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1 From the Laboratory of Immunology and the 2 Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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METHODS. In the present study the authors examined the ability of B10.RIII mice, the most susceptible strain known so far, to develop EAU in response to the retinal antigen, interphotoreceptor retinoid-binding protein (IRBP), and to a major uveitogenic epitope of IRBP, peptide (p)161-180, in the absence of PTX treatment.
RESULTS. The data indicate that high disease scores in response to IRBP and
p161-180 were found in B10.RIII mice, without the need for PTX as part
of the immunization protocol. Unlike the B10.A strain in which
appreciable disease did not develop without PTX, B10.RIII mice mounted
a high IFN-
response to IRBP in the absence of PTX treatment.
Interestingly, and unlike the effect with IRBP, in vitro recall
response to p161-180 was low in IFN-, despite good EAU scores.
CONCLUSIONS. The data indicate that an important mechanism through which PTX
facilitates induction of cell-mediated autoimmunity is by promoting a
Th1 polarization of the immune response. The propensity of B10.RIII
mice to mount a more polarized Th1 response to IRBP than other strains
may contribute to their ability to develop EAU without pertussis
adjuvant. Nevertheless, the induction of EAU by p161-180 in the context
of a relatively limited IFN- production indicates that non–Th1- and
Th-related mechanisms are likely to act in concert to determine the
outcome of disease.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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EAU in mice can be induced by immunization with the interphotoreceptor retinoid-binding protein (IRBP); the retinal S-Ag is poorly uveitogenic in mice.1 Most mouse strains are relatively resistant to induction of EAU, and immunization protocols have required the use of pertussis adjuvant to elicit disease.1 2 The most potent and most useful form of pertussis adjuvant is purified pertussis toxin (PTX), and our previous work has shown that there is little or no disease in the susceptible B10.A strain if PTX is not used as part of the immunization regimen.2
The need for PTX in the induction protocol confounds the picture by adding a potent adjuvant with pleiotropic activities to the immunization protocol. PTX has been used for many years to enhance induction of autoimmune disease and overcome resistance in low-responder strains.3 It is known to have multifaceted effects on the immune response, including enhancement of vascular permeability, histamine sensitization, lymphocyte recirculation, mitogenic effects on T and B cells, and other effects.4 5 6 7 8 9 10 11 12 13 This can make interpretation of experimental data difficult, and limits the usefulness of the model for some types of studies.
In the present study we re-examined the possibility of inducing EAU in
mice without pertussis toxin, using the most susceptible strain known
thus far, B10.RIII, immunized with IRBP or with a major pathogenic
epitope of IRBP. The results show that EAU in B10.RIII mice, unlike in
B10.A mice, can be induced by IRBP without pertussis treatment.
Furthermore, EAU can be induced in B10.RIII mice by the pathogenic
peptide (p)161-180 without pertussis. Delayed hypersensitivity and
lymphocyte proliferation were strongly enhanced by PTX treatment in all
cases. Antigen-specific production of IFN- indicated that the
cellular response of B10.RIII mice to IRBP in the absence of PTX was
more polarized toward type 1 than that of B10.A, and that PTX treatment
elevated IFN- production in B10.A mice in response to IRBP to the
level found in B10.RIII mice. We propose that this explains in part the
tendency toward development of EAU in the B10.RIII mouse after IRBP
immunization without PTX treatment. We further propose that one of
the mechanisms that contribute to the well-documented property of PTX
to promote cell-mediated autoimmunity is its ability to polarize the
immune response toward the Th1 pathway.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Antigens
Whole bovine IRBP was purified from retinas by concanavalin
A-Sepharose–affinity chromatography and high-performance liquid
chromatography.14
Human p161-180 (sequence
SGIPYIISYLHPGNTILHVD) was synthesized on a peptide synthesizer (model
461; Applied Biosystems; Foster City, CA) using Fmoc chemistry.
EAU Induction and Scoring
EAU was induced by active immunization with graded doses of IRBP
or p161-180 in phosphate-buffered saline (PBS) emulsified 1:1 vol/vol
in complete Freund’s adjuvant (CFA) that had been supplemented with
Mycobacterium tuberculosis strain H37RA (Sigma, St. Louis,
MO) to 2.5 mg/ml. A total of 200 µl emulsion was injected
subcutaneously, divided among three sites: base of tail and both
thighs. In some groups, 0.5 µg of Bordetella pertussis
toxin (PTX) (Sigma) was injected intraperitoneally at the same time.
