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*
Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; and
Laboratory Service, Veterans Administration Health Care System, Palo Alto, CA 94304, and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF-
) when stimulated with an
encephalitogenic peptide, and induce very severe EAE upon transfer into
wild-type mice. In contrast, while IL-4 transgenic mice develop similar
disease compared with their nontransgenic littermates, mice transgenic
for IL-10 are completely resistant to the development of EAE. Taken
together, our data suggest that IL-10 plays a more critical role
in the regulation of EAE by regulating autopathogenic Th1
responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Subpopulations of CD4+ Th cells produce distinct patterns
of cytokines; this has led to the concept of functional heterogeneity
among Th cells (2). Th1-type cells produce IL-2 and/or IFN- and
TNF-ß, elicit delayed-type hypersensitivity responses, and activate
macrophages. Th2-type cells, on the other hand, produce IL-4, IL-5, and
IL-10, are especially important for IgE production and eosinophilic
inflammation, and may suppress cell-mediated immunity. These two Th
cell populations cross-regulate one another because their respective
cytokines act antagonistically. IL-4 and IFN- show reciprocal
inhibition, and IL-10 inhibits the production of IFN- and other Th1
cytokines by interfering with Ag presentation and activation of
macrophages (3). Conversely, IL-4 causes Th2 differentiation and
inhibits the development of IFN--secreting cells (4). Cytokines play
a pivotal role in the initiation, propagation, and regulation of
tissue-specific autoimmune injury. Cellular and cytokine changes in the
CNS have been described in several studies of myelin basic
protein-induced EAE. Th1 cytokines are present in inflammatory EAE
lesions in the CNS, whereas Th2 cytokines are absent, strongly
suggesting that Th1 cytokines play a role in the pathogenesis of the
disease (5). Conversely, recovery from EAE in mice and rats is
associated with an increase in the presence of Th2 cytokines and
TGF-ß in the CNS (6). In other studies, examination of brains and
spinal cords from diseased animals revealed the presence of mRNA for
IFN- and TNF- during clinical episodes, whereas mRNA for IL-10
appeared at the time of clinical remissions (7, 8). These findings,
along with the observation that Th2 cytokines can inhibit the actions
of inflammatory Th1 cytokines, suggest that the induction and
activation of Th2 cells may potentially prevent EAE and other
autoimmune diseases mediated by Th1 cells. In support of this
hypothesis, Racke et al. have shown that IL-4-induced immune deviation
can be used as a therapy in EAE (9). However, IL-4-deficient mice did
not show any increased susceptibility to EAE, suggesting that the role
of this Th2 cytokine in the regulation of EAE is complex (10).
To date, most encephalitogenic clones examined have been Thl cells (11, 12), although a recent report suggested that in immunocompromised animals myelin Ag-reactive Th2 cells may also induce EAE (13). We previously reported that proteolipid protein (PLP)-specific IL-4- and IL-10-producing Th2 clones could inhibit EAE if they were given at the time of immunization, and reverse disease if given at the first signs of EAE (14). Based on these data, we suggested that Th2 cells may function as regulators of EAE, and the predominant and preferential production of Th2 cytokines in response to autoantigen may confer resistance to autoimmune diseases. In support of this hypothesis are recently published results in which myelin Ag-reactive T cells genetically transduced with a retroviral plasmid containing the IL-4 gene or T cells transfected with IL-10 cDNA could prevent and/or reverse EAE (15, 16). However, direct administration of Th2 cytokines or anti-Th2 cytokine-blocking Abs to animals has produced conflicting effects on the clinical course of EAE (9, 17, 18). To address the issue of which of the two Th2 cytokines (IL-4 or IL-10) plays a more critical role in the disease process, we used IL-4- and IL-10-deficient (IL-4-/- and IL-10-/-) mice and transgenic mice overexpressing these cytokines. The results presented in this study demonstrate that IL-10-deficient mice develop a more severe clinical EAE than IL-4-deficient or wild-type (WT) mice and that IL-10-overexpressing transgenic mice are resistant to the development of disease, suggesting that IL-10 plays a more critical role in the regulation of EAE.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female C57BL/6 and IL-4- and IL-10-deficient mice on the C57BL/6 background were obtained from The Jackson Laboratory (Bar Harbor, ME). The generation of IL-4- and IL-10-deficient mice used in the present study has been described previously. These mice have been backcrossed for >10 generations on the C57BL/6 background (19, 20). Transgenic mice on the FVB background (H-2q), which express IL-4 and IL-10 in T cells, were obtained from Dr. Robert Tepper (Department of Genetics, Harvard Medical School and Massachusetts General Hospital, Boston). The IL-4 T cell transgenic mice (UD) have been described (21). Although homozygous IL-4 transgenic mice have altered T cell development, the heterozygous mice used in the present study have normal T cell development. For the generation of IL-10 transgenic mice (UR), IL-10 cDNA was cloned under the CD2 promoter (22). Activation of T cells from IL-10 transgenic mice leads to the production of significantly high amounts of IL-10. The transgenic mice were crossed with SJL, and the (SJL x FVB)F1 mice were used for the experiments described in this study. All mice were used at 6 to 7 wk of age.
