.
In initial studies with L. donovani-infected BALB/c mice, animals were dosed during days 7 to
11 of infection, as performed in standard chemotherapy studies. In two
separate experiments, 20 mg of tucaresol per kg, the optimal dose
reported by Rhodes et al. (36), resulted in 26.2 and 24.1%
inhibition of liver amastigotes. In three further experiments that
explored higher and lower doses of tucaresol, an optimum dose of 5 mg/kg was observed, with 43.8% (P < 0.05), 59.5% (P < 0.01) (Fig. 2A), and 62.4%
(P < 0.01) (Fig. 2B) suppression of liver amastigotes
and limited or no activity at the extremes of the dose range, 1.25 and
80 mg/kg. Although the levels of liver infection in control (untreated) mice varied by 50% between experiments (P < 0.05),
from 8.9 × 105 ± 7.1 × 104
amastigotes to 1.7 × 106 ± 1.5 × 105 amastigotes, the levels of inhibition caused by 5 mg/kg
were similar, at 59.5 and 62.4%, respectively. Evaluation of the
activity of tucaresol against spleen amastigotes was not possible
during days 7 to 11 of infection due to low parasite numbers.
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FIG. 2.
(A) Dose-response activity of tucaresol and sodium
stibogluconate (Pentostam) against L. donovani in BALB/c
mice. Mice were dosed during days 7 to 11 of infection, and the
inhibition of liver amastigotes was determined at day 14 postinfection.
The 5-mg/kg dose of tucaresol results in a highly significant
(P < 0.01) inhibition of liver amastigotes relative to
the numbers in untreated controls (Student's t test). Data
represent means ± SEMs derived from five mice per group. (B)
Dose-response activity of tucaresol and sodium stibogluconate
(Pentostam) alone and in combination against L. donovani in
BALB/c mice. Mice were dosed during days 7 to 11 of infection, and the
inhibition of liver amastigotes was determined at day 14 postinfection.
The 5-mg/kg dose of tucaresol (Tucaresol 5) results in a highly
significant (P < 0.01) inhibition of liver amastigotes
relative to the numbers in untreated controls (Student's t
test). Data represent means ± SEMs derived from five mice per
group.
|
|
The effect of tucaresol on liver and spleen amastigote loads during the
course of infection in BALB/c mice was determined
at the previously
determined optimum dose of 5 mg/kg. Groups of
mice were separately
treated during either week 1, 2, 3, 4, 5,
6, 7, or 8 of infection and
were killed 3 days after the completion
of dosing. The pattern of
infection of
L. donovani in BALB/c mice,
with liver
infections reaching a maximal level by weeks 4 to 8
postinfection and
spleen parasite numbers increasing after weeks
4 to 8 of infection, has
been reported elsewhere (
21). In this
study and in an
earlier study with 20 mg/kg, tucaresol was inactive
during the first
week of infection. At 5 mg/kg, activity against
the liver infection
reached a maximum (46.8 and 42.3%, respectively)
during weeks 2 to 3, whereas activity against the splenic infection
reached a maximum
(59.5%) during week 6 (Fig.
3).
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FIG. 3.
Activity of 5 mg of tucaresol per kg against L. donovani infections in livers ( ) and spleens ( ) of BALB/c
mice. Groups of mice were separately treated during either week 1, 2, 3, 4, 5, 6, 7, or 8 of infection and were killed 3 days after the
completion of dosing. Data represent means ± SEMs derived from
five mice per time point.
|
|
The activity of tucaresol administered during days 7 to 11 of infection
was also ascertained in two other strains of mice.
In separate
experiments, within the range of 80 to 1.25 mg/kg,
the maximum efficacy
of tucaresol against liver infections in
C57BL/6 mice was 40.8% (Fig.
4) and 48.7% at an optimal dose of
5 mg/kg. The compound showed no activity against liver or spleen
infections in C.B-17
scid mice in the range of 80 to 1.25 mg/kg.
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FIG. 4.
