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Antimicrobial Agents and Chemotherapy, March 2001, p. 686-689, Vol. 45, No. 3
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.3.686-689.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Efficacy of Recombinant Gamma Interferon for
Treatment of Systemic Cryptococcosis in SCID Mice
Karl V.
Clemons,*
Jon E.
Lutz, and
David A.
Stevens
Department of Medicine, Division of Infectious
Diseases, Santa Clara Valley Medical Center, and California Institute
for Medical Research, San Jose, California 95128, and Department of
Medicine, Division of Infectious Diseases and Geographic Medicine,
Stanford University, Stanford, California 94305
Received 6 January 2000/Returned for modification 16 July
2000/Accepted 25 October 2000
 |
ABSTRACT |
We have previously shown that gamma interferon (IFN-
) is a
useful adjunct to therapy of experimental systemic cryptococcosis in
normal mice. To better emulate AIDS patients, SCID mice were infected
intravenously with Cryptococcus neoformans. Mice received no therapy, 3 mg of amphotericin B (AmB) per kg of body weight, or
105 U of IFN- alone (prophylactically and
therapeutically or only therapeutically) or with AmB. In the first
experiment, >75% of the mice survived. Therapy with AmB alone was
efficacious compared to no therapy in all organs. Both regimens of
IFN- alone were efficacious in the brain and lungs, and the
combination of AmB and IFN- showed significant synergy in the
kidneys. AmB alone cured 40% of mice of infection, whereas the
combination regimens cured >50% of the mice and 90% of the brain
infections. In a second study, IFN- again proved efficacious alone,
and when given with AmB its efficacy was improved. Therapeutic IFN-
alone was effective only in the liver compared to no therapy, and the
combination regimen, although highly effective, showed no significant
synergy. In a third experiment, AmB alone or in combination with
IFN- prolonged survival compared to no therapy or IFN- alone. The combination regimen showed significant synergy over AmB alone in the
brain, liver, kidneys, and lungs. AmB alone cured no mice of infections
in more than two organs, whereas AmB in combination with IFN- cured
55% of infections in three or more organs. These results indicate that
IFN- has therapeutic efficacy in severely immunodeficient animals,
especially in combination with AmB. Significant synergistic activity
was noted in all organs except the spleen. Overall, IFN- has utility
as an adjunctive therapy against systemic cryptococcosis in the
severely immunocompromised host.
| |
INTRODUCTION |
Cryptococcal meningitis is a fungal
disease that requires therapeutic intervention, whether it is
manifested in immunocompetent or immunocompromised patients
(18). Although currently available antifungal therapies
have been shown to be beneficial, relapses while on therapy and
mortality are not uncommon (8, 9, 12). Thus, the
improvement of therapeutic options is of prime importance in the
successful treatment of this disease. One potential therapeutic option
involves the use of cytokines as an adjunct to conventional antifungal
therapy (18, 23).
Previous studies have demonstrated that adjunctive cytokine therapy
with interleukin-12 or gamma interferon (IFN-) could improve the
outcome of experimental murine cryptococcosis (5, 7, 15, 17,
23). In addition, synergistic efficacy has been demonstrated by
the addition of either interleukin-12, an inducer of IFN-, or
IFN- to a regimen of conventional therapy (5, 15, 17).
However, these studies were done with nonimmunocompromised animals,
whereas the majority of patients with meningeal cryptococcosis are immunocompromised.
In the present study, we have examined the utility of IFN- alone or
in combination with amphotericin B (AmB) therapy against systemic
cryptococcosis established in a severely immunocompromised host,
namely, the SCID mouse. This animal has severe combined immunodeficiency with no functional B or T cells and most closely emulates the patient with AIDS (4). Our rationale
for choosing this model was to determine whether immunomodulation
with IFN- alone or as an adjunct to conventional AmB treatment would
have therapeutic efficacy in a host incapable of a normal cell-mediated or humoral immune response. Were IFN- to prove beneficial in this
system, it might provide a clinical option for the treatment of
cryptococcal meningitis in immunocompromised patient populations.