EAU by adoptive transfer was induced by intraperitoneal injection of
pooled spleen and lymph node cells obtained from primed donors and
stimulated in culture with 20 µM p161-180 in the presence or absence
of 50 ng/ml interleukin (IL)-12, essentially as previously
described.15
In some adoptive transfer recipients, 1 µg
PTX was administered intravenously just before the adoptive transfer.
Clinical EAU was evaluated by fundoscopy under a binocular microscope
after dilation of the pupil and graded on a scale of 0 to 4 using
criteria described in detail elsewhere.16
Eyes harvested
21 days after immunization or 10 days after adoptive transfer were
prefixed in 4% phosphate-buffered glutaraldehyde for 1 hour (to
prevent artifactual detachment of the retina), and then transferred to
10% phosphate-buffered formaldehyde until processing. Fixed and
dehydrated tissue was embedded in methacrylate, and 4- to 6-µm
sections were stained with standard hematoxylin and eosin. Eye sections
cut at different planes were scored in a masked fashion. Incidence and
severity of EAU were graded on a scale of 0 to 4 in half-point
increments, using the criteria described previously,16
which are based on the type, number, and size of lesions present.
Incidence was shown as the number of positive animals of all animals in
the group. Severity of disease was the average score of eyes from those
animals in which disease developed (if disease was unilateral, both
eyes were averaged).
Delayed-Type Hypersensitivity
To assess delayed-type hypersensitivity (DTH), 10 µg IRBP or
peptide in 10 µl PBS was injected into the ear pinna. Ear-thickness
increment was measured 48 hours later using a spring-loaded micrometer.
The response was calculated as the difference between ear thickness
before and after challenge.
Lymphocyte Proliferation Assay
Draining (inguinal and iliac) lymph nodes were collected after 21
days, and were pooled within the group. Triplicate 0.2-ml cultures
containing 5 x 105 cells were seeded in
round-bottomed 96-well microtiter plates. The RPMI medium
(Biowhittaker, Walkersville, MD) was supplemented with mouse serum,
mercaptoethanol, antibiotics, glutamine, and nonessential amino acids,
as described,1
and contained 30 µg/ml IRBP or 20 µM
p161-180 as stimulants. The cultures were incubated for a total of 60
hours. Tritiated thymidine (1 µCi/well) was added during the last 18
hours. The data are shown as 
cpm (cpm = mean cpm in cultures
with antigen, minus the mean cpm in control cultures without antigen).
Cytokine Assays
Lymph node and spleen cells were cultured in 96-well flat-bottomed
plates (1 x 106 cells/0.2 ml culture medium
per well) either alone or with stimulants at the concentrations
mentioned earlier. Supernatants were collected after 48 to 72 hours and
were kept frozen in small aliquots at -70°C. Cytokine production was
measured by enzyme-linked immunosorbent assay (ELISA) using antibody
pairs from Pharmingen (La Jolla, CA) for IL-4, or from Endogen (Boston,
MA) for IL-5 and IFN-, or from R&D (Minneapolis, MN) for TNF-
, as
described previously.17
18
Adoptive Transfer of EAU
Donor B10.RIII mice were immunized with 50 µg p161-180. Lymph
node cells and spleen cells collected on day 14 after immunization were
pooled. The cell suspension was adjusted to 107
cells/ml in RPMI medium supplemented as for the proliferation assay,
and the cultures were stimulated in 75-cm2 flasks
for 72 hours with 20 µM p161-180 in the presence or absence of 50
ng/ml IL-12. To remove excess adherent cells (macrophages), the
stimulating cultures were transferred into new flasks after 24 hours
and again after 48 hours. After 3 days, the lymphocytes were separated
from erythrocytes and debris by discontinuous density gradient
centrifugation on Ficoll (Lympholyte M; Accurate, Westbury, NY) and
counted. Each recipient mouse was injected intraperitoneally with the
specified number of cells. Some recipient mice were injected with 1
µg PTX intravenously just before the adoptive transfer. Eyes were
collected from the recipients after 10 days and were evaluated for EAU
by histopathology.
