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*
Laboratory of Immunology and
Laboratory of Retinal Cell and Molecular Biology, the National Eye Institute, and the
Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, National Institutes of Health, Bethesda, MD 20892
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-deficient mice, EAU develops in the
context of an effector response having Th2-like elements, and
administration of IL-12 to mice immunized for EAU induction can be
protective. We, therefore, investigated whether endogenous IL-12 is
required for development of EAU. IL-12 p40-deficient mice (12KO) were
resistant to EAU induced with the uveitogenic retinal Ag
interphotoreceptor retinoid binding protein (IRBP). Delayed
hypersensitivity to IRBP was marginally reduced, whereas Ag-specific
proliferation was enhanced. Primed lymphocytes of wild-type (wt) mice,
cultured with IRBP, produced a Th1-like cytokine profile and
transferred EAU to syngeneic wt recipients. Interestingly, the same
cells were inefficient in transferring EAU to 12KO recipients, unless
IL-12 was included in the culture. Primed cells of the 12KO mice
produced a Th2-like cytokine profile and failed to transfer EAU.
However, when IL-12 was added to the culture, 12KO cells produced large
amounts of IFN- and transferred EAU to naive 12KO recipients. We
conclude that resistance to EAU of 12KO mice is not due to an inherent
inability of these mice to develop ocular disease. Despite an apparent
similarity in Ag-specific cytokine responses to IFN--deficient mice,
12KO mice have inhibited generation of uveitogenic effector cells, a
situation that can be reversed even after priming, by adding exogenous
IL-12 ex vivo. Lastly, the diminished ability of primed wt lymphocytes
to induce EAU in 12KO mice indicates a role for endogenous IL-12 in the
efferent phase of disease expression that is distinct from its role
during Ag priming. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-12 is a heterodimeric protein composed of two disulfide-linked
subunits of 40 kDa (p40) and 35 kDa (p35) (5, 6). APCs secrete IL-12 in
response to engagement of the MHC class II and CD40 molecules (7, 8).
Following secretion, IL-12 induces the release of IFN- from NK cells
and T cells and augments cell-mediated immune responses in vitro and in
vivo (9, 10, 11, 12, 13, 14). IL-12 also regulates Th cell-dependent immune responses
by priming T cells for high IFN- production and inducing them to
differentiate toward the Th1 pathway (15, 16, 17, 18, 19).
Previous results from our laboratory suggest that the pathogenesis of
EAU is associated with a Th1 response. Pathogenic, but not
nonpathogenic, T cell populations produce large amounts of IFN-, and
susceptible strains of rodents mount a Th1-dominated response to the
uveitogen, whereas resistant strains do not (20, 21). However, in
apparent contradiction to these findings, mice deficient in IFN- are
susceptible to EAU and develop the disease in the context of a deviant
effector response containing elements of a Th2 response profile (22).
Furthermore, administration of IL-12 to EAU-susceptible mice immunized
for disease induction aborts development of
disease3 (23). We therefore
wished to investigate whether endogenous IL-12 production was in fact
required for the development of the pathogenic effector cells and
expression of disease.
Recently, an IL-12-deficient mouse (12KO) with a disruption at the p40 locus was developed and characterized (24, 25). These mice develop a normal immune system but have impaired Th1 responses (26). These mice were therefore used to study the need for IL-12 and for a Th1 response in the development of EAU. The present data show that IL-12-deficient mice were unable to develop EAU after immunization with a maximal disease-inducing regimen, and their Ag-specific responses to the uveitogenic Ag were Th2-like. However, they were able to develop EAU when infused with their own primed cells that had been incubated with Ag in the presence of IL-12. We therefore conclude that the resistance of 12KO mice to EAU involves an inability to develop a pathogenic Th1 response to the uveitogen and that endogenous IL-12 is required for pathogenesis of EAU.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 female mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Mice with a targeted disruption of the IL-12, p40 gene (12KO) were developed, screened, and back-crossed for five generations onto the C57BL/6 background. Breeding stock as well as mice for some of the experiments were obtained from Jeanne Magram of Hoffman LaRoche (Nutley, NJ). All animals were housed under conventional conditions, were given water and chow ad libitum, and were used at 1.5 to 6 mo of age. The use of the animals conformed to institutional and National Institutes of Health guidelines.