(These studies were presented in part to the 4th Congress of the
European Confederation of Medical Mycology held in Glasgow, Scotland,
in May 1998.)
| |
MATERIALS AND METHODS |
Mice.
The animals used in this experiment were 6-week-old
male C.B-17 scid/scid (SCID) mice. These mice were purchased
from Taconic, Germantown, N.Y. Mice were housed in sterile
microisolator cages and were provided sterilized chow and sterilized
water ad libitum. Strict protocols were followed in handling these mice
to reduce the possibility of animals contracting opportunistic
infections. Mice were housed five per cage. All cages were changed at
least twice weekly.
Experiment 1.
Six groups of 10 mice each were randomly
assigned to therapy groups. The groups were mice receiving no therapy,
mice receiving 100,000 U of IFN- (recombinant murine IFN-
supplied by Genentech, Inc., South San Francisco, Calif.) given
intravenously (i.v.) in 0.25 ml either therapeutically or prior to
infection and then therapeutically, and mice receiving 3.0 mg of AmB
(Pharma-Tek, Inc., Huntington, N.Y.) per kg of body weight given
intraperitoneally in 0.20 ml alone or in combination with one of the
two IFN- regimens. IFN- was administered i.v. on the basis of
prior data in our laboratory, which indicated better efficacy by this
route than by a subcutaneous route in normal animals (data not shown).
Experiments 2 and 3.
Four groups of 10 mice each were
randomly assigned to therapy groups. Mice received either no therapy,
100,000 U of IFN- (Genentech) given i.v. in 0.25 ml, or 3.0 mg of
AmB (Pharma-Tek, Inc.) per kg given intraperitoneally in 0.20 or 0.25 ml alone or in combination with the IFN- regimen.
In all three experiments, IFN- was diluted in sterile saline prior
to dosing and AmB was diluted in 5% dextrose water. Mice receiving AmB
were given six doses on an every-other-day (QOD) schedule beginning on
day 1 postinfection. Mice receiving pretreatment with IFN- were
dosed on a QOD schedule on days 7, 5, 3, and 1 prior to infection.
Therapeutic IFN- was given on a QOD schedule beginning on day 1 postinfection and continuing through day 27 of infection, for total of
14 doses of IFN-.
Infection model.
Cryptococcus neoformans strain
9759 (serotype A) was grown for the preparation of an infecting
inoculum as described previously (4, 6, 13, 14). The
numbers of yeast cells were estimated by hemacytometer count, and the
cells were serially diluted in sterile saline to the number desired for
infection. Plating onto Sabouraud's agar plus chloramphenicol was done
to determine the number of viable yeast cells in the inoculum. On day
0, all mice were infected i.v. with viable C. neoformans
given i.v. in a 0.25-ml volume (4). Mice received 2,000 yeast cells in experiment 1, 3,000 yeast cells in experiment 2, and
5,000 yeast cells in experiment 3, as determined by hemacytometer counts.
One to three days after the cessation of therapy, all surviving mice
were euthanatized by CO
2 asphyxiation. Various organs
were
removed aseptically, weighed, and homogenized in 5 ml of
saline. Organ
homogenates were serially diluted, and samples were
plated for the
determination of the number of viable
C. neoformans cells
remaining in the entire organ. The number of CFU in each
organ was
determined and expressed as the log
10 number of CFU
per
organ. All data are presented as the log
10 geometric mean
number of CFU from surviving mice. A value of 0 indicates that
the
number of CFU in the organ was below the detection limit of
the assay,
which is approximately 5 to 10 CFU per organ. Statistical
analyses of
comparative burdens of
C. neoformans recovered from
the
organs were done using a Mann-Whitney U test (GB-STAT, version
6.0;
Dynamic Microsystems, Inc., Silver Spring, Mad.), with an
arbitrary
value of log
10 7 assigned to data points missing because
of
the death of an animal due to infection. This ensures that
death is
considered a worse outcome than survival with any amount
of organism
burden. Analyses of comparative survival were done
by day of death
using a Wilcoxon rank sum
test.
| |
RESULTS |
Experiment 1.