Antigens
Bovine myelin PLP was prepared from a washed total lipid extract of bovine white matter (23). The protein was extracted by the chloroform-methanol method, converted to an aqueous phase, dialyzed overnight against double distilled water, and then used immediately. Peptides used in this study include myelin oligodendrocyte glycoprotein (MOG) 35–55 peptide (MEVGWYRSPFSRVVHLYRNGK), or as control, MOG92–106 peptide (DEGGYTCFFRDHSYQ). The peptides were synthesized by Dr. David Teplow at the Biopolymer Facility, Center for Neurologic Diseases, on an Applied Biosystems 430A peptide synthesizer (Foster City, CA) using F-moc chemistry.
Proliferative response
Lymph node (LN) cells of mice immunized with 100 µg of MOG35–55 in CFA (Difco Laboratories, Detroit, MI) were removed 10 days after immunization and cultured for 72 h in 96-well plates in HL-1 medium (BioWhittaker, Walkersville, MD) in the presence of various concentrations of peptide. They were pulsed with 1 µCi of [3H]thymidine for the last 16 to 18 h, and the mean incorporation of thymidine in insoluble DNA in the triplicate wells was determined in a scintillation counter (model LS 5000; Beckman Instruments, Fullerton, CA).
Cytokine ELISA and ELISPOT
LN cells derived from immunized mice were activated in vitro
with the peptide. Culture supernatants were harvested at 24 or 48
h, and the ELISAs were performed as described previously (14). Briefly,
96-well plates were coated overnight with the capture Ab (1 µg/ml)
specific for a particular cytokine. The plates were washed and
incubated with a blocking solution (Kirkegaard and Perry, Gaithersburg,
MD). Culture supernatants and standards were incubated overnight at
4°C. The plates were then washed and incubated with biotinylated
anti-cytokine-detecting mAb (1 µg/ml) for 1 h. The plates
were developed by adding avidin peroxidase and its substrate. The Ab
pairs used were: IL-10, JES5-2A5 and SXC-1; IL-5, TRFK5 and TRFK4;
IFN-, R4-6A2 and XMG1.2; TNF-, MP6-XT22 and Rbt a-Ms/Rt TNF-
(all from PharMingen, San Diego, CA).
For detection of cytokine by ELISPOT, LN cells derived from mice immunized with MOG35–55 were stimulated for 8 h with the peptide. Cells (8 x 104) were then incubated overnight at 37°C in a sterile nitrocellulose-based 96-well microplate (Millipore, Bedford, MA) coated with the capture Ab. The development of ELISPOT was performed as for ELISA except that the spots were revealed by avidin-alkaline phosphatase and its substrates (Sigma, St. Louis, MO, and Life Technologies, Gaithersburg, MD). The number of spots for each cytokine was counted under a dissecting microscope and expressed as the number of positive spots/106 cells.
Preparation and maintenance of T cell lines
C57BL/6, IL-4-/-, and IL-10-/- mice were immunized s.c. in the flank with 100 µg of MOG35–55 in CFA. LN cells were removed 10 days after immunization and cultured with MOG35–55 in complete RPMI 1640 medium (L-glutamine, 5 x 10-5 M ß-mercaptoethanol, 100 U/µg penicillin/streptomycin) (BioWhittaker) supplemented with 10% FCS. The cells were subsequently stimulated with syngenic spleen cells as APCs and MOG35–55 every 10 to 15 days and maintained in 10% FCS complete RPMI supplemented with 0.6% T-stim (Collaborative Biomedical Products, Bedford, MA).
