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Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production but did
not result in a significant reduction in numbers of parasite or promote
more rapid healing. However, local treatment with an Ab to TGF-ß led
to both a decrease in parasite numbers and more rapid healing, despite
the fact that such treatment did not significantly alter the pattern of
IL-4 and IFN- production. Immunohistochemical studies showed
that anti-TGF-ß treatment resulted in increased nitric oxide
production within parasitized lesions. Our results suggest that TGF-ß
may play an important regulatory role during chronic stages of a
L. major infection by suppressing
macrophage production of nitric oxide and that, in the absence of
TGF-ß, even the relatively low levels of IFN- observed in mice
with dominant Th2-type responses are sufficient to activate macrophages
to destroy amastigotes within parasitized lesions. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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before or
at the time of infection with L. major will abrogate the
development of a protective Th1-type response and lead to the
development of a dominant Th2 response and enhanced susceptibility to
infection (1, 2, 3). Conversely, treatment of highly susceptible BALB/c
mice at the time of parasite inoculation with either rIL-12 or
anti- IL-4 Ab will promote the development of a dominant Th1 type
response and resistance to infection (4, 5, 6, 7). These results emphasize
the importance of IL-12 and IFN- in promoting the differentiation of
naive CD4+ cells to Th1-type effector cells and the primary
role of IL-4 in promoting Th2 cell development. In addition to IL-4,
IL-12, and IFN-, TGF-ß is also thought to influence
CD4+ T cell maturation, although contradictory effects on T
cell differentiation have been reported with various in vitro studies
showing that TGF-ß can either promote or suppress Th1 development
(8, 9, 10, 11). TGF-ß also exerts potent regulatory effects on macrophage
function, including suppression of IL-12 production (12, 13) and
IFN--induced macrophage activation including inhibition of inducible
nitric oxide synthase (iNOS)4
protein and NO production (14, 15), events critical to resolution of a
leishmanial infection. Evidence for a role of TGF-ß in suppressing
resistance to L. major infection comes from the observations
that TGF-ß-producing cells are more prominent in lesions of
susceptible BALB/c compared with resistant C57BL/6 mice and that
TGF-ß levels appear to correlate inversely with iNOS levels within
parasitized lesions (16). In addition, it has been shown that treatment
with TGF-ß clearly promotes disease in resistant C57BL/6 mice
infected with either Leishmania amazonensis or
Leishmania braziliensis while treatment of susceptible
BALB/c mice with anti-TGF-ß Ab, given throughout the first few
weeks of infection, promotes both enhanced resistance to L.
amazonensis as well as the development of a more pronounced
Th1-type response (17). Given the effects of anti-TGF-ß Ab treatment administered during the first several weeks of a L. amazonensis infection plus the observation that TGF-ß and iNOS production are inversely correlated within L. major-infected lesions, we have examined how anti-TGF-ß Ab treatment administered during chronic stages of an L. major infection influences the subsequent course of disease and the immune response. We have utilized L. major infection in CB6F1 mice as our model system since this mouse strain exhibits intermediate susceptibility to infection compared with the BALB/c and C57BL/6 parental strains (18, 19). Following inoculation of L. major promastigotes, CB6F1 initially develop a Th2-dominant response, but this Th2 response eventually switches to a Th1-type response and the mice are able to resolve their infection (19). In this report, we show that in vivo neutralization of TGF-ß in CB6F1 mice at a time of infection when Th2-type responses are still dominant can lead to a rapid decrease in lesion size and in numbers of parasites within infected lesions without significantly altering the phenotype of the subsequent immune response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female (BALB/c x C57BL/6)F1 (CB6F1) mice were purchased from The Jackson Laboratory (Bar Harbor, ME) and were 5–7 wk of age at the time of infection. L. major (WHO MHOM/IL/80/Friedlin) was maintained in Grace’s insect cell culture medium (Life Technologies, Grand Island, NY) containing 20% FBS, 2 mM L-glutamine, 100 mg of streptomycin, and 100 units of penicillin G-potassium per ml. Metacyclic promastigotes were selected from stationary-phase cultures with Arachis hypogaea agglutinin as previously described (20). Soluble leishmanial Ag (SLA) was prepared from promastigotes as previously described (21).