Reagents
Interphotoreceptor retinoid-binding protein (IRBP) was isolated
from bovine retinas by Con A-Sepharose affinity chromatography and fast
performance liquid chromatography, as described previously (27). BSA,
-methyl-D-mannopyranoside (-MMP), Con A,
pertussis toxin (PTX), CFA, and conalbumin were purchased from Sigma
(St. Louis, MO). Horseradish peroxidase (HRPO)-streptavidin was
purchased from Southern Biotechnology Associates (Birmingham, AL).
Mycobacterium tuberculosis strain H37RA was purchased from
Difco (Detroit, MI). Ab pairs for ELISA were purchased from PharMingen
(La Jolla, CA) and Southern Biotechnology Associates. Murine TNF-
ELISA detection kits were purchased from Endogen (Cambridge, MA).
Purified murine recombinant IL-12 was generously provided by M. K.
Gately of Hoffman LaRoche (Nutley, NJ).
Immunization and IL-12 administration
Wild-type C57BL/6 mice were immunized s.c. in the thighs and base of tail with 100 µg IRBP in 0.2 ml emulsion 1:1 v/v with CFA containing 2.5 mg/ml M. tuberculosis and were simultaneously injected i.p. with 1 µg PTX in 0.1 ml as an additional adjuvant. In experiments with 12KO mice, the concentrations of IRBP and PTX were doubled (200 µg and 2 µg respectively) to achieve the maximum disease-inducing conditions. Reconstitution of 12KO mice with IL-12 was done in two ways: 1) During the priming phase, actively immunized 12KO mice were given daily injections of IL-12, at the specified doses. 2) During the expression phase, 12KO mice that were adoptively transferred with cultured lymph node cells from IRBP-primed wt donors were given daily injections of IL-12, as specified.
Histopathology and EAU grading
Whole eyes were collected and prepared for histopathologic evaluation on day 21 at the termination of an experiment. The eyes were immersed for 1 h in 4% phosphate-buffered glutaraldehyde and then transferred into 10% phosphate-buffered formaldehyde until processing. Fixed and dehydrated ocular tissue was embedded in methacrylate, and 4- to 6-µm sections were cut through the pupillary-optic nerve plane. Sections were stained by hematoxylin and eosin. An ocular pathologist evaluated the presence or absence of disease in a masked fashion after examining six sections cut at different levels for each eye. Severity of EAU for each eye was scored on a scale of 0 (no disease) to 4 (maximum disease) in half-point increments, according to a semiquantitative system described previously (28). Briefly, the minimal criterion to score an eye as positive by histopathology was inflammatory cell infiltration of the ciliary body, choroid, or retina (EAU grade 0.5). Progressively higher grades were assigned for presence of discrete lesions in the tissue, such as vasculitis, granuloma formation, retinal folding and/or detachment, photoreceptor damage, etc. The grading system takes into account lesion type, size, and number.
Delayed hypersensitivity
Two days before the termination of an experiment, mice received 10 µg of IRBP in 10 µl intradermally into the pinna of one ear. The other ear was injected similarly but with PBS. Ear swelling was measured at the termination of the experiment 48 h later with a spring loaded micrometer. Delayed hypersensitivity results are expressed as Ag-specific swelling, calculated as the difference between the thickness of the IRBP-injected ear and the PBS-injected ear.
Lymphocyte proliferation
Draining lymph nodes (inguinals and iliacs) were collected at
the termination of an experiment and pooled within each group.