Over the course of the 29 days of experimental
infection, 7 of 9 untreated control mice survived. The two deaths
occurred on days 21 and 29 postinfection. A single mouse succumbed to
infection on day 25 postinfection in the group receiving pretreatment
and therapeutic IFN- alone. No other mice died of infection with any
other regimen. Because of the low mortality in the untreated control
group, no survival advantage could be demonstrated for any treatment regimen.
The primary parameter used to evaluate the efficacy of IFN-
therapy
in this study was the comparative burden of
C. neoformans recovered from the organs at day 29 postinfection. The
log
10 geometric
mean burdens and the 95% confidence
intervals of these burdens
are presented in Table
1. In the brain, kidneys, and lungs, the
untreated controls had the highest mean burdens of
C. neoformans,
whereas in the livers and spleens, mice given IFN-
alone on a
pretreatment and therapeutic schedule had higher mean
burdens
than did the untreated controls. Thus, all treatment regimens
showed some efficacy in reducing the mean burden of yeast cells
in
three or more organs.
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TABLE 1.
Recovery of C. neoformans from organs of
surviving SCID mice treated with IFN- or AmB alone or in
combination in experiment 1
|
|
The significance of the apparent treatment efficacies was determined by
comparison of the burdens between treatment groups.
Therapy with AmB
alone was efficacious compared to no treatment
in all five organs in
reducing the burden of organisms. Therapy
with IFN-
alone by either
dosing schedule also proved effective.
However, this activity was
significant only in the brain and lungs
for both regimens and in the
liver for the therapeutic regimen
of IFN-
. The addition of IFN-
to the AmB regimen further increased
the efficacy of the treatment in
all organs. However, statistically
significant synergistic activity was
noted only in the
kidneys.
With respect to cure (defined as no detectable infection in the organs
assayed), only mice given a regimen which included
AmB were free of
detectable
C. neoformans in all five organs.
AmB alone
cleared the infection in 40% of the treated animals,
whereas AmB plus
therapeutic IFN-
cleared it in 50% of the mice.
Administration of
IFN-
as a pretreatment and then therapeutically
in combination with
AmB cleared 66% of the treated mice of infection.
All were free of
infection in the brain and
kidney.
Experiment 2.
Over the course of the 28 days of experimental
infection, 6 of 10 untreated control mice survived. The deaths occurred
on days 15, 17, 24, and 26 postinfection. No other mice died of
infection with any other regimen. Because of the low mortality in the
untreated control group, no survival advantage could be demonstrated
for any treatment regimen.
The mean burdens of
C. neoformans were highest in the
untreated control group and the IFN-
-treated group (Table
2). In all
organs, except the liver,
those animals given IFN-
carried higher,
but not significant, mean
burdens than did surviving mice that
had received no treatment. AmB
treatment alone was efficacious
in all five organs in reducing the
burden of organisms. Therapy
with IFN-
alone proved significantly
effective only in the liver.
The combination regimen of IFN-
and AmB
was more efficacious
than AmB alone in organs other than the brain, but
this did not
attain statistical significance.
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|
TABLE 2.
Recovery of C. neoformans from organs of
surviving SCID mice treated with IFN- or AmB alone or in
combination in experiment 2
|
|
Similar to the results of the first experiment, AmB alone cleared
infection in 20% of the treated animals, whereas AmB plus
IFN-
cleared the infection in 60% of the mice. However, by Fisher's
exact
test this comparative rate of cure was not significantly
different
(
P = 0.085).
Experiment 3.
Over the course of the 30-day experimental
infection, 2 of 10 untreated control mice survived. In comparison, 6 of
10 mice given AmB alone, 0 of 10 mice given IFN- alone, and 9 of 9 mice given the combination regimen of AmB and IFN- survived (1 mouse died of an injection-related trauma and was not included in any analysis) (Fig. 1). Statistical
comparison showed that both AmB and the combination regimen
significantly prolonged survival in comparison with no treatment or
IFN- alone (P < 0.01 to 0.001). IFN- alone did
not significantly prolong survival, nor was synergy demonstrated with
the combination regimen, i.e., IFN- plus AmB was equivalent to AmB
alone, and IFN- alone was equivalent to no treatment (P < 0.05).
