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*
Oral Infection and Immunity Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892; and
Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and suppression of chronic arthritis.
Moreover, IL-10 was increased in tolerized spleen lymphocytes, and
unexpectedly, this SCW-specific IL-10 production was TGF-ß dependent.
These data support a pivotal role for TGF-ß, although not necessarily
in the joint, in the regulation of specific immune tolerance
responsible for suppressed synovial inflammation and matrix
destruction. The distant induction and up-regulation of regulatory
cytokines and/or cells may contribute to the inhibition of the immune
response through blunted infiltration of inflammatory cells to the
joint. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(5), and IL-4
(6), have been shown to effectively suppress pathogenesis in this
arthritis model. Oral administration of Ag is a classic method of inducing Ag-specific peripheral immune tolerance (7, 8) with suppression of experimental autoimmune diseases, including EAE (7), uveitis (9), collagen-induced arthritis (10), and diabetes in the NOD (nonobese diabetic) mouse (11). Oral tolerance can be induced and/or mediated by different mechanisms, including active suppression (12), anergy (13), and peripheral deletion of Ag-specific T cells (14) depending on the dose of Ag administered. Although clinical trials of oral administration of Ags, such as myelin basic protein for multiple sclerosis and type II collagen for rheumatoid arthritis, have provided intriguing results (7, 15, 16, 17), confounding variables, including simultaneous nonsteroidal anit-inflammatory drugs (NSAIDs) (18) and administration of Ag only after disease symptoms occur, complicate the interpretation of its effectiveness. Therefore, understanding the cellular and molecular mechanisms of oral tolerance and, especially, exploring approaches to induce tolerance after disease has developed will facilitate the potential application of this method for human autoimmune diseases.
In this report we explore the role of oral administration of a nonself Ag on arthritis induced by bacterial cell walls. Our data are the first to demonstrate that oral administration of bacterial components effectively suppresses SCW-induced erosive arthritis. Efficacy is dependent on the dose and time of Ag administration, and importantly, oral administration of Ag mediates tolerance not only before but also after induction of disease. Moreover, inhibition of chronic inflammation appears to be associated with the up-regulation of regulatory cytokines, including TGF-ß, in the intestine-associated lymphoid tissues as well as in the peripheral circulation, rather than being limited to a localized effect within the afflicted joints.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Arthritis was induced in pathogen-free LEW female rats (
100
g; Charles River Breeding Laboratories, Wilmington, MA) by i.p.
injection of group A SCW peptidoglycan-polysaccharide complexes (Lee
Laboratories, Grayson, GA; 30 µg of rhamnose/g of body mass) (2, 4).
The course of acute and chronic joint pathology was clinically
monitored by determining the articular index (AI), which reflects the
degree of joint erythema, swelling, and distortion on a scale of 0
(normal) to 4 (severe inflammation) for each joint (1). The indexes for
a group of animals were averaged and reported as the mean AI ±
SEM. In some experiments the degree of joint swelling was monitored
with a plethysmometer (UGO Basile, Varese, Italy) and was recorded as
the mean volume ± SEM. Radiographs taken with direct exposure
(1:1) on X-OMAT TL Kodak film (Eastman Kodak, Rochester, NY) using
60-kV, 345-mA, 60-s exposure by a Faxitron x-ray machine (Faxitron
x-ray, Buffalo Grove, IL) were evaluated for soft tissue swelling,
joint space narrowing, bone erosions, and deformity.
Induction of oral tolerance
Oral tolerance was induced by a multiple dose feeding regimen (12) with some modifications. Animals were fed by gastric intubation with an 18-gauge stainless steel feeding needle (Thomas Scientific, Swedesboro, NJ) with different doses of SCW dissolved in 0.5 ml of PBS or with PBS only. Rats were fed daily for 5 days before or after SCW injection as indicated.