Triplicate cultures of 5 x 105 cells/0.2 ml/well
were stimulated with 30 µg/ml IRBP in 96-well flat-bottom plates in
RPMI 1640 containing 1% naive mouse serum and 20 mg/ml -MMP. The
cultures were incubated for 60 h and were pulsed with
[3H]thymidine (1.0 µCi/10 µl/well) for the last
18 h. The data are shown as Ag-specific stimulation index (SI),
calculated as mean cpm in cultures stimulated with IRBP divided by mean
counts in control cultures with no stimulus.
Determination of lymphokine production in lymphocyte culture supernatants
Draining lymph node cells and spleens were removed at the
termination of an experiment and pooled within each group. The cells
were cultured in 96-well flat-bottom plates (1 x
106 cells/0.2 ml/well) with 50 µg/ml of IRBP in RPMI
1640 medium containing 1% fresh-frozen syngeneic mouse serum and 20
mg/ml -MMP (to neutralize possible traces of Con A, which is used
during the purification of IRBP). Supernatants were collected for
cytokine production analysis after 48 h. IFN-, IL-4, IL-5,
IL-6, and IL-10 were measured by ELISA using Ab pairs from PharMingen,
as described previously (29). The murine cytokine ELISA detection kits
from Endogen were used to measure TNF- in all experiments.
Measurement of Ag-specific IgG isotypes
Serum levels of anti-IRBP IgG2a and IgG1 subclasses were determined by ELISA, as described previously for another Ag (30). Briefly, 96-well microtiter plates (Costar, Cambridge, MA) were coated with IRBP (1 µg/ml). After blocking the plates with BSA and an overnight incubation with serum samples, the plates were developed using horseradish peroxidase-conjugated goat anti-IgG subclass-specific Abs (Southern Biotechnology Associates). The concentration of anti-IRBP Ab was estimated using standard curves constructed by coating wells with anti-Ig Ab and by adding polyclonal Ig standards of the pertinent isotype.
Adoptive transfer of EAU
Donor mice were immunized with a uveitogenic regimen of IRBP (12KO donors with 200 µg IRBP + 2 µg PTX; wt donors with 100 µg IRBP + 1 µg PTX). Lymph node cells and spleen cells collected on day 14 after immunization were pooled within the respective groups. The cell suspension was adjusted to 107 cells/ml in RPMI 1640 medium supplemented as for the proliferation assay, and the cultures were stimulated for 72 h with 30 µg/ml of IRBP in the presence or absence of 50 ng/ml of IL-12, in 75cm2 flasks. To remove excess adherent cells (macrophages), the stimulating cultures were transferred into new flasks after 24 h and again after 48 h. After 3 days, the lymphocytes were separated from erythrocytes and debris by discontinuous density gradient centrifugation on Ficoll and counted. Each recipient mouse was injected i.p. with 40 x 106 cells. Eyes were collected from the recipients after 10 days and were evaluated for EAU by histopathology.
Reproducibility and statistical analysis
Experiments were repeated at least twice, and usually three or more times. Statistical analysis of EAU scores was by Snedecor and Cochran’s test for linear trend proportions (nonparametric, frequency based) (31). Each mouse (average of both eyes) was treated as one statistical event. Delayed hypersensitivity scores were analyzed by independent t test. Probability values of p < 0.05 were considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To examine whether endogenous IL-12 production is required to
induce EAU, 12KO and C57BL/6 mice were immunized with 200 µg and 100
µg IRBP, respectively, as described in Materials and
Methods. In four separate experiments, 12KO mice were highly
resistant to EAU compared with wt C57BL/6 mice (Fig. 1
). None of the eleven 12KO mice (0%)
developed disease, whereas 15 of 19 C57BL/6 controls (79%) developed
EAU, with a mean score of 1.1 ± 0.2. The incidence and severity
of EAU in the controls was typical of the C57BL/6 strain, which is
moderately susceptible to EAU (32).
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production by primed lymph node cells of the treated mice (data not
shown). Cellular responses of IL-12-deficient mice
At the termination of each experiment, 48-h DTH responses were
measured, and IRBP-specific proliferation of lymph node cultures was
assayed, as described in Materials and Methods. The DTH
responses of 12KO mice were only marginally reduced compared with
controls, and the difference between the groups did not achieve
statistical significance (p < 0.11) (Fig. 2). In contrast, in four separate
experiments, the IRBP-specific proliferation of 12KO lymph node cells
in culture was consistently elevated compared with wt controls (Fig. 3).