Infections and treatment protocols
Mice were inoculated into one hind footpad with 5 x 105 metacyclic promastigotes. Lesion size was measured with a dial caliper (L. S. Starrett, Athol, MA) and expressed as the difference in thickness between the infected and the uninfected contralateral footpad. Parasites were enumerated by a limiting dilution assay as previously described in which homogenates of infected lesions were serially diluted in Grace’s insect culture medium (Life Technologies) and observed 5–7 days later for growth of promastigotes (22). Parasite numbers are expressed as the negative log10 dilution at which promastigote growth was observed. At 1 mo of infection, groups of mice were treated with recombinant TGF-ß2 or with anti-TGF-ß Ab administered alone or in combination with rIL-12 delivered directly into the parasitized footpad. Control mice were treated with PBS or normal mouse IgG.
Reagents
Monoclonal mouse anti-TGF-ß Ab 11D11.16 specific for TGF-ß1, -ß2, and -ß3 was kindly provided by Genzyme (Cambridge, MA). Recombinant human TGF-ß2 was kindly provided by Celtrix Pharmaceuticals (Santa Clara, CA). Recombinant murine IL-12 was a gift from Genetics Institute (Cambridge, MA).
Cell culture and ELISAs
Single cell suspensions of popliteal lymph nodes draining sites
of footpad infection were cultured at 5 x 106
cells/ml in DMEM containing 10% FBS, 2 mM glutamine, and 5 x
10-5 M 2-ME in the presence of 50 µg/ml L.
major Ag (SLA). Supernatants were collected at 72 h and
assayed for IFN- and IL-4 by ELISA as previously described.
Recombinant murine IFN- and murine IL-4 used as standards
were generously provided by Genentech (South San Francisco, CA)
and DNAX (Palo Alto, CA), respectively.
NADPH diaphorase staining
For detection of NADPH diaphorase activity, 6.0 µm cryostat sections of infected footpad lesions were fixed in acetone. The tissue sections were then incubated at 37°C for 30 min in 50 mM Tris chloride (pH 8.0), 0.2% Triton X-100, 0.5 mM nitroblue tetrazolium salt, and 1 mM ß-NADPH as previously described (23). Diaphorase activity was assessed by microscopic visualization of purple formazan in tissue sections.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Starting at wk 4 of infection with L. major, CB6F1 mice
were treated every 3 days with recombinant human TGF-ß2 for a period
of 3 wk. The TGF-ß (50 ng/injection) was inoculated directly into
parasitized footpads. Control mice were injected with an equal volume
of PBS. As can be seen in Fig. 1
A, mice treated with TGF-ß2
developed significantly larger lesions than did control mice inoculated
with PBS. When lesion parasite numbers were determined at wk 9 of
infection, TGF-ß2-treated mice were found to harbor
approximately 104 more parasites than control mice (Fig. 1B).
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following stimulation with parasite Ag. IFN- production by lymph
node cells at 9 wk of infection was not altered by TGF-ß2 treatment;
however, cells from TGF-ß2-treated mice produced approximately
twofold more IL-4 than did cells from control mice (Fig. 2).
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We have previously shown that CB6F1 mice develop L.
major infections that are intermediate in severity compared with
those in the BALB/c and C57BL/6 parental strains. Although predominant
Th2-type responses are observed during the early weeks of infection,
CB6F1 mice will eventually develop Th1-dominant responses and resolve
their infections. At 4 wk of infection, the time point chosen in this
study for initiation of immunotherapy, mRNA transcripts for IFN-,
IL-4, IL-10, and TGF-ß are all elevated within parasitized lesions of
CB6F1 mice (19). Mice were treated intralesionally on days 28 and 31 of
infection with anti-TGF-ß Ab alone (80 µg/injection), IL-12
alone (200 ng/injection), or a combination of anti-TGF-ß Ab plus
IL-12. IL-12 treatment alone had little demonstrable effect on lesion
progression (Fig. 3A). In
contrast, anti-TGF-ß Ab treatment, administered both alone or in
combination with IL-12, led to a reduction in lesion size compared with
that in control mice (Fig. 3A). Lesion parasite numbers at
10 wk of infection were similarly reduced in mice treated with IL-12
plus anti-TGF-ß Ab or anti-TGF-ß Ab alone, compared with
those in the control and IL-12-treated groups (Fig. 3B).