Induction and assessment of EAE
By active immunization. C57BL/6, IL-10-/-, and IL-4-/- mice were injected s.c. in the flank with an emulsion containing 200 µg of the peptide MOG35–55, which is the encephalitogenic epitope in C57BL/6 (H-2b) mice (24) and CFA supplemented with 400 µg of Mycobacterium tuberculosis H37 Ra (Difco Laboratories). In some experiments, mice also received 200 ng of pertussis toxin (List Biological Laboratories, Campbell, CA) i.v. on day 0 and day 2. IL-10 and IL-4 transgenic mice and (FVB x SJL)F1 nontransgenic mice were injected as described above with 100 µg of the whole PLP, which induces potent EAE in SJL mice (25). Although MOG35–55 peptide can induce very potent disease in B6 mice, this encephalitogenic peptide does not induce disease in the (FVB x SJL)F1 (H-2qxs) mice; therefore, whole PLP was used for inducing disease in the F1 mice.
By adoptive transfer of T cell lines. T cell lines derived from C57BL/6 WT, IL-10-/-, and IL-4-/- mice were stimulated with 20 µg/ml of MOG35–55. Four days later, cells were washed and resuspended in PBS, then, 107 cells were injected i.v. into C57BL/6 WT mice. Where indicated, mice also received an injection of 200 ng of pertussis toxin immediately after cell transfer and 2 days later.
Mice were observed daily and assessed for clinical signs of disease according to the following criteria: 0, no disease; 1, limp tail; 2, hind leg weakness or partial paralysis; 3, complete hind leg paralysis; 4, front and hind limb paralysis; 5, moribund state. Mean clinical score was calculated as follows: individual score were added and divided by the total number of mice in each group for each day of observation; this included the animals that did not develop any disease. Animals were sacrificed at the termination of the experiment (experiment with pertussis toxin) or at the peak of disease (experiment without pertussis toxin). Brains and spinal cords were removed and fixed in 10% formalin. Paraffin-embedded sections were stained with Luxol fast blue-hematoxylin and eosin for light microscopy. Inflammatory foci were counted in meninges and parenchyma as described previously (26).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To investigate the relative roles of IL-10 and IL-4 in the
development of EAE, we immunized IL-10-/- and
IL-4-/- mice with the encephalitogenic
MOG35–55 peptide in CFA plus pertussis toxin. We first
compared EAE development in IL-10-/- and C57BL/6 WT mice.
As shown in Figure 1
A and
Table I, IL-10-/- mice were
highly susceptible to disease in that all these mice developed EAE and
the disease was significantly more severe than in the control WT mice.
In this experiment, WT mice showed a complete remission of disease
after the first acute episode, but the IL-10-/- mice
developed a chronic and persistent disease with no evidence of
remission. The severe and persistent disease observed in mice lacking
IL-10 suggests that IL-10 is important for limiting EAE progression. We
repeated the experiment with the addition of IL-4-/-
mice. The IL-4-/- mice developed more severe disease than
WT mice (Fig. 1B and Table I). However, there was no
significant difference in the incidence of disease between these two
groups (Table I). IL-10-/- mice developed more severe
disease than IL-4-/- and WT mice (Fig. 1B and
Table I). In these experiments, pertussis toxin was used as an adjuvant
in the induction of EAE. To further test the differences in
susceptibility between the groups, mice were immunized with the
encephalitogenic peptide alone, without the toxin (Fig. 1C
and Table I). With this protocol, the majority (92%) of
IL-10-/- mice developed EAE with a mean clinical score of
2.7. In contrast, only 17% of either WT or IL-4-/- mice
developed EAE. The two mice in the WT group that developed EAE also
showed a very late onset of disease. Histopathologic analysis of the
brains and spinal cords of these mice was performed (Table I). We did
not see any differences in the number of inflammatory foci between
groups of mice immunized with MOG35–55 plus pertussis
toxin. However, brains and spinal cords from IL-10-/-
mice immunized with the peptide without addition of toxin showed higher
numbers of inflammatory foci compared with WT or IL-4-/-
mice. The greater susceptibility and severity of disease in
IL-10-/- mice suggests that IL-10 probably plays a
central role in the regulation of EAE.