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Draining lymph node cells and spleen cells were pooled within each
group and were stimulated in culture with IRBP. Supernatants were
assayed for cytokine content by ELISA as described in Materials
and Methods. Lymph node cultures from 12KO mice showed increased
production of IL-5 and IL-10, and decreased production of IFN-
compared with those from controls (Fig. 4). IL-4 was secreted minimally by both
groups. The same cytokine production pattern was observed in splenic
cultures (Fig. 5). TNF- and IL-6 were
also detected, but there was little difference observed between the two
groups of mice (data not shown).
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Serum was collected from individual mice at the termination of an
experiment and was analyzed for IRBP-specific Ab production as
described in Materials and Methods. IgG2a and IgG1 isotypes
were measured. Ag-specific IgG isotype production did not differ
significantly between 12KO mice and C57BL/6 controls. Contrary to
expectations, (IFN--dependent) IgG2a isotype Abs were not reduced.
If anything, there appeared to be a slight increase in IgG2a production
in the IRBP-immunized 12KO mice compared with wt (Fig. 6).
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As mentioned above, attempts to reconstitute the ability of
IRBP-immunized 12KO mice to develop disease through administration of
exogenous IL-12 were largely ineffective. Therefore, it was necessary
to address the question whether disruption of the IL-12 gene might have
rendered the 12KO inherently unable to develop EAU. Primed lymph node
cells were isolated from wt mice 2 wk after immunization, were
stimulated with Ag in culture, and were infused into naive 12KO or wt
recipients. While stimulated lymph node cells of wt mice transferred
EAU efficiently to wt recipients, they were extremely poor at
transferring EAU to 12KO recipients (Fig. 7a). Addition of IL-12
to the culture up-regulated IFN- production by the wt cells
approximately sevenfold (from 48 to 346 ng/ml, as measured in 48-h
supernatants) and strongly enhanced their ability to transfer EAU to
12KO recipients (p < 0.004) (Fig. 7b). Interestingly, reconstitution of the 12KO
recipients with 5 ng of IL-12 per day appeared to have the same effect
on their ability to develop EAU as culturing the transferred cells with
IL-12 (Fig. 7c). This was in contrast to the
inefficiency of reconstitution by IL-12 administered to actively
immunized 12KO mice (that would have to generate their own effector T
cells to express disease).
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when cultured with exogenous
IL-12
We next wanted to address the question whether primed lymphocytes
of 12KO mice are able to become uveitogenic effectors if the missing
IL-12 is supplied to them exogenously. Draining lymph node cells of
12KO mice were collected 2 wk after immunization, were stimulated with
Ag in culture in the presence, or in the absence, of exogenous IL-12,
and were infused into naive 12KO recipients. While primed 12KO lymph
node cells cultured without IL-12 were completely unable to transfer
EAU, the cells cultured in the presence of IL12 induced EAU in the 12KO
recipients. The culture with IL-12 converted the cytokine profile of
the 12KO cells from IFN--low to IFN--high, apparently without
affecting the IL-5 production (Fig. 8).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production is inhibited and the
Ag-specific response deviates toward a nonpathogenic Th2-like
phenotype. Nevertheless, the humoral responses of 12KO mice appeared to
be relatively unaffected.
IRBP-specific proliferative responses were not only present, but were
in fact elevated, in 12KO mice, indicating that inadequate Ag priming
was not the mechanism of EAU resistance. The cytokine profile that
these cells produced, however, differed markedly from the wt (see
ahead). It is likely that decreased IFN- production in these
cultures contributed to the observed increase in proliferation, because
IFN- has been shown to exert anti-proliferative effects in
vitro, and is in line with our previous data showing that
IFN--deficient mice also had enhanced proliferative responses (22).