Histopathology and immunohistochemistry
Tissue specimens were fixed in 10% buffered formalin, decalcified in 10% EDTA, sectioned, and stained with hematoxylin and eosin for histopathologic analysis (2, 4). For cytokine detection, the prepared tissues were stained with monoclonal anti-TGF-ß1, -2, and -3 Ab (Genzyme, Cambridge, MA) using the ABC Elite Kit (Vector Laboratories, Burlingame, CA). Briefly, deparaffinized sections were washed with PBS and were preincubated for 20 min with blocking serum to inhibit nonspecific protein binding, followed by incubation with primary Ab. The sections were then stained with biotinylated secondary Ab, washed, and treated with the ABC reagent. Finally, the sections were incubated with peroxidase substrate solution for 5 min and counterstained with hematoxylin for microscopic examination.
RNA isolation and assessment of cytokine mRNAs in synovial tissues
Total RNA was isolated from excised synovial tissues (19) using a modification of the guanidinium isothiocyanate method (RNeasy Kit, Qiagen, Chatsworth, CA). Cytokine mRNAs expressed in synovial tissues were identified using an RNase protection assay (RiboQuant, PharMingen, San Diego, CA) according to the manufacturer’s protocol. A multiprobe template rCK-1 set was used, and radiolabeled probes were generated using [33P]dUTP (New England Nuclear, Boston, MA). Labeled probes were hybridized overnight with 5 µg of RNA at 56°C. Free probe and other ssRNA were digested with RNase, and riboprobe-RNA complexes were then subjected to 6% denaturing polyacrylamide gel electrophoresis with an unprotected probe set as markers. The gels were exposed to phosphor screens for 1 day and analyzed by a PhosphorImager (Molecular Dynamics, Sunnyvale, CA) using ImageQuant software.
Northern blot analysis
Total RNA was fractionated on 1% agarose gels containing formaldehyde and was transferred to Nytran membranes (Schleicher and Schuell, Keene, NH). The blots were hybridized with the 32P-labeled cDNA murine TGF-ß1 probe (Genentech, South San Francisco, CA), exposed to phosphor screens, analyzed by a PhosphorImager using ImageQuant software, then stripped and screened with a probe encoding constitutively expressed glyceraldehyde-3-phosphate dehydrogenase (GAPDH).
Cell culture
Spleens and mesenteric lymph nodes (MLN) were removed
aseptically, and single cell suspensions were prepared. The cells from
each group of rats were pooled and washed twice before resuspending
them in DMEM containing 10% (v/v) heat-inactivated FBS, 2 mM
glutamine, 15 mM HEPES, 1% nonessential amino acids, 1 mM sodium
pyruvate, penicillin (100 U/ml), streptomycin (50 µg/ml), and 50 µM
2-ME (all from BioWhittaker, Walkersville, MD). After lysis of RBCs
with ACK lysing buffer (BioWhittaker), 2–4 x 105
cells in 200 µl were cultured in round-bottom microtiter plates
(Costar, Cambridge, MA) and stimulated with SCW (1 µg/ml). In some
wells, anti-TGF-ß1, -2, and -3 Ab (20 µg/ml) was included from
the beginning of the culture. Cell-free supernatants were collected at
48 h for the determination of TNF-, IFN-, IL-4, and IL-10.
For TGF-ß analysis, cells were cultured in X-Vivo-20 serum-free
medium (BioWhittaker) for 72 h, and supernatants were harvested.
Cytokine ELISA
Quantitative ELISAs for TNF-, IFN-, IL-4, and IL-10 were
performed using the respective ELISA Kits (BioSource International,
Camarillo, CA). TGF-ß was determined by TGF-ß1Emax
ImmunoAssay System (Promega, Madison, WI). For determination of TGF-ß
in serum, samples were diluted 1/30 with the sample dilution buffer
included in the TGF-ß1 kit. For the measurement of total TGF-ß, 50
µl of sample was treated with 1 µl of HCl (1 N) at room temperature
for 15 min followed by addition of 1 µl of NaOH (1 N).