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To study the mechanism, we tested whether the absence of IL-10
affected the induction and expansion of MOG35–55-specific
T cell responses. We immunized groups of IL-10-/-,
IL-4-/-, and WT mice with MOG35–55, and 10
days later we measured the proliferative responses of the LN cells to
the immunizing MOG peptide and control MOG92–106 peptide.
As shown in Figure 2A, LN
cells derived from WT and IL-4-/- mice showed similar
proliferation to the peptide. By contrast, equal numbers of LN cells
from IL-10-/- mice showed significant proliferation at
lower doses of the peptide, and proliferation was higher at most of the
peptide doses tested. We also analyzed the expression of the CD62L
marker—an L-selectin expressed on all leukocytes, which is
down-regulated on T lymphocytes upon activation (27)—on the surface of
LN and spleen cells derived from mice 6 days following immunization
with MOG35–55. We found that 59% of LN
CD4+ T cells and 71% of splenic CD4+ T cells
in IL-10-/- mice have down-regulated the CD62L marker
compared with 21% of LN and 23% splenic CD4+ T cells in
WT mice; and 23% of LN and 37% of splenic CD4+ T cells in
IL-4-/- mice (data not shown). These data suggest that in
the absence of IL-10, relatively more T cells become activated and
proliferate in response to MOG35–55.
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and TNF-
cytokines and the anti-inflammatory cytokines (IL-4 and IL-10)
48 h after stimulation with different dosages of
MOG35–55. As shown in Figure 2
B, cells derived
from IL-4-/- and WT mice produced much lower levels of
IFN- compared with LN cells derived from IL-10-/-
mice. The supernatants from the LN cells did not show detectable
production of IL-2 or of the anti-inflammatory cytokines IL-4 and
IL-10 (data not shown). To determine whether the increased cytokine
production was due to an increased expansion of Ag-specific cells, LN
cells from mice immunized with MOG35–55 were harvested and
stimulated in vitro with the peptide for 6 h, then tested for
IFN- and TNF- production by individual cells using the ELISPOT
technique. The numbers of cells producing TNF- and IFN- were very
high in IL-10-/- cells 6 h after stimulation with
the peptide, whereas fewer IL-4-/- and WT cells secreted
these cytokines (Fig. 2, C and D). These data
indicate that the frequency of IFN-- and TNF--producing cells is
increased by encephalitogenic Ag stimulation in IL-10-/-
mice.
To differentiate whether the cytokines were produced by T cells or
other cells in the unseparated LN cells, short term
MOG35–55 T cell lines were generated and reactivated with
plate-bound anti-CD3 mAb. We found that, in addition to IFN-, T
cells derived from WT mice secreted large quantities of IL-10 and IL-5,
indicating their ability to produce Th2 cytokines in addition to Th1
cytokines (Fig. 3, A and
B). By contrast, T cells from IL-4-/- and
IL-10-/- mice secreted a lower level or no IL-10,
respectively, and T cells from both groups produced a lower level of
IL-5 (Fig. 3, A and B). We did not detect
significant levels of IL-4 in the supernatants from the three groups.
We confirmed that T cells derived from IL-10-/- mice
produced a large amount of TNF-, while comparatively low amounts of
this cytokine were secreted by T cells from WT and
IL-4-/- mice (Fig. 3C). These results show
that IL-10 plays a central role in down-regulating IFN- and TNF-
production by autoreactive T cells and that IL-4 does not appear to
inhibit production of proinflammatory cytokine to the same extent.