Our findings are in agreement with Magram et al. (25), who showed that
12KO mice develop a reduced Ag-specific DTH response; however, in our
hands the reduction was marginal compared with wt animals. This is in
contrast to findings by Mattner et al., where 12KO mice did not mount a
DTH response to Leishmania Ag (26). The discrepancy implies
that factors in addition to the ability to produce IL-12, such as
nature of the Ag, levels of endogenous IFN- production (reduced, but
not absent, in 12KO mice), and other genetic factors affect the
development of cellular immune responses in these mice.
EAU-resistant 12KO mice produced anti-IRBP Ab responses of similar
magnitude and isotype composition to wt. This was unexpected, because
the reduced IFN- response of these mice should have resulted in
lowered Ag-specific IgG2a. The reason for this is unclear and could be
influenced by factors such as mouse strain and the nature of the Ag.
Our results differ from those of McIntyre et al. in collagen-induced
arthritis in 12KO DBA1 mice. These investigators reported decreased
titers of anti-collagen type II serum Abs of both IgG2a and IgG1
isotypes in the 12KO mice that paralleled a reduction (but not
abrogation) of joint inflammation (33). Pathogenesis of
collagen-induced arthritis is known to be highly dependent on Abs
(34, 35, 36, 37). Our data thus support the notion that Abs play a minimal role
in EAU and indicate that in the absence of a pathogenic cellular
response, serum Abs by themselves are insufficient to induce
pathology.
IRBP-specific cytokine production was dramatically altered in immunized
12KO mice. The C57BL/6 strain characteristically produces high levels
of IFN- in response to IRBP and little or no IL-4, which is typical
of a dominant Th1 responder to the uveitogen (38). In the
IL-12-deficient mouse, lymph node and splenic cultures produced
elevated levels of IL-5 and IL-10, and some IL-4 was detectable in the
spleen. IFN- was reduced up to 10-fold in lymph node cultures and up
to 100-fold in the spleen. Our observations thus confirm findings from
previous studies that, in the absence of endogenous IL-12, the immune
response deviates toward the Th2 pathway (26).
Because it proved difficult to reconstitute the ability of actively
immunized 12KO mice to develop EAU by administering replacement doses
of exogenous IL-12, the question arose whether these mice were able to
develop disease under any circumstances. To address this issue, 12KO
mice were infused with cultured lymph node cells from wt mice primed
with IRBP. These cultures contained Th1-like effector cells, as judged
by the fact that they produced IFN- in response to IRBP and were
capable of adoptively transferring EAU to naive wt recipients.
Interestingly, the same cells were able to induce only marginal EAU in
12KO recipients. However, adding IL-12 to the culture resulted in a
more potent effector population that not only produced sevenfold more
IFN- but also was able to induce full-blown EAU in 100% of 12KO
recipients. Restoration of the ability to develop EAU was also achieved
by reconstituting the 12KO recipients with IL-12. These results led to
the conclusion that 12KO mice are not inherently unable to develop EAU
and suggested that endogenous IL-12 in the adoptive host has a role in
pathogenesis during the expression phase of EAU, after the uveitogenic
effector cell has already been primed. Similar conclusions had been
reached by Leonard et al. in the model of adoptively transferred
experimental autoimmune encephalomyelitis, in which recipient mice were
treated with neutralizing Abs to IL-12 (39). The effective
reconstitution of the adoptive host was in contrast to the
ineffectiveness of reconstitution of the actively immunized animal and
is compatible with an interpretation that IL-12 has different roles in
the priming stage vs the expression stage of disease. The present
results also indicate that whatever the role played by IL-12 during the
expression stage of EAU, it can be offset by driving the primed T cells
in culture with exogenous IL-12 toward a more polarized Th1 effector
phenotype.