Flow cytometry
Cells (1–5 x 105) were resuspended in PBS without Ca2+ and Mg2+ (BioWhittaker) containing 1% BSA (Irvine, Santa Ana, CA) and 0.1% sodium azide (Sigma, St. Louis, MO; PBS-Az). For the staining of surface Ags, cells were incubated with FITC-conjugated anti-rat CD3 and phycoerythrin-conjugated anti-CD4 or anti-CD8 mAbs (Caltag, San Francisco, CA) on ice for 30 min. After being washed twice with 1 ml of PBS-Az, cells were resuspended in 0.5 ml of PBS-Az for analysis by flow cytometry (FACScan, Becton Dickinson, NJ). Ten thousand events were routinely collected and analyzed using LYSIS II software (Becton Dickinson).
Statistical analysis
Student’s t test was used for analysis of the statistical significance of data.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To assess the effects of oral administration of SCW on arthritis,
the peptidoglycan-polysaccharide complexes were administered orally at
doses of 3, 30, and 300 µg/rat daily for 5 days. Initially, feeding
was begun 7 days before the i.p. injection of arthritogenic SCW.
Whereas SCW-injected animals that received oral PBS only displayed
typical acute and chronic joint swelling and deformity (Fig. 1
A), animals that received 3
µg of oral SCW for 5 days (days -7 to -2) preceding arthritis
induction displayed a very blunted acute inflammatory response (AI
= 0.87 ± 0.5 vs 8.25 ± 0.25; p < 0.01; day
5) and almost no chronic inflammatory phase (AI = 1.25 ± 1.2
vs 8.75 ± 0.75; p < 0.01) measured 20 days later
(Fig. 1A). Joint volume was also monitored by
plethysmometer, which paralleled the markedly diminished swelling of
the joints detected by AI (Fig. 1B). A significant
diminution of the acute and chronic components of the evolving
SCW-induced polyarthritis was also observed in those animals that
received 300 µg/rat orally for 5 days (Fig. 1A). In
contrast, when animals were given 30 µg/rat orally, no significant
suppression of either the severity or the incidence of chronic
inflammatory disease was noted, although the acute inflammatory
response was partially suppressed by this regimen of oral feeding (Fig. 1A).
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Because of the profound tolerance induced by low and high doses of
Ag on the evolution of arthritic lesions when feeding was initiated
before the onset of inflammation, we next assessed whether oral
administration of SCW could influence the course of disease after its
onset. Since low dose feeding resulted in the most striking inhibition,
we used the regimen of 3 µg/rat for 5 days in the following studies.
Oral administration of SCW was begun on day 0 (onset of the acute
phase), day 10 (remission phase), or day 15 (onset of the chronic
phase) and was compared with the effective low dose feeding of SCW
beginning on day -7. Again, oral administration of SCW before the
onset of the arthritis (days -7 to -2) led to a profound prevention
and inhibition of both the acute and chronic synovial inflammation.
However, when oral administration was begun on day 0 for 5 continuous
days, the disease score of this group was the same as that of the
animals receiving PBS only during the acute phase and was even worse
during the chronic inflammatory disease (Fig. 2).
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). However, when oral administration was
begun on day 15, the benefits of oral feeding were modest, but
transient (Fig. 2). These data indicate that the timing of oral feeding
is critical, but that suppression can readily be induced even after
arthritis has been established with long-lasting effects. Oral administration of SCW suppresses inflammatory cell recruitment, synovitis, and proinflammatory cytokines
SCW localization to the synovium induces a characteristic pattern
of leukocyte infiltration (1, 2) that is markedly inhibited in animals
receiving oral SCW. Whether evaluated at 4 days (not shown) or 4 wk
(Fig. 3) after SCW-induced arthritis, the
synovial tissues of arthritic animals fed SCW had dramatically reduced
infiltration of inflammatory cells (Fig. 3f), more closely
resembling the control synovium than the arthritic synovium (Fig. 3e). Corresponding to the decrease in synovitis, a marked
reduction in pannus, bone erosion, and cartilage degradation was
evident. Whereas pronounced osteoclast formation and bone resorption
were observed in untreated arthritic joints (Fig. 3e),
osteoclasts were infrequent in oral SCW-treated joint tissues (Fig. 3f). In parallel with the histopathologic evidence of
reduced tissue destruction, radiologic examination revealed
diminished soft tissue swelling and bone abnormalities after oral
administration of SCW (Fig. 3, c and d).