Reproducibility and Data Presentation
Experiments were repeated at least twice. Results were highly
reproducible. Figures show pooled data from repeat experiments, or
representative experiments, as indicated.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B10.RIII mice were immunized with graded doses of p161-180 in CFA, with or without concomitant administration of 0.5 µg PTX. Mice immunized without PTX had good EAU scores that at peptide doses between 10 and 25 µg peptide per mouse were only slightly lower than those in mice immunized with PTX (Fig. 2) . However, use of PTX appeared to lower the threshold of antigen dose required for EAU induction and to eliminate the plateau of maximal achievable disease score observed at the highest doses of immunizing peptide. Thus, similar to EAU induced by whole IRBP, EAU induced by p161-180 in B10.RIII mice appears relatively independent of PTX as an additional adjuvant, except at extremely low or high antigen doses.
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Dependence on PTX Treatment of DTH Scores and Lymphocyte
Proliferation in Response to IRBP, Irrespective of Disease Development
The same mice that were immunized for development of EAU were
challenged 2 days before the end of the experiment for DTH responses to
the immunizing antigen (IRBP or p161-180). The ear-swelling responses
48 hours after challenge showed that in all cases DTH scores were
highly dependent on inclusion of PTX in the immunization regimen (Fig. 3) . This was irrespective of the antigen, mouse strain, and disease
scores resulting from the immunization.
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production, lymphocyte migration, and vascular
permeability, that may tend to keep IFN-–producing,
antigen-specific lymphocytes in the circulation for a longer than
normal period, while facilitating their egress into inflammatory
sites.9
10
12
13
Similarly, effects on recirculation may
inhibit emigration of primed lymphocytes from the draining lymph node,
accounting for higher proliferative responses in vitro.
Development of a More Polarized Type 1 Response to IRBP in B10.RIII
Mice Than in B10.A Mice in the Absence of PTX Treatment
Our previous data indicate that EAU is strongly dependent on the
presence of a type 1 response to the uveitogenic
antigen.19
20
We therefore examined the cytokine profile
of the response to IRBP and to p161-180 in mice immunized in the
presence and absence of PTX. Draining lymph node cells were collected
21 days after immunization, antigen-stimulated supernatants were
generated from the different groups and were assayed for content of
IFN-, IL-4, IL-5, and TNF- by ELISA. The results showed that
neither strain produced detectable IL-4 titers in response to IRBP and
both had low antigen-specific IL-5 responses, indicating absence of a
significant type 2 response. This response pattern was previously
observed by us to be typical of the B6 and B10 genetic
backgrounds.18
20
Interestingly, however, B10.RIII mice
produced 10 times more IFN- and almost 3 times as much TNF- in
response to IRBP than did B10.A mice (Table 2)
. PTX treatment of B10.A mice elevated the production of IFN- and
TNF- to the levels produced by untreated B10.RIII mice.
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Response response in culture and disease development did
not hold up. Although this peptide was uveitogenic even without PTX
treatment, the in vitro response to the peptide was low in IFN-,
indicating a low type 1 response (Table 3)
. It was also low in IL-4 and IL-5, indicating absence of an
appreciable type 2 response (Table 3) . Such a null cytokine pattern was
previously observed by us to be associated with genetic resistance to
EAU19
20
and contrasts with the usual response to
uveitogenic antigen in the susceptible strains. Nevertheless, culturing
primed lymph node cells of (PTX-untreated) p161-180–immunized mice in
the presence of IL-12 strongly enhanced their ability to produce
IFN- as well as their ability to transfer disease adoptively to
naive recipients (Table 4
and Fig. 5
). The enhancement of uveitogenicity on adoptive transfer was
particularly apparent at limiting cell numbers (Fig. 5)
. Thus, 5
million cells from cultures treated in vitro with IL-12 and
showing a predominant Th1 cytokine profile induced close to maximal
disease, whereas the same number of cells without IL-12 treatment and
showing the IFN- low cytokine profile were unable to transfer
disease. Thus, although an effector response low in IFN- production
induced EAU disease in the case of this peptide, polarization of the response toward Th1 enhanced disease expression.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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.22
The
observation that EAU can be induced in B10.RIII mice without PTX
treatment increases the usefulness of the mouse model for basic studies
of ocular autoimmunity, by eliminating a pleiotropic adjuvant substance
with many known and unknown effects on the immune system. Our results shed light on the long-debated effects of pertussis adjuvant on cell-mediated autoimmunity. Although it has long been known that pertussis administered concurrently with immunization promotes induction of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and EAU, the mechanism by which this comes about is controversial. Some investigators have attributed enhancement of EAE by pertussis to histamine sensitization of vascular endothelial cells and increase of vascular permeability, whereas others have proposed effects on the sensitization phase of EAE.4 5 6 12 Because pertussis is administered at the time of immunization, it should be gone long before effector cell infiltration into the target organ occurs 7 to 9 days later. We therefore believe that the effects are more likely to be exerted on early events that coincide temporally with presence of PTX in the system, such as priming of effector T cells and their commitment to the Th1 pathway.