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, cells from
anti-TGF-ß-treated mice produced similar amounts of IFN- and
only slightly less IL-4 than cells from control mice, despite the fact
that anti-TGF-ß promoted a marked reduction in lesion size and
parasite numbers. In contrast, cells from mice treated with either
IL-12 alone, or a combination of IL-12 and anti-TGF-ß Ab,
produced increased amounts of IFN-, compared with cells from control
mice, although only the later treatment resulted in a significant
decrease in lesion size and parasite numbers. Although IFN-
production by cells from mice treated with IL-12 plus anti-TGF-ß
Ab was significantly enhanced compared with the levels observed in
control mice, cells from the treated mice still produced significant
amounts of IL-4, suggesting that decreased levels of infection were not
accompanied by a significant switch from a Th2- to a Th1-dominant
immune response.
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production by cells from chronically infected CB6F1 mice
Although in vivo treatment with anti-TGF-ß Ab alone did not
induce an increase in IFN- production in infected mice, it is
possible that the site of Ab inoculation (intralesional) was unable to
dramatically influence the in vivo response within draining lymph
nodes. Therefore, we tested whether in vitro neutralization of TGF-ß,
in the presence or absence of IL-12, would enhance IFN- production
by cells from infected mice. Lymph node cells from mice infected for 4
wk were stimulated with parasite Ag plus anti-TGF-ß (20 µg/ml)
Ab and/or IL-12 (2 ng/ml), and culture supernatants were collected at
72 h and assayed for IFN- by ELISA. Although IL-12, in the
presence or absence of anti-TGF-ß Ab, induced a significant
increase in IFN- production, anti-TGF-ß Ab alone had no
demonstrable effect on IFN- levels (Fig. 5).
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Since anti-TGF-ß Ab treatment appeared to promote more rapid
healing of an L. major infection without inducing a
significant increase in IFN- production, we next examined whether
this treatment had any immediate effects on lesion parasite numbers.
Groups of mice were treated as above and sacrificed 5 days after the
last injection of IL-12 and/or anti-TGF-ß Ab for analysis of
lesion parasite numbers. As can be seen in Fig. 6, mice inoculated with anti-TGF-ß
Ab, alone or in combination with IL-12, harbored about 104
fewer lesion parasites than controls on day 5 after treatment. Mice
treated with IL-12 alone did not exhibit a similar decrease in parasite
numbers. The decrease in parasite levels in the
anti-TGF-ß-treated group appeared to be independent of any change
in the pattern of IFN- or IL-4 production by draining lymph node
cells assayed at the same time point (Fig. 7). IL-12 treatment promoted a marked
increase in IFN- production by draining lymph node cells; however,
lesion parasite numbers were not significantly reduced unless IL-12 was
combined with anti-TGF-ß Ab treatment. Increased NO production by
lymph node cells was noted in all treatment groups (Fig. 7), but these
increased NO levels did not directly correlate with decreased infection
levels within parasitized lesions.
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Since in vivo inoculation of anti-TGF-ß Ab resulted in a
dramatic decrease in numbers of lesion parasites within 5 days of
treatment without altering the production of either IFN- or IL-4, it
is likely that neutralization of TGF-ß directly influenced
microbicidal function of lesion macrophages, especially since TGF-ß
has been shown to down-regulate NO production by reducing iNOS message
stability and mRNA translation. Since NADPH diaphorase has been shown
to be a NOS (23) and since iNOS activity within L.
major-parasitized lesions has been shown to match NADPH diaphorase
activity (16), we utilized histochemistry to assess the capacity of
iNOS to convert tetrazolium salts and NADPH to insoluble formazan. The
results in Fig. 8 demonstrate that only
low levels of iNOS activity are demonstrable in tissue sections of
lesions from control CB6F1 mice infected for 4 wk with L.
major. Histochemistry was also performed on lesion sections from
mice treated 2 days previously with anti-TGF-ß Ab and/or IL-12.