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Since IL-10 is produced by both T cells and APCs, it was not clear
whether the enhanced disease in IL-10-/- mice was due to
a lack of regulation of T cell responses by IL-10 produced by the APC
compartment or whether T cells from the IL-10-deficient mice were more
pathogenic. To address this issue, we generated long term T cell lines
specific for the MOG35–55 from the WT and IL-4- and
IL-10-deficient mice. The T cell lines were stimulated three to four
times with the peptide, and 4 days after the last stimulation, T cells
were transferred into naive C57BL/6 mice that were either left
untreated or were further injected with pertussis toxin. As shown in
Figure 4A, WT mice that
received lines derived from C57BL/6 mice (B6.31) developed no disease
if the toxin was not injected but developed a mild disease if pertussis
toxin was coinjected with the T cells. Lines derived from
IL-4-/- mice (4.21) induced a more severe disease in WT
C57BL/6 mice that were not injected with the toxin, but all of the mice
recovered spontaneously without any signs of relapse (Fig. 4B). However, when 4.21 T cell lines were injected together
with pertussis toxin, the severity of the disease was enhanced and the
disease was persistent (Fig. 4B). The mice that received T
cell lines derived from IL-10-/- mice (10.22) but without
any pertussis toxin developed fulminant disease and died by day 9 after
the transfer (Fig. 4C). In contrast, the mice that received
10.22 T cell lines together with the toxin developed disease within a
week, but these mice recovered spontaneously. These data demonstrate
that the encephalitogenic T cell lines derived from IL-10-deficient
mice induce a lethal EAE and that pertussis toxin permits recovery of
mice, possibly by hyperstimulating and promoting
activation-induced cell death in these T cells.
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Inasmuch as studies with IL-10-/- and
IL-4-/- mice demonstrated a role for IL-10 in limiting
EAE, we attempted to confirm this by inducing disease in transgenic
mice overexpressing IL-4 and IL-10 in T cells (Fig. 5). Since IL-4 and IL-10 transgenic mice
were available only on the FVB background, which is not susceptible to
EAE, we made an F1 cross between SJL and FVB mice. The
F1 mice were immunized with whole PLP in CFA to induce EAE.
Using this protocol, we induced disease with a mean maximum score of
2.4 in 66% of the (FVB x SJL)F1 mice. The (FVB
x SJL)F1 UD (IL-4 transgenic) mice developed a disease
with a slighly lower incidence (60%) as compared with the (FVB x
SJL)F1 WT mice (p < 0.03
calculated with Fisher’s exact test) with a mean maximum score of 2.2.
However, (FVB x SJL)F1 UR (IL-10 transgenic) mice
were completely resistant to induction of EAE (Fig. 5). The disease
incidence of IL-10 transgenic mice was significantly different
(p < 0.005) when compared with the
F1 control mice. None of the mice showed any clinical sign
of disease. These data demonstrate that overexpression of IL-10
completely inhibits clinical signs of disease and protects the animals
from developing EAE. The lack of disease in the IL-10 transgenic mice
was not due to the lack of a T cell response to the immunizing protein,
since we found that T cells from IL-10 transgenic mice develop a good
proliferative response to the PLP (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cytokines play a pivotal role in the initiation or regulation of
autoimmune disease, and detailed in vivo studies looking at EAE lesions
in the CNS implicate Th1 cytokines in the progression of disease and
Th2 cytokines in disease remission (7). Kennedy et al. found that mRNA
for TNF- was present in the CNS of mice during clinical episodes
(8). Using in situ methods, they also found that IFN- peaked before
the disease, strongly suggesting that Th1 cytokines play an important
role in the pathogenesis of the disease especially in its initiation.
However, IL-10 and IL-4 mRNAs were detected only during disease
remission. The remission phase of the disease was also associated with
increased levels of TGF-ß (6). However, conflicting results have been
obtained when recombinant cytokines have been administered in vivo.
Treatment of mice with IL-4, in an adoptive transfer experiment,
resulted in an amelioration of EAE (9); on the other hand, a recent
report shows that IL-4 treatment was ineffective in inhibiting disease
(29). While Rott et al. found that administration of IL-10 during the
induction phase of EAE in rats could suppress the clinical signs of the
disease (17), Cannella et al. showed that injection of IL-10 in mice
worsened its clinical course (18). Systemic administration of cytokines
raises potential problems because of their short half-life and the
issue of access to the appropriate organ. Furthermore, because of the
complex interplay of cytokines it is difficult to know when, during the
establishment of disease, cytokines are produced and where regulation
occurs. Thus, administration of cytokines may not mimic their in vivo
expression in the tissue microenvironment. Although,
cytokine-transgenic and -deficient mice also do not provide a
physiologic way of analyzing the overexpression or deficiency of a
particular cytokine on the disease phenotype, nonetheless these mice
provide the best tools available at the present time. The use of
conditional knock out with cell type-specific loss or overexpression of
a specific cytokine may, in the future, provide a better model to
understand how these cytokines are regulating disease induction and
progression.