Dose-response activity of tucaresol and sodium
stibogluconate (Pentostam) against L. donovani in C57BL/6
mice. Mice were dosed during days 7 to 11 of infection, and the
inhibition of liver amastigotes was determined at day 14 postinfection.
Data represent means ± SEMs derived from five mice per group.
|
|
In all studies, sodium stibogluconate was included as the standard
control and showed a normal dose-response effect (Fig.
2A and B) with
ED
50s against
L. donovani in the range of 10.9
to 16.8 mg of SB
V per kg in BALB/c mice and 15.9 mg of
SB
V per kg in C57BL/6 mice, and limited activity in C.B-17
scid mice.
Combinations of tucaresol at 5 mg of
Sb
v per kg with sodium stibogluconate at 45, 15, and 5 mg/kg during
days 7 to 11 of infection in BALB/c mice showed no
synergistic
or additive effects (Fig.
2B).
| |
DISCUSSION |
VL in humans is characterized by downregulation of the
Th2-associated immune response, which involves the action of IL-4 and IL-10, suppression of the secretion of IL-12, and possible inhibition of IFN- production and macrophage responsiveness to IFN-
(15, 32, 37). The most detailed studies of the immune
response have been determined with murine models of experimental VL, in which, in addition to disease-promoting Th2- and disease-suppressing Th1-associated immune responses, L. donovani has also been
shown to bring about the downregulation of macrophage costimulatory molecules and major histocompatibility complex class II expression, which leads to poor T-cell and macrophage costimulation and parasite persistence (27, 32). Tucaresol could overcome this anergic state by acting as a donor for the naturally occurring T-cell ligands
associated with the costimulatory activation of T cells (17,
36) to produce the IFN- necessary for macrophage activation and Leishmania killing. In this study we have demonstrated
that tucaresol is active against experimental L. donovani
infections at the low dose of 5 mg/kg in both the BALB/c (noncure
haplotype) and the C57BL/6 (cure haplotype) murine models by oral
administration. There was little difference in the activity profile for
L. donovani in BALB/c mice (59.5 to 62.4%) (Fig. 2A and B)
and C57BL/6 mice (40.8 to 48.7%) (Fig. 4), despite the different host
genetic backgrounds and immunological responses to infection in these
two murine models (25, 27). Interestingly, IFN- also
produces a similar (50 to 60%) reduction in liver amastigote levels in
BALB/c mice when administered alone (31), but unlike
IFN-, tucaresol does not act in synergy or have an additive response
with sodium stibogluconate. The T-cell-dependent action of sodium
stibogluconate is well documented (27, 33, 37), with the
synergy with IFN- possibly due to an alteration in the macrophage
activation threshold (27).
The absence of activity in scid mice, which lack T and B
cells (13), as well as the lack of activity against
amastigotes in either elicited PEMs or naive BMMs in vitro, would seem
to confirm that tucaresol is functioning as an immunomodulator. Further evidence is provided by the characteristic bell-shaped dose-response curve, a possible consequence of high tucaresol doses interfering with
antigen-presenting cell-T-cell conjugation, also reported by Rhodes et
al. (36). The difference in the activity of tucaresol against liver and spleen infections in BALB/c mice follows the pattern
of T-cell responses in these two organs, as reported elsewhere (21). In particular, the absence of any antileishmanial
activity during the early weeks of infection in the spleen is due to
the slow development of infection in this organ, which reaches a
maximal level only after 4 to 8 weeks postinfection. In contrast, liver parasite numbers increase quickly, reaching a maximum in the first 3 to
4 weeks (21). The optimal activity of tucaresol against liver and spleen infections in BALB/c mice (Fig. 3) reflects not only
the development of the parasite burdens in these organs but also the
development of parasite persistence and T-cell anergy (26).
Potentially, this could have an effect upon the timing of tucaresol
dosing postinfection, but it also suggests that tucaresol is acting
more like a cytokine, such as IL-12 (27, 34), in which the
timing of administration determines success or failure.