Treatment with IL-12 alone induced a moderate increase in lesion iNOS
activity (Fig. 8B), but even more iNOS activity was
demonstrable in lesion sections from mice treated with anti-TGF-ß
Ab (Fig. 8C). The highest levels of iNOS were detected in
lesion sections from mice treated with a combination of
anti-TGF-ß Ab and IL-12 (Fig. 8D). Direct staining of
lesion tissue sections for iNOS protein confirmed the results noted for
detection of NADPH diaphorase activity (results not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production and reduced IL-4 production, suggesting that
anti-TGF-ß Ab treatment promoted the development of a dominant
Th1-type response (34).
In this report, we extend previous studies of the role of TGF-ß in
regulating immunity to cutaneous leishmaniasis by showing that
treatment with TGF-ß aggravates an existing L. major
infection while in vivo neutralization of TGF-ß activity in
chronically infected mice will promote more rapid healing, even in the
absence of a dominant Th1-type immune response. The mouse strain used
in this study is the CB6F1, which is intermediate in susceptibility
compared with the highly susceptible BALB/c and resistant C57BL/6
parental strains (18). CB6F1 mice develop larger lesions than do
C57BL/6 mice and, at the parasite dose used in this study, often take
two to four times longer to resolve their infections than do the
C57BL/6 parental strain (19). During the early weeks of an L.
major infection, cells from CB6F1 mice produce high levels of IL-4
and only moderate levels of IFN- and generally exhibit a
Th2-dominant response, although this pattern of cytokine production is
reversed when infections eventually begin to resolve (19). We have also
previously noted that mRNA transcripts for IFN-, IL-4, IL-10, and
TGF-ß are all elevated within lesions of infected CB6F1 mice at wk 4
of infection (19). It is not surprising that treatment of mice with
TGF-ß at this time period promotes increased levels of infection
since similar results have been previously described for L.
amazonensis- and L. braziliensis-infected mice.
Analysis of cytokine production several weeks after TGF-ß treatment
revealed an increase in IL-4, but not IFN-, production. Although it
is possible that, in this experimental system, in vivo TGF-ß
treatment preferentially promotes the production of Th 2-type
cytokines, it is just as likely that the elevated levels of IL-4 seen
in these mice is simply an exaggeration of the existing Th2-type
response due to increased antigenic stimulation resulting from the
higher infection levels in the TGF-ß-treated animals.
In contrast to the effects noted following the injection of TGF-ß,
treatment with anti-TGF-ß Ab, either alone or in combination with
IL-12, promoted more rapid healing in chronically infected mice while
treatment with IL-12 alone had only a marginal effect on the course of
disease. The decrease in lesion size in healing
anti-TGF-ß-treated mice was accompanied by a similar decrease in
parasite numbers within infected lesions. These effects were extremely
rapid as evidenced by a 4 log decrease in lesion parasites by 5 days
posttreatment. Curiously, the more rapid pattern of lesion healing in
anti-TGF-ß-treated mice was not paralleled by a shift in cytokine
production indicative of a switch to a more dominant Th1-type response.
Analysis of lesion mRNA by RT-PCR did show that anti-TGF-ß
treatment led to a 50% decrease in IL-4 message, but transcript levels
for IFN-, IL-10, IL-12 p40, and iNOS were not demonstrably altered
(data not shown). We were also unable to detect any alteration in
either IL-4 or IFN- production within local draining lymph nodes in
anti-TGF-ß-treated mice, nor were we able to detect increased
IFN- production by lymph node cells following in vitro stimulation
with leishmanial Ag in the presence of neutralizing anti-TGF-ß
Ab. Our results (failure to observe enhanced IFN- production
following in vitro neutralization of TGF-ß) differ from those of a
previous study that showed that such treatment enhanced IFN- levels
in cultures of cells from BALB/c mice infected for 2 days with L.
major (3). However, in that study, it is likely that NK cells were
the source of IFN- production, whereas T cells are a more likely
source of IFN- production in mice at wk 4 of infection.