While analyzing the mechanism by which IL-10-/- mice
developed such severe disease, it became clear that LN cells from
IL-10-/- mice developed a higher proliferative response
with the production of more Th1 cytokines when compared with the LN
cells from the IL-4-/- or WT mice immunized identically
with the same myelin Ag. This suggests that the increased incidence and
severity of disease in the IL-10-deficient mice may be due to more
rapid expansion of myelin Ag-reactive T cells and/or enhanced
production of Th1 cytokines from T cell lines following Ag-specific
activation. Our results cannot differentiate whether increased severity
and incidence of disease in the IL-10-/- mice is due to
more expansion of pathogenic T cells following active immunization, to
a higher frequency of myelin Ag-specific T cells, or to both. Our
ongoing studies with the generation of T cell clones from the different
mouse strains and adoptive transfer of equal numbers of the T cell
clones from each of the lines will directly address this issue. These
data also raise an important question of whether IL-10 normally plays a
role in regulating the size of the expanded population of T cells and
the type and the amount of Th1 cytokines produced following specific
immunization? In support of this hypothesis are the data showing that
the T cell lines derived from C57BL/6 control mice immunized with the
encephalitogenic peptide MOG35–55 besides producing Th1 cytokines also
produce IL-10 and IL-5. These T cell lines do not induce as potent EAE
when transferred into wild-type mice compared with T cell lines from
IL-10-/- mice, suggesting that IL-10 producing T cells
are normally induced following immunization, and these T cells probably
play a critical role in keeping immune responses under control.
Similarly, an immunoregulatory role of IL-10 has been shown in a number
of other system; a nonlytic IL-10/Fc fusion protein was found to block
autoimmunity and prevent diabetes (31) and administration of rhIL-10
was found to inhibit autoimmune thyroiditis (32). Sundstedt et al.
found that repeating injection of SEA in mice results in a T cell
hyporesponsiveness characterized by an impaired IFN- and TNF-
production and with an increased IL-10 response called "Th10" (33).
A recent evidence supports that the inhibitory effects of IL-10 may be
due to induction of a regulatory T cell population. Groux et al.
reported that IL-10 gives rise to CD4+ T cell clones, which
themselves produce high levels of IL-10 with little or no IL-4 or IL-2
(34). These T cells suppress the proliferation of CD4+ T
cells and prevent colitis when transferred into SCID mice. The authors
designated these IL-10-producing T cells as Tr1, a unique subset of
regulatory T cells that have the capacity to suppress Ag-specific
immune responses and actively down-regulate autoimmune responses in
vivo. It is likely that in IL-10-/- mice this regulatory
population of Tr1 cells is not generated, thus leading to enhanced
Ag-specific proliferative responses and more intense autoimmunity, as
demonstrated by the increased severity and incidence of EAE.
We and others previously reported that myelin Ag-specific IL-4- and
IL-10-producing Th2 cells could inhibit EAE if given at the time of
immunization and could reverse disease if given at the first signs of
EAE (14, 30, 35, 36). These data have been further supported by the
results from other groups showing that myelin Ag-reactive T cells
transduced with a retroviral vector containing the IL-4 gene or T cells
transfected with IL-10 cDNA could both inhibit and/or reverse EAE (15, 16). The higher disease severity and incidence observed in
IL-10-/- and IL-4-/- mice compared with WT
mice favor a protective role of these Th2 cytokines in the development
of EAE. However, our results suggest that both cytokines are not
equally protective. IL-10, and to a lesser extent IL-4, seems to be
essential for limiting TNF- and IFN- production (Fig. 2, B–D). Besides its role in the generation of
regulatory Tr1 cells and inhibition of autopathogenic Th1 cell
generation, IL-10 may protect from the development of autoimmunity by
inhibiting the production of proinflammatory cytokines and the
activation of macrophages that have been implicated in the pathogenesis
of EAE.
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Acknowledgments |
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Footnotes |
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2 Current address: Millennium Pharmaceuticals Inc., Cambridge, MA 02139.
3 Address correspondence and reprint requests to Dr. Vijay K. Kuchroo, Center for Neurologic Diseases, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail address:
4 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; ELISPOT, enzyme-linked immunospot; MOG, myelin oligodendrocyte glycoprotein; IL-10-/-, IL-10-deficient; IL-4-/-, IL-4-deficient; LN, lymph node; CNS, central nervous system; PLP, proteolipid protein; WT, wild type.