In conclusion, we have demonstrated the novel but limited activity of
the immunomodulator tucaresol against experimental VL. As no
interactions with the standard antileishmanial agent sodium stibogluconate were shown, further studies will need to explore combinations with other drugs, as well as establish the basis of the
interaction with the immune system that leads to the killing of
Leishmania parasites.
| |
ACKNOWLEDGMENTS |
This investigation received financial support from the UNDP/World
Bank/WHO Special Programme for Research and Training in Tropical
Diseases (TDR).
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom. Phone: 44 (0)
20 7927 2345. Fax: 44 (0) 20 7636 8739. E-mail:
simon.croft{at}lshtm.ac.uk.
| |
REFERENCES |
| 1.
|
Adinolfi, L. E., and P. F. Bonventre.
1985.
Enhancement of Glucantime therapy of murine Leishmania donovani infection by a synthetic immunopotentiating compound (CP-46,665-1).
Am. J. Trop. Med. Hyg.
34:270-277.
|
| 2.
|
Adinolfi, L. E.,
P. F. Bonventre,
M. Vander Pas, and D. A. Eppstein.
1985.
Synergistic effect of Glucantime and a liposome-encapsulated muramyl dipeptide analog in therapy of experimental visceral leishmaniasis.
Infect. Immun.
48:409-416[Abstract/Free Full Text].
|
| 3.
|
Alvar, J.,
C. Cañavate,
B. Gutiérrez-Solar,
M. Jiménez,
F. Laguna,
R. López-Vélez,
R. Molina, and J. Moreno.
1997.
Leishmania and human immunodeficiency virus coinfection: the first 10 years.
Clin. Microbiol. Rev.
10:298-319[Abstract].
|
| 4.
|
Arya, R.,
P. E. Rolan,
R. Wootton,
J. Posner, and A. J. Bellingham.
1996.
Tucaresol increases oxygen affinity and reduces haemolysis in subjects with sickle cell anaemia.
Br. J. Haematol.
93:817-821[CrossRef][Medline].
|
| 5.
|
Ashford, R. W.,
P. Desjeux, and P. DeRaadt.
1992.
Estimation of population at risk of infection and number of cases of leishmaniasis.
Parasitol. Today
8:104-105[CrossRef][Medline].
|
| 6.
|
Avila, J. L.,
F. Biondo,
H. Monzon, and J. Convit.
1982.
Cutaneous leishmaniasis in mice: resistance to glucan immunotherapy, either alone or combined with chemotherapy.
Am. J. Trop. Med. Hyg.
31:53-59.
|
| 7.
|
Badaro, R.,
C. Nascimento,
J. S. Carvalho,
F. Badaro,
D. Russo,
J. L. Ho,
S. G. Reed,
W. D. Johnson, Jr., and T. C. Jones.
1994.
Recombinant human granulocyte-macrophage colony-stimulating factor reverses neutropenia and reduces secondary infections in visceral leishmaniasis.
J. Infect. Dis.
170:413-418[Medline].
|
| 8.
|
Barrett, M. P.,
G. H. Coombs, and J. C. Mottram.
1999.
Recent advances in identifying and validating drug targets in trypanosomes and leishmanias.
Trends Microbiol.
7:82-88[CrossRef][Medline].
|
| 9.
|
Berman, J. D.
1997.
Human leishmaniasis: clinical, diagnostic, and chemotherapeutic developments in the last 10 years.
Clin. Infect. Dis.
24:684-703[Medline].
|
| 10.
|
Berman, J. D.,
R. Badaro,
C. P. Thakur,
K. M. Wasunna,
K. Behbehani,
R. Davidson,
F. Kuzoe,
L. Pang,
K. Weerasuriya, and A. D. M. Bryceson.
1998.
Efficacy and safety of liposomal amphotericin B (AmBisome) for visceral leishmaniasis in endemic developing countries.
Bull. W. H. O.
76:25-32[Medline].
|
| 11.
|
Bhakuni, V.,
U. K. Sigha,
G. P. Dutta,
H. B. Levy, and R. K. Maheshwari.
1996.
Killing of Leishmania donovani amastigotes by poly ICLC in hamsters.