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and IL-1, have been
implicated in the pathogenesis of arthritis (reviewed in 20 . To
determine whether oral tolerance impacted on synovial cytokine levels,
cytokine mRNAs in synovial tissues were monitored in treated and
untreated animals. Cytokine mRNAs were not detected in naive rat
synovium, but arthritic synovial tissues from animals receiving oral
PBS displayed increased expression of IL-1, IL-1ß, IL-6, and
TNF- (Fig. 4). Oral administration of
low dose SCW, however, virtually eliminated mRNA expression of these
proinflammatory cytokines. Corresponding to the AI scores (Fig. 1),
oral delivery of intermediate doses of SCW (30 µg, five times) failed
to block the expression of these inflammatory cytokines. IL-2 and
IFN- mRNAs were minimally detected in arthritic or tolerized animals
(Fig. 4). Although IL-4 and IL-10 have been implicated in orally
tolerized EAE animals (20), no enhancement of RNA for these cytokines
was observed in the synovium of orally tolerized rats (Fig. 4).
Consistent with our previous observations (19), SCW-induced arthritic
animals displayed substantial expression of TGF-ß mRNA in the joints
during acute and chronic inflammation. Surprisingly, oral
administration of low dose SCW did not result in detectable increases
in synovial TGF-ß as determined by mRNA Northern blot analysis and
protein staining with anti-TGF-ß mAb (data not shown).
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The marked reduction in inflammatory cell infiltrate and in
proinflammatory cytokines in joint tissues prompted studies to explore
the underlying mechanisms mediating oral tolerization. We first
analyzed the effects of oral administration of Ag on circulating
hemopoietic cells. As reported, injection of an arthritic dose of SCW
induced prolonged leukocytosis (2, 3). Oral feeding with SCW (3
µg/day; days -7 to -2) suppressed the elevation in circulating
leukocytes (Fig. 5A),
particularly the number of circulating monocytes (CD4+,
CD3-), and reversed the aberrant cell phenotypes to a more
normal distribution (Fig. 5B).
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was
monitored before (days 10–12) and after (days 28–30) the onset of
chronic inflammation. Corresponding to the increase in proinflammatory
cytokines in synovial tissue, TNF- was markedly elevated in the
circulation of arthritic animals (Fig. 6A). Oral administration of
SCW, however, profoundly inhibited serum TNF- levels. In marked
contrast to TNF-, total TGF-ß in serum was significantly increased
in orally tolerized animals both before (days 10–12) and after (days
28–30) the onset of chronic inflammation (Fig. 6B).
Bioactive TGF-ß was most readily detected during chronic
inflammation, and elevated TGF-ß in orally tolerized animals (Fig. 6C) coincided with the suppression of chronic arthritis
(Fig. 1). This inverse correlation between synovial inflammation and
circulating TGF-ß was further verified in the animals treated with
SCW at different intervals. Oral administration of SCW on days 10–15,
which markedly inhibited arthritis (Fig. 2), was accompanied by
enhanced systemic TGF-ß, whereas the animals given oral SCW on days
0–5 or days 15–20 exhibited neither increased circulating TGF-ß nor
amelioration of arthritis (Fig. 7). Thus,
there appears to be an association between increased circulating
TGF-ß and reversal of disease symptoms.
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We then focused on potential sources of TGF-ß, including
gut-associated lymphoid tissues, where lymphocytes first contact
digested Ag, and oral tolerance is probably initiated (7). In contrast
to peripheral blood (Fig. 5), MLN displayed comparable percentages of
CD4+, CD8+ T cells and macrophages between
tolerized and control rats. Nonetheless, increased TGF-ß was evident
in MLN of orally tolerized animals stained with anti-TGF-ß Ab,
whereas only sparse staining was apparent in MLN of PBS-treated
arthritic animals (Fig. 8, A
and B). When MLN or splenic lymphocytes from tolerized
animals (day 10) were incubated with SCW (1 µg/ml) in vitro for
72 h, SCW-specific TGF-ß was significantly enhanced (Fig. 8C). In contrast to TGF-ß, SCW-specific induction of
TNF- and IFN- in in vitro cultures of MLN and spleen lymphocytes
was profoundly inhibited (50–80% inhibition compared with that in
PBS-fed animals) in tolerized rats. Anti-TGF-ß neutralizing Ab
partially reversed the inhibition of these inflammatory cytokines in
vitro (data not shown).