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FIG. 1.
Cumulative mortality of mice infected with C. neoformans and treated with AmB or IFN- alone or in combination
in experiment 3.
|
|
The comparative burdens of
C. neoformans recovered from the
organs at day 30 postinfection are presented in Table
3. AmB
treatment alone was efficacious in
only the spleen and liver in
reducing the burden of organisms. The
addition of IFN-
to the
AmB regimen increased the efficacy of the
treatment in all organs
except the spleen (Table
3). Statistically
significant synergistic
activity was noted in the brain, liver,
kidneys, and lungs with
the AmB and IFN-
regimen.
View this table:
[in this window]
[in a new window]
|
TABLE 3.
Recovery of C. neoformans from organs of
surviving SCID mice treated with IFN- or AmB alone or in
combination in experiment 3
|
|
AmB alone cleared none of the treated animals in more than two organs,
whereas AmB plus IFN-
cleared 55% of the mice of detectable
infection in three or more organs; one mouse was free of infection
in
all five
organs.
| |
DISCUSSION |
There exists a substantial body of literature dealing with the
involvement of IFN- in host resistance to C. neoformans
(1-3, 5, 7, 10, 11, 15, 16, 19-22, 24). Both in vitro and in vivo studies have shown IFN- to play a role in host
resistance to this organism. In our previous studies, we have shown
that in immunocompetent mice the administration of IFN- in
combination with AmB, but not fluconazole, significantly improves the
host's capacity to restrict the proliferation of the organism,
especially in the brain, in a synergistic manner (17).
The question of whether IFN- would have utility in the treatment of
systemic cryptococcosis in a severely immunocompromised host has been
addressed in the present studies. We have demonstrated that IFN-
indeed shows therapeutic efficacy in severely immunodeficient animals.
Although the results from the three experiments are not in exact accord
with one another, all are indicative of IFN- having therapeutic
efficacy against systemic cryptococcosis, particularly against
meningeal infection. In each experiment, mice given the combination
regimen of IFN- and AmB carried lower mean burdens of yeast cells in
the brain, which is the main target organ in this model, than did
untreated controls. Thus, the efficacy of IFN- was demonstrated when
given alone as well as in combination with conventional AmB therapy. In
some instances, the efficacy of sole IFN- treatment was not
different from that of conventional AmB treatment.
It is important to note that the combination regimens effected complete
cures in the greatest number of animals (experiments 1 and 2) and in
the greatest number of organs (experiments 1 to 3). However, it should
be noted that the cure rates observed in these studies were very likely
influenced by the severity of the infections. In the two studies in
which few mice succumbed to infection, both AmB and IFN- alone or in
combination showed efficacy. However, in the rapidly fatal disease
established in the third experiment, fewer cures of mice or individual
organs occurred. Thus, the question of efficacy in the setting of
severe immunodeficiency with meningeal disease was best answered by the
results from the third experiment, in which significant synergistic
efficacy in prolongation of survival as well as clearing of brain
infection was observed. This increased efficacy was not limited to the
brain but was found in all other organs except the spleen. The greater severity of infection in the third experiment also reduced the apparent
efficacy of sole AmB or sole IFN- therapy and allowed for a clearer
demonstration of the increased activity of the combination regimen.
The results of this study showing efficacy of treatment by IFN-
alone are in contrast to previous data for normal mice which indicated
that IFN- given alone was unable to cause a significant reduction in
organism burden in any organ (15, 17; K. V. Clemons and D. A. Stevens, XIII Int. Soc. Human Animal Mycoses, abstr. S89, p. 63, 1997). One possible explanation for this difference likely is related
to the use in the present study of immunodeficient SCID mice, which are
known to have lower naturally occurring levels of IFN- due to T-cell
defects and thus probably respond to a larger degree to the exogenous
IFN-.