J. Interferon Cytokine Res.
16:321-325[Medline].
|
| 12.
|
Bogdan, C., and M. Rollinghoff.
1998.
The immune response to Leishmania: mechanisms of parasite control and evasion.
Int. J. Parasitol.
28:121-134[CrossRef][Medline].
|
| 13.
|
Bosma, G. C.,
R. P. Custer, and M. J. Bosma.
1983.
A severe combined immunodeficiency mutation in the mouse.
Nature
301:527-530[CrossRef][Medline].
|
| 14.
|
Buates, S., and G. Matlashewski.
1999.
Treatment of experimental leishmaniasis with the immunomodulators imiquimod and S-28463: efficacy and mode of action.
J. Infect. Dis.
179:1485-1494[CrossRef][Medline].
|
| 15.
|
Cenini, P.,
N. Berhe,
A. Hailu,
K. McGinnes, and D. Frommel.
1993.
Mononuclear cell subpopulations and cytokine levels in human visceral leishmaniasis before and after chemotherapy.
J. Infect. Dis.
168:986-994[Medline].
|
| 16.
|
Chen, H.,
S. Hall,
B. Heffernan,
N. T. Thompson,
M. V. Rogers, and J. Rhodes.
1997.
Convergence of Schiff base costimulatory signaling and TCR signaling at the level of mitogen-activated protein kinase ERK2.
J. Immunol.
159:2274-2281[Abstract/Free Full Text].
|
| 17.
|
Chen, H.,
S. Hall,
B. Zheng, and J. Rhodes.
1997.
Potentiation of the immune system by Schiff base-forming drugs.
Biodrugs
7:217-231.
|
| 18.
|
Cillari, E.,
F. Arcoleo,
M. Dieli,
R. D'Agostino,
G. Gromo,
F. Leoni, and S. Milano.
1994.
The macrophage-activating tetrapeptide tuftsin induces nitric oxide synthesis and stimulates murine macrophages to kill Leishmania parasites in vitro.
Infect. Immun.
62:2649-2652[Abstract/Free Full Text].
|
| 19.
|
Cohen, H.
1979.
Induction of delayed-type sensitivity to Leishmania parasite in a case of leishmaniasis cutanea diffusa with BCG and cord-factor (trehalose-6-6' dimycolate).
Acta Dermatovener.
59:547-549[Medline].
|
| 20.
|
Coleman, R. E.,
J. D. Edman, and L. H. Semprevivo.
1988.
Effect of cimetidine and 2'-deoxyguanosine on the development of Leishmania mexicana in BALB/c mice.
Trans. R. Soc. Trop. Med. Hyg.
82:232-233[CrossRef][Medline].
|
| 21.
|
Engwerda, C. R.,
M. L. Murphy,
S. E. Cotterell,
S. C. Smelt, and P. M. Kaye.
1998.
Neutralization of IL-12 demonstrates the existence of discrete organ-specific phases in the control of Leishmania donovani.
Eur. J. Immunol.
28:669-680[CrossRef][Medline].
|
| 22.
|
Gradoni, L.,
A. Bryceson, and P. Desjeux.
1995.
Treatment of Mediterranean visceral leishmaniasis.
Bull. W. H. O.
73:191-197[Medline].
|
| 23.
|
Grimaldi, G. F.,
P. L. Moriearty, and R. Hoff.
1980.
Leishmania mexicana in C3H mice: BCG and levamisole treatment of established infections.
Clin. Exp. Immunol.
41:237-242[Medline].
|
| 24.
|
Guru, P. Y.,
A. K. Agrawal,
U. K. Singha,
A. Singhal, and C. M. Gupta.
1989.
Drug targeting in Leishmania donovani infections using tuftsin-bearing liposomes as drug vehicles.
FEBS Lett.
245:204-208[CrossRef][Medline].
|
| 25.
|
Honore, S.,
Y. J.-F. Garin,
A. Sulahian,
J.-P. Gangneux, and F. Derouin.
1998.
Influence of the host and parasite strain in a mouse model of visceral Leishmania infantum infection.
FEMS Immunol. Med. Microbiol.