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IL-10, a potent immunoregulatory cytokine thought to contribute to
oral tolerance (21, 22), was also evaluated. IL-10 was increased in
orally tolerized spleen cell cultures (Fig. 8D), although no
increased circulating levels of IL-10 could be detected in the
tolerized animals. When spleen cells were stimulated with Ag in vitro,
SCW-specific IL-10 was significantly augmented in SCW-tolerized,
compared with PBS-treated, animals. Interestingly, anti-TGF-ß
neutralizing mAb down-regulated SCW-specific IL-10 production in
tolerized rat spleen cells, but not in those from untreated arthritic
animals (Fig. 8D). These data suggest that the induction of
IL-10 in tolerized animals may be dependent in part on TGF-ß.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One of the novelties in the current study is the time dependence of Ag feeding for optimal tolerance induction. Consistent with prior protocols for oral tolerance induction through feeding the animals before the disease is initiated, we have observed a reproducible inhibition of SCW arthritis. However, one of the most important but least studied aspects of oral tolerance is whether tolerance can be induced and maintained after the onset of the autoimmune disease. In this study, we address this question by oral Ag delivery at different time intervals. Whereas oral administration of SCW begun during acute inflammation (days 0–5) or after the onset of the chronic destructive phase (days 15–20) is unable to suppress or even possibly worsens the synovial inflammation, there is a window of time during the remission and early chronic inflammation when oral Ag gives rise to a remarkable inhibition of the ensuing inflammation. Clinically, many autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and diabetes, are characterized by periods of relapse and remission. Potential tolerance induction and therapeutic manipulation in those patients might rely heavily on the kinetics and duration of oral Ag delivery. Based on our data, periods of remission may be the most appropriate target for the generation of immune tolerance. If, as suggested (7), the remission of chronic inflammatory diseases is related to the up-regulation of inhibitory cytokines such as TGF-ß, induction of oral tolerance may prolong this phase to prevent relapse. The regulatory T cells and cytokines induced by oral administration of Ag at this phase, by promoting and enhancing active suppression (12), may shift the balance of the immune response toward suppression.
To establish whether oral SCW-induced tolerance does, in fact, shift
the cytokine balance, we monitored local and systemic cytokine levels
in the treated animals. Oral administration of low dose SCW virtually
eliminates expression of the proinflammatory cytokines, TNF, IL-1, and
IL-6, which typically increase in SCW synovium (Fig. 4), and
purportedly contribute to synovial pathology (24, 25). In contrast to
oral tolerance in other animal models such as EAE (20), however,
Th2-like cytokines such as IL-4 and IL-10 are not evidently
up-regulated in the tolerized synovial tissues. These results imply
that active suppression is not taking place within the synovium if Th2
cytokines are involved. Another difference between the two models is
that all rats with EAE spontaneously recover from the disease (20, 23),
whereas all animals with SCW-induced arthritis will experience
persistent, unresolved arthritis unless treated (1).