Overall, these studies are suggestive of the potential use of
immunomodulation using IFN- as an adjunctive therapy against cryptococcosis. These results provide a rationale for IFN- therapy in the immunocompromised patient.
| |
ACKNOWLEDGMENT |
These studies were funded in part by a grant from Genentech, Inc.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Division of
Infectious Diseases, Santa Clara Valley Medical Center, 751 South
Bascom Ave., San Jose, CA 95128. Phone: (408) 998-4557. Fax: (408)
998-2723. E-mail: Karl.Clemons{at}slip.net.
| |
REFERENCES |
| 1.
|
Aguirre, K.,
E. A. Havell,
G. W. Gibson, and L. L. Johnson.
1995.
Role of tumor necrosis factor and gamma interferon in acquired resistance to Cryptococcus neoformans in the central nervous system of mice.
Infect. Immun.
63:1725-1731[Abstract].
|
| 2.
|
Brummer, E.,
F. Nassar, and D. A. Stevens.
1994.
Effect of macrophage colony-stimulating factor on anticryptococcal activity of bronchoalveolar macrophages: synergy with fluconazole for killing.
Antimicrob. Agents Chemother.
38:2158-2161[Abstract/Free Full Text].
|
| 3.
|
Brummer, E., and D. A. Stevens.
1994.
Macrophage colony-stimulating factor induction of enhanced macrophage anticryptococcal activity: synergy with fluconazole for killing.
J. Infect. Dis.
170:173-179[Medline].
|
| 4.
|
Clemons, K. V.,
R. Azzi, and D. A. Stevens.
1996.
Experimental systemic cryptococcosis in SCID mice.
J. Med. Vet. Mycol.
34:331-335[Medline].
|
| 5.
|
Clemons, K. V.,
E. Brummer, and D. A. Stevens.
1994.
Cytokine treatment of central nervous system infection: efficacy of interleukin-12 alone and synergy with conventional antifungal therapy in experimental cryptococcosis.
Antimicrob. Agents Chemother.
38:460-464[Abstract/Free Full Text].
|
| 6.
|
Clemons, K. V., and D. A. Stevens.
1998.
Comparison of Fungizone, Amphotec, AmBisome, and Abelcet for treatment of systemic murine cryptococcosis.
Antimicrob. Agents Chemother.
42:899-902[Abstract/Free Full Text].
|
| 7.
|
Decken, K.,
G. Köhler,
K. Palmer-Lehmann,
A. Wunderlin,
F. Mattner,
J. Magram,
M. K. Gately, and G. Alber.
1998.
Interleukin-12 is essential for a protective Th1 response in mice infected with Cryptococcus neoformans.
Infect. Immun.
66:4994-5000[Abstract/Free Full Text].
|
| 8.
|
Denning, D. W.,
R. M. Tucker,
L. H. Hanson,
J. R. Hamilton, and D. A. Stevens.
1989.
Itraconazole therapy for cryptococcal meningitis and cryptococcosis.
Arch. Intern. Med.
149:2301-2308[Abstract/Free Full Text].
|
| 9.
|
Denning, D. W.,
R. M. Tucker,
L. H. Hanson, and D. A. Stevens.
1990.
Itraconazole in opportunistic mycoses: cryptococcosis and aspergillosis.
J. Am. Acad. Dermatol.
23:602-607[Medline].
|
| 10.
|
Harrison, T. S., and S. M. Levitz.
1996.
Role of IL-12 in peripheral blood mononuclear cell responses to fungi in persons with and without HIV infection.
J. Immunol.
156:4492-4497[Abstract].
|
| 11.
|
Hoag, K. A.,
M. F. Lipscomb,
A. A. Izzo, and N. E. Street.
1997.
IL-12 and IFN--gamma are required for initiating the protective Th1 response to pulmonary cryptococcosis in resistant C.B-17 mice.
Am. J. Respir. Cell Mol. Biol.
17:733-739[Abstract/Free Full Text].
|
| 12.
|
Hostetler, J.,
D. W. Denning, and D. A. Stevens.
1992.
US experience with itraconazole in Aspergillus, Cryptococcus and Histoplasma infections in the immunocompromised host.