Received for publication March 5, 1998. Accepted for publication May 29, 1998.
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ß-transgenic system. Proc. Natl. Acad. Sci. USA 89:6065.4 integrin by CD4 T cells is required for their entry into brain parenchyma. J. Exp. Med. 177:57.This article has been cited by other articles:
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  D. Frenkel, A. S. Pachori, L. Zhang, A. Dembinsky-Vaknin, D. Farfara, S. Petrovic-Stojkovic, V. J. Dzau, and H. L. Weiner Nasal vaccination with troponin reduces troponin specific T-cell responses and improves heart function in myocardial ischemia-reperfusion injury Int. Immunol., July 1, 2009; 21(7): 817 - 829. [Abstract] [Full Text] [PDF]
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P. De Sarno, R. C. Axtell, C. Raman, K. A. Roth, D. R. Alessi, and R. S. Jope Lithium Prevents and Ameliorates Experimental Autoimmune Encephalomyelitis J. Immunol., July 1, 2008; 181(1): 338 - 345. [Abstract] [Full Text] [PDF]
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D. L. Smith-Bouvier, A. A. Divekar, M. Sasidhar, S. Du, S. K. Tiwari-Woodruff, J. K. King, A. P. Arnold, R. R. Singh, and R. R. Voskuhl A role for sex chromosome complement in the female bias in autoimmune disease J. Exp. Med., May 12, 2008; 205(5): 1099 - 1108. [Abstract] [Full Text] [PDF]
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S. Reinwald, C. Wiethe, A. M. Westendorf, M. Breloer, M. Probst-Kepper, B. Fleischer, A. Steinkasserer, J. Buer, and W. Hansen CD83 Expression in CD4+ T Cells Modulates Inflammation and Autoimmunity J. Immunol., May 1, 2008; 180(9): 5890 - 5897. [Abstract] [Full Text] [PDF]
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H. Sasaki, N. Suzuki, R. Kent Jr., N. Kawashima, J. Takeda, and P. Stashenko T Cell Response Mediated by Myeloid Cell-Derived IL-12 Is Responsible for Porphyromonas gingivalis-Induced Periodontitis in IL-10-Deficient Mice J. Immunol., May 1, 2008; 180(9): 6193 - 6198. [Abstract] [Full Text] [PDF]
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 A. R. Folgueras, A. Fueyo, O. Garcia-Suarez, J. Cox, A. Astudillo, P. Tortorella, C. Campestre, A. Gutierrez-Fernandez, M. Fanjul-Fernandez, C. J. Pennington, et al. Collagenase-2 Deficiency or Inhibition Impairs Experimental Autoimmune Encephalomyelitis in Mice J. Biol. Chem., April 4, 2008; 283(14): 9465 - 9474. [Abstract] [Full Text] [PDF]
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S. Scabeni, M. Lapilla, S. Musio, B. Gallo, E. Ciusani, L. Steinman, R. Mantegazza, and R. Pedotti CD4+CD25+ Regulatory T Cells Specific for a Thymus-Expressed Antigen Prevent the Development of Anaphylaxis to Self J. Immunol., April 1, 2008; 180(7): 4433 - 4440. [Abstract] [Full Text] [PDF]
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R. K. Selvaraj and T. L. Geiger Mitigation of Experimental Allergic Encephalomyelitis by TGF-{beta} Induced Foxp3+ Regulatory T Lymphocytes through the Induction of Anergy and Infectious Tolerance J. Immunol., March 1, 2008; 180(5): 2830 - 2838. [Abstract] [Full Text] [PDF]
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B. Zhu, Y. Bando, S. Xiao, K. Yang, A. C. Anderson, V. K. Kuchroo, and S. J. Khoury CD11b+Ly-6Chi Suppressive Monocytes in Experimental Autoimmune Encephalomyelitis J. Immunol., October 15, 2007; 179(8): 5228 - 5237. [Abstract] [Full Text] [PDF]
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 E. D. Ponomarev, K. Maresz, Y. Tan, and B. N. Dittel CNS-Derived Interleukin-4 Is Essential for the Regulation of Autoimmune Inflammation and Induces a State of Alternative Activation in Microglial Cells J. Neurosci., October 3, 2007; 27(40): 10714 - 10721. [Abstract] [Full Text] [PDF]