Since NO appears to be the primary molecule associated with the killing of leishmanial amastigotes (35, 36, 37, 38), it was somewhat surprising that anti-TGF-ß therapy did not lead to an increase in iNOS transcripts within parasitized lesions, especially since such treatment led to a marked decrease in parasite numbers. However, TGF-ß has been shown to suppress NO production by macrophages primarily by altering iNOS mRNA stability and iNOS translation so message level may not be a reliable indicator of functional NO activity (15). We did note a twofold increase in NO production by lymph node cells from anti-TGF-ß-treated mice, suggesting that the treatment may have enhanced macrophage microbicidal function. When lesions were examined histologically, we also noted an increase in NADPH daphorase activity, indicative of in increase in functional iNOS by 48 h after anti-TGF-ß treatment. These results strongly suggest that inhibition of TGF-ß within lesions could directly lead to increased NO production and a decrease in parasite numbers. NADPH daphorase activity also appeared to be increased in lesions of IL-12-treated mice, although not to the extent noted in the anti-TGF-ß treated group. It is unclear why NO production appeared to increase yet parasite numbers were not significantly reduced following IL-12 treatment. A possible explanation is that treatment with recombinant IL-12 resulted in only a transient increase in NO production while treatment with Ab to TGF-ß produced a more sustained effect. Whatever the case, our results do suggest that TGF-ß plays a dominant role in regulating resistance to L. major during chronic stages of infection in CB6F1 mice, probably by suppressing NO production within parasitized lesions. In addition, our data show that in vivo neutralization of TGF-ß can alter the local environment within a parasitized lesion to support parasite killing, even in the presence of a dominant Th2-type response.
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Acknowledgments |
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Footnotes |
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2 Present Address: Department of Immunology, Centocor, Inc., 200 Great Valley Parkway, Malvern, PA 19355.
3 Address correspondence and reprint requests to Dr. Jay P. Farrell, Department of Pathobiology, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104.
4 Abbreviations used in this paper: iNOS, inducible nitric oxide synthase; NO, nitric oxide; SLA, soluble leishmanial Ag; NADPH, nicotinamide adenine dinucleotide phosphate.
Received for publication June 3, 1998. Accepted for publication October 6, 1998.
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 H. Hochrein, M. O'Keeffe, T. Luft, S. Vandenabeele, R. J. Grumont, E. Maraskovsky, and K. Shortman Interleukin (Il)-4 Is a Major Regulatory Cytokine Governing Bioactive IL-12 Production by Mouse and Human Dendritic Cells J. Exp. Med., September 18, 2000; 192(6): 823 - 834. [Abstract] [Full Text] [PDF]
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 N. A. Gomes, V. Barreto-de-Souza, and G. A. DosReis Early in vitro priming of distinct Th cell subsets determines polarized growth of visceralizing Leishmania in macrophages Int. Immunol., September 1, 2000; 12(9): 1227 - 1233. [Abstract] [Full Text] [PDF]
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D. E. Jones, L. U. Buxbaum, and P. Scott IL-4-Independent Inhibition of IL-12 Responsiveness During Leishmania amazonensis Infection J. Immunol., July 1, 2000; 165(1): 364 - 372. [Abstract] [Full Text] [PDF]
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C. D. Mills, K. Kincaid, J. M. Alt, M. J. Heilman, and A. M. Hill M-1/M-2 Macrophages and the Th1/Th2 Paradigm J. Immunol., June 15, 2000; 164(12): 6166 - 6173. [Abstract] [Full Text] [PDF]
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M. A. Marovich, M. A. McDowell, E. K. Thomas, and T. B. Nutman IL-12p70 Production by Leishmania major-Harboring Human Dendritic Cells Is a CD40/CD40 Ligand-Dependent Process J. Immunol., June 1, 2000; 164(11): 5858 - 5865. [Abstract] [Full Text] [PDF]
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N. A. Gomes, C. R. Gattass, V. Barreto-de-Souza, M. E. Wilson, and G. A. DosReis TGF-{beta} Mediates CTLA-4 Suppression of Cellular Immunity in Murine Kalaazar J. Immunol., February 15, 2000; 164(4): 2001 - 2008. [Abstract] [Full Text] [PDF]
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