Support for this interpretation is also provided by the observation that PTX completely abrogated disease when administered with adoptive transfer of exogenously generated uveitogenic effector cells. If effects on vascular permeability were a primary mechanism, enhancement of disease would be expected. We propose that inhibition of adoptively transferred EAU is related to the documented inhibitory effects of PTX on recirculation and homing of lymphocytes.7 13 Because PTX is a known uncoupler of G-proteins, we hypothesize that these effects may be secondary to blocking of chemokine signaling through G-protein–coupled receptors, which is necessary for migration and extravasation of effector lymphocytes and recruited leukocytes into the target organ.23 24 This hypothesis is currently under investigation in a separate study.
Interestingly, B10.RIII mice appeared to produce less IFN- in
response to p161-180 of IRBP than to the whole IRBP molecule.
Furthermore, a Th1-dominant response to this epitope did not appear to
be a prerequisite for its ability to induce disease, except under
conditions of suboptimal uveitogenic challenge (insufficient or
excessive immunization dose, or a limiting number of adoptively
transferred effector cells). One reason for this apparent paradox may
be the identity of the antigenic epitopes involved. It is known that
the type of response evoked is in part dependent on the epitope itself,
and is affected by the affinity of the interaction with T cell receptor
and major histocompatibility complex (MHC). High-affinity (or
high-avidity) interactions in several antigen systems have been seen to
promote development of type 1 responses, whereas low-affinity
interactions may encourage type 2 responses.25
26
27
28
We
hypothesize that the response to p161-180 involves mostly the
self-specific repertoire from which high-affinity cells have been
deleted, and therefore results in an IFN-–poor response. In
contrast, the bovine IRBP molecule contains also multiple nonconserved,
bovine-specific epitopes that can interact with the T-cell receptor
with high affinity and cause abundant production of IFN-. Although
these arguments may explain the difference in response phenotype to the
peptide and the whole IRBP molecule, they do not explain the
dissociation between the type of response to the peptide in vitro (low
Th1) and the response to the same peptide in vivo (uveitis). The
ability of p161-180 to induce disease in the context of a response
relatively low in IFN- supports the interpretation that factors
besides Th1–Th2 balance influence pathogenicity.
In summary, EAU induction in the B10.RIII mouse strain by active
immunization with IRBP or with its immunodominant epitope 161-180 was
found not to require the use of pertussis adjuvant. Unlike B10.A,
B10.RIII mice showed strong Th1 response and high TNF- levels to
IRBP without PTX treatment, although even in this strain the disease
was enhanced by PTX under suboptimal or supraoptimal conditions of
induction. Although in the past it has been proposed that PTX promotes
induction of cell-mediated autoimmunity because of its effects on
vascular permeability, the present data, as well as data published by
us previously,19
indicate that PTX-driven Th1 polarization
may play an important role. Nevertheless, the ability of p161-180 to
elicit EAU, apparently without inducing a strong Th1 response, remains
a paradox and points to the involvement of additional factors besides
Th1–Th2 balance in pathogenicity. The present investigation broadens
the usefulness of the mouse EAU model and permits its use in studies in
which pertussis treatment is undesirable or would confound the
conclusions.
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Footnotes |
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Commercial relationships policy: N.
Corresponding author: Rachel R. Caspi, Laboratory of Immunology, National Eye Institute, NIH, Building 10, Room 10N222, 10 Center Drive, MSC 1857, Bethesda, MD 20892. E-mail: rcaspi{at}helix.nih.gov
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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