Chemotherapy
38(Suppl. 1):12-22.
|
| 13.
|
Hostetler, J. S.,
K. V. Clemons,
L. H. Hanson, and D. A. Stevens.
1992.
Efficacy and safety of amphotericin B colloidal dispersion compared with those of amphotericin B deoxycholate suspension for treatment of disseminated murine cryptococcosis.
Antimicrob. Agents Chemother.
36:2656-2660[Abstract/Free Full Text].
|
| 14.
|
Hostetler, J. S.,
L. H. Hanson, and D. A. Stevens.
1993.
Effect of hydroxypropyl- -cyclodextrin on efficacy of oral itraconazole in disseminated murine cryptococcosis.
J. Antimicrob. Chemother.
32:459-463[Abstract/Free Full Text].
|
| 15.
|
Joly, V.,
L. Saint-Julien,
C. Carbon, and P. Yeni.
1994.
In vivo activity of interferon-gamma in combination with amphotericin B in the treatment of experimental cryptococcosis.
J. Infect. Dis.
170:1331-1334[Medline].
|
| 16.
|
Lipovsky, M. M.,
A. E. Juliana,
G. Gekker,
S. Hu,
A. I. M. Hoepelman, and P. K. Peterson.
1998.
Effect of cytokines on anticryptococcal activity of human microglial cells.
Clin. Diagn. Lab. Immunol.
5:410-411[Abstract].
|
| 17.
|
Lutz, J. E.,
K. V. Clemons, and D. A. Stevens.
2000.
Enhancement of antifungal chemotherapy by interferon-gamma in experimental systemic cryptococcosis.
J. Antimicrob. Chemother.
46:437-442[Abstract/Free Full Text].
|
| 18.
|
Mitchell, T. G., and J. R. Perfect.
1995.
Cryptococcosis in the era of AIDS 100 years after the discovery of Cryptococcus neoformans.
Clin. Microbiol. Rev.
8:515-548[Abstract].
|
| 19.
|
Mody, C. H.,
C. L. Tyler,
R. G. Sitrin,
C. Jackson, and G. B. Toews.
1991.
Interferon-activates rat alveolar macrophages for anticryptococcal activity.
Am. J. Respir. Cell Mol. Biol.
5:19-26.
|
| 20.
|
Nassar, F.,
E. Brummer, and D. A. Stevens.
1994.
Effect of in vivo macrophage colony-stimulating factor on fungistasis of bronchoalveolar and peritoneal macrophages against Cryptococcus neoformans.
Antimicrob. Agents Chemother.
38:2162-2164[Abstract/Free Full Text].
|
| 21.
|
Nassar, F.,
E. Brummer, and D. A. Stevens.
1995.
Macrophage colony-stimulating factor (M-CSF) induction of enhanced anticryptococcal activity in human monocyte-derived macrophages: synergy with fluconazole for killing.
Cell. Immunol.
164:113-118[CrossRef][Medline].
|
| 22.
|
Salkowski, C. A., and E. Balish.
1991.
A monoclonal antibody to gamma interferon blocks augmentation of natural killer cell activity induced during systemic cryptococcosis.
Infect. Immun.
59:486-493[Abstract/Free Full Text].
|
| 23.
|
Stevens, D. A.,
J. E. Domer,
R. B. Ashman,
R. Blackstock, and E. Brummer.
1994.
Immunomodulation in mycoses.
J. Med. Vet. Mycol.
32(Suppl. 1):253-265.
|
| 24.
|
Zhang, T.,
K. Kawakami,
M. H. Qureshi,
H. Okamura,
M. Kurimoto, and A. Saito.
1997.
Interleukin-12 (IL-12) and IL-18 synergistically induce the fungicidal activity of murine peritoneal exudate cells against Cryptococcus neoformans through production of gamma interferon by natural killer cells.
Infect. Immun.
65:3594-3599[Abstract].
|
Antimicrobial Agents and Chemotherapy, March 2001, p. 686-689, Vol. 45, No. 3
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.3.686-689.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Top
Abstract
Introduction