21:231-239[Medline].
|
| 26.
|
Kaye, P. M.
1995.
Costimulation and the regulation of antimicrobial immunity.
Immunol. Today
16:423-427[CrossRef][Medline].
|
| 27.
|
Kaye, P. M.,
M. Gorak,
M. Murphy, and S. Ross.
1995.
Strategies for immune intervention in visceral leishmaniasis.
Ann. Trop. Med. Parasitol.
89:75-81.
|
| 28.
|
Kiderlen, A. F., and P. M. Kaye.
1990.
A modified colorimetric assay of macrophage activation for intracellular cytotoxicity against Leishmania parasites.
J. Immunol. Methods
127:11-18[CrossRef][Medline].
|
| 29.
|
Kirkwood, J. M.,
S. Schuchter,
S. Donnelly,
L. Stover,
P. Drobins,
T. L. Whiteside,
J. P. Burnham,
C. K. Heitman, and J. M. Johnston.
1997.
A novel immunopotentiating agent, tucaresol: results from a multicenter, pilot study in patients with metastatic melanoma.
Proc. Am. Assoc. Cancer Res.
38:402.
|
| 30.
|
Murray, H. W.
1997.
Endogenous interleukin-12 regulates acquired resistance in experimental visceral leishmaniasis.
J. Infect. Dis.
175:1477-1479[Medline].
|
| 31.
|
Murray, H. W.,
J. D. Berman, and D. Wright.
1988.
Immunochemotherapy for Leishmania donovani infection: interferon plus pentavalent antimony.
J. Infect. Dis.
157:973-978[Medline].
|
| 32.
|
Murray, H. W.,
J. Hariprashad, and R. L. Coffman.
1997.
Behaviour of visceral Leishmania donovani in an experimentally induced T helper cell 2 (Th2)-associated response model.
J. Exp. Med.
185:867-874[Abstract/Free Full Text].
|
| 33.
|
Murray, H. W.,
M. J. Oca,
A. M. Granger, and R. D. Schreiber.
1989.
Requirement for T cells and effect of lymphokines in successful chemotherapy for an intracellular infection. Experimental visceral leishmaniasis.
J. Clin. Investig.
83:1253-1257.
|
| 34.
|
Nabors, G. S.,
L. C. Afonso,
J. P. Farrell, and P. Scott.
1995.
Switch from a type 2 to a type 1 T helper cell response and cure of established Leishmania major infection in mice is induced by combined therapy with interleukin 12 and Pentostam.
Proc. Natl. Acad. Sci. USA
92:3142-3146[Abstract/Free Full Text].
|
| 35.
|
Neal, R. A., and S. L. Croft.
1984.
An in-vitro system for determining the activity of compounds against the intracellular amastigote form of Leishmania donovani.
J. Antimicrob. Chemother.
14:463-475[Abstract/Free Full Text].
|
| 36.
|
Rhodes, J.,
H. Chen,
S. R. Hall,
J. E. Beesley,
D. C. Jenkins,
P. Collins, and B. Zheng.
1995.
Therapeutic potentiation of the immune system by co-stimulatory Schiff-base-forming drugs.
Nature
377:71-75[CrossRef][Medline].
|
| 37.
|
Sundar, S.,
S. G. Reed,
S. Sharma,
A. Mehrotra, and H. W. Murray.
1997.
Circulating T helper 1 (TH1) cell and TH2 cell-associated cytokines in Indian patients with visceral leishmaniasis.
Am. J. Trop. Med. Hyg.
56:522-525.
|
| 38.
|
Sundar, S.,
F. Rosenkaimer, and H. W. Murray.
1994.
Successful treatment of refractory visceral leishmaniasis in India using antimony plus interferon.
J. Infect. Dis.
170:659-662[Medline].
|
| 39.
|
Wang, C. C.
1997.
Validating targets for antiparasite chemotherapy.
Parasitology
114:S31-S44.
|
Antimicrobial Agents and Chemotherapy, June 2000, p. 1494-1498, Vol. 44, No. 6
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Copyright © 2000, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