If oral administration of SCW abrogates the proinflammatory cytokines in synovial tissues, but the anticipated tolerance-mediating cytokines are not apparent within the joint, where and how might this inhibition of inflammatory response occur? Our data support a role for elevated circulating TGF-ß levels, which are accompanied by a decrease in inflammatory cytokines and inhibition of the arthritic response. The inverse correlation between systemic TGF-ß and arthritis further strengthens the hypothesis that TGF-ß is a key player in mediating oral tolerance (7). This finding also has significant implications for clinical monitoring of oral tolerance. Enhanced TGF-ß, evident in spleen and MLN of the tolerized animals, may contribute to the higher levels of blood TGF-ß. It has been elegantly shown that oral administration of myelin basic protein in mice induces an active suppression mediated by Th2 and TGF-ß-secreting (Th3) T cells in MLN (12, 26). Whether TGF-ß, under the conditions in our experiments, is secreted from CD4+ T cells or CD8+ T cells is not currently clear, but our preliminary data indicate that both CD4+ and CD8+ T cells are responsible (W. Chen et al., manuscript in preparation). One of the remaining unresolved issues is whether oral SCW induces a specific T cell subset in MLN that then migrates to blood and spleen to mediate inhibition of the immune response, as reported in other animal models (12), or whether cell-free TGF-ß enters the circulation to arrest the SCW-induced inflammatory response. Since we have not yet been successful in isolating the SCW-specific regulatory T cells from the tolerized animals, we can only assume that both are possible. Regardless of which mechanism is used, the eventual outcome is the up-regulation of the suppressive cytokines and the down-regulation of the ongoing chronic inflammation.
The role that TGF-ß plays in SCW-induced arthritis is complex (27),
in that local secretion or intra-articular administration drives the
inflammatory response, whereas systemic delivery of TGF-ß inhibits
arthritis (2). Recent evidence also documents that systemic delivery of
TGF-ß following gene therapy is therapeutically beneficial (28).
Consistent with these observations, the consequences of oral
administration of SCW appear to result in systemic routing of this
cytokine to favor its potent immunosuppressive actions. TGF-ß
inhibits the activation and function of both CD4+ Th1 cells
(12, 29)3 and
monocyte/macrophages (27, 29). CD4+ T cells and monocytes
have been documented to play a significant role in initiating and
promoting the chronic inflammatory arthritis in this model (3, 6, 27).
TGF-ß, therefore, may prevent and/or suppress proinflammatory
cytokines such as TNF- and IFN- directly or indirectly. Recent
evidence also suggests that systemic TGF-ß targets endothelial cells,
where it inhibits E-selectin expression to block adhesion and targeting
of leukocytes to the site of inflammation (27, 30). Moreover, since
leukocytes are normally sensitive to a concentration gradient of
chemotactic signals emanating from the site of inflammation, the
presence of elevated TGF-ß in the blood would eliminate such an
outward gradient (27).
The uncovering of a role for TGF-ß in the up-regulation of IL-10
secretion in SCW-tolerized spleen supplies further clues of the
beneficial side of TGF-ß (27). IL-10 induces long term anergy of
human CD4+ T cells in vitro (21) and regulates B7
costimulatory molecules (31), while suppressing IFN- production by
inhibiting IL-12 (32) and inducing Th2 cell differentiation (33). IL-10
is also believed to be involved in the induction of oral tolerance (12, 20), although it is not known how IL-10 is up-regulated. That
anti-TGF-ß mAb inhibits IL-10 production in spleen cell cultures
from tolerized animals has important implications not only in exploring
the mechanisms of oral tolerance, but also in defining the regulation
of IL-10 in general. Up-regulation of IL-10 may perpetuate the impact
of TGF-ß in this tolerance induction. Therefore, a combination of
factors, rather than a single cytokine or cell subset, probably
prevents or inhibits activation of the inflammatory cascade culminating
in chronic erosive arthritis. Using this unique model in which SCW can
be used to induce oral tolerance may enable dissection of the
mechanisms of tolerance and has significant implications not only for
autoimmune diseases but also perhaps for other chronic diseases
mediated by bacterial persistence.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: SCW, streptococcal cell wall; EAE, experimental autoimmune encephalomyelitis; AI, articular index; MLN, mesenteric lymph node; PBS-Az, phosphate-buffered saline without Ca2+ and Mg2+ and containing 1% bovine serum albumin and 0.1% sodium azide.
3 W. Chen and S. M. Wahl. TGF-Banergizes CD4+ Th1 and Th2, but induces TGF-B-secreting T cells. Submitted for publication.
Received for publication June 18, 1998. Accepted for publication July 30, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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inhibits inflammatory cell recruitment and the evolution of bacterial cell wall-induced arthritis. J. Immunol. 146:95.[Abstract]
by IL-4 contribute to resolution of experimental arthritis. J. Immunol. 151:4344.[Abstract]
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