The relative ineffectiveness of IL-12 replacement in the actively
immunized 12KO mice also raised the question whether 12KO T cells
themselves possessed the ability to develop into uveitogenic effector
cells. That 12KO T cells could differentiate into pathogenic effectors
under the appropriate conditions was confirmed by the finding that,
following culture in the presence of exogenous IL-12, primed
lymphocytes of 12KO donors were able to produce IFN- and to induce
EAU in naive 12KO recipients. This indicated that 12KO lymphocytes
could be driven to become pathogenic Th1-like effectors under the
influence of exogenous IL-12 even after priming.
The cytokine profile produced by 12KO lymphocytes in response to Ag was
very reminiscent of the cytokine profile produced by IFN--deficient
mice (22). The response of the IFN--deficient animals was also
typified by unchanged production of TNF-, elevated IL-5 and IL-10,
and reduced IFN-, accompanied by lack of detectable IL-4 production
by lymph node cells. Nevertheless, while the IFN--deficient mice
were quite susceptible to EAU, 12KO mice were resistant. The exact
nature of the uveitogenic effector T cell in IFN--deficient mice
remains to be determined; nevertheless, the present data clearly point
out that a uveitogenic effector can be generated in the absence of
IFN-, but not in the absence of IL-12. This further indicates that
it is not simply the capacity of IL-12 to up-regulate endogenous
IFN- production that underlies its role in pathogenesis and points
out a role for IL-12 that is independent of IFN-. These issues are
being currently addressed in IFN--deficient mice treated with
neutralizing anti-IL-12 Abs.
In summary, the present study shows that the pathogenesis of EAU is
dependent on endogenous IL-12 production not only during the induction,
but also during the expression, stage of EAU. Further studies are
needed to dissect the IFN--dependent from the IFN--independent
actions of IL-12 in the pathogenesis of tissue-specific, cell-mediated
autoimmunity.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: EAU, experimental autoimmune uveitis; IRBP, interphotoreceptor retinoid-binding protein; KO, knockout; PTX pertussis toxin; 12KO, IL-12 p40-deficient; wt, wild type; -MMP, -methyl-D-mannopyranoside; DTH, delayed-type hypersensitivity.
3 Tarrant, T., P. Silver, L. Rizzo, C. Chan, B. Wiggert, and R. Caspi. Interleukin-12 protects from a Th1-mediated autoimmune disease, experimental autoimmune uveitis, through a mechanism involving IFN- and NO. Submitted for publication.
Received for publication December 24, 1997. Accepted for publication February 27, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. J. Allergy Clin. Immunol. 99:(No. 1 Part II):S368. (Abstr. 1503).
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B. Sun, S.-H. Sun, C.-C. Chan, B. Wiggert, and R. R. Caspi Autoimmunity to a pathogenic retinal antigen begins as a balanced cytokine response that polarizes towards type 1 in a disease-susceptible and towards type 2 in a disease-resistant genotype Int. Immunol., August 1, 1999; 11(8): 1307 - 1312. [Abstract] [Full Text] [PDF]
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K. Hong, A. Chu, B. R. Ludviksson, E. L. Berg, and R. O. Ehrhardt IL-12, Independently of IFN-{gamma}, Plays a Crucial Role in the Pathogenesis of a Murine Psoriasis-Like Skin Disorder J. Immunol., June 15, 1999; 162(12): 7480 - 7491. [Abstract] [Full Text] [PDF]
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R. K. Agarwal, C.-C. Chan, B. Wiggert, and R. R. Caspi Pregnancy Ameliorates Induction and Expression of Experimental Autoimmune Uveitis J. Immunol., March 1, 1999; 162(5): 2648 - 2654. [Abstract] [Full Text] [PDF]
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T. K. Tarrant, P. B. Silver, J. L. Wahlsten, L. V. Rizzo, C.-C. Chan, B. Wiggert, and R. R. Caspi Interleukin 12 Protects from a T Helper Type 1-mediated Autoimmune Disease, Experimental Autoimmune Uveitis, through a Mechanism Involving Interferon {gamma}, Nitric Oxide, and Apoptosis J. Exp. Med., January 18, 1999; 189(2): 219 - 230. [Abstract] [Full Text] [PDF]
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