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S. Xiao, N. Najafian, J. Reddy, M. Albin, C. Zhu, E. Jensen, J. Imitola, T. Korn, A. C. Anderson, Z. Zhang, et al. Differential engagement of Tim-1 during activation can positively or negatively costimulate T cell expansion and effector function J. Exp. Med., July 9, 2007; 204(7): 1691 - 1702. [Abstract] [Full Text] [PDF]
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T. Chitnis, J. Imitola, Y. Wang, W. Elyaman, P. Chawla, M. Sharuk, K. Raddassi, R. T. Bronson, and S. J. Khoury Elevated Neuronal Expression of CD200 Protects Wlds Mice from Inflammation-Mediated Neurodegeneration Am. J. Pathol., May 1, 2007; 170(5): 1695 - 1712. [Abstract] [Full Text] [PDF]
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K. J. Staples, T. Smallie, L. M. Williams, A. Foey, B. Burke, B. M. J. Foxwell, and L. Ziegler-Heitbrock IL-10 Induces IL-10 in Primary Human Monocyte-Derived Macrophages via the Transcription Factor Stat3 J. Immunol., April 15, 2007; 178(8): 4779 - 4785. [Abstract] [Full Text] [PDF]
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M. K. Mann, K. Maresz, L. P. Shriver, Y. Tan, and B. N. Dittel B Cell Regulation of CD4+CD25+ T Regulatory Cells and IL-10 Via B7 is Essential for Recovery From Experimental Autoimmune Encephalomyelitis J. Immunol., March 15, 2007; 178(6): 3447 - 3456. [Abstract] [Full Text] [PDF]
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J. Ochoa-Reparaz, C. Riccardi, A. Rynda, S. Jun, G. Callis, and D. W. Pascual Regulatory T Cell Vaccination without Autoantigen Protects against Experimental Autoimmune Encephalomyelitis J. Immunol., February 1, 2007; 178(3): 1791 - 1799. [Abstract] [Full Text] [PDF]
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M. A. Kleinschek, A. M. Owyang, B. Joyce-Shaikh, C. L. Langrish, Y. Chen, D. M. Gorman, W. M. Blumenschein, T. McClanahan, F. Brombacher, S. D. Hurst, et al. IL-25 regulates Th17 function in autoimmune inflammation J. Exp. Med., January 22, 2007; 204(1): 161 - 170. [Abstract] [Full Text] [PDF]
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A. Hilliard, B. Hilliard, S.-J. Zheng, H. Sun, T. Miwa, W. Song, R. Goke, and Y. H. Chen Translational Regulation of Autoimmune Inflammation and Lymphoma Genesis by Programmed Cell Death 4 J. Immunol., December 1, 2006; 177(11): 8095 - 8102. [Abstract] [Full Text] [PDF]
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K. M. Spach, F. E. Nashold, B. N. Dittel, and C. E. Hayes IL-10 Signaling Is Essential for 1,25-Dihydroxyvitamin D3-Mediated Inhibition of Experimental Autoimmune Encephalomyelitis J. Immunol., November 1, 2006; 177(9): 6030 - 6037. [Abstract] [Full Text] [PDF]
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C. Gianfrani, M. K. Levings, C. Sartirana, G. Mazzarella, G. Barba, D. Zanzi, A. Camarca, G. Iaquinto, N. Giardullo, S. Auricchio, et al. Gliadin-Specific Type 1 Regulatory T Cells from the Intestinal Mucosa of Treated Celiac Patients Inhibit Pathogenic T Cells J. Immunol., September 15, 2006; 177(6): 4178 - 4186. [Abstract] [Full Text] [PDF]
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A. Agrawal, S. Dillon, T. L. Denning, and B. Pulendran ERK1-/- Mice Exhibit Th1 Cell Polarization and Increased Susceptibility to Experimental Autoimmune Encephalomyelitis J. Immunol., May 15, 2006; 176(10): 5788 - 5796. [Abstract] [Full Text] [PDF]
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Y. Jee, R. Liu, X.-F. Bai, D. I. Campagnolo, F.-D. Shi, and T. L. Vollmer Do Th2 cells mediate the effects of glatiramer acetate in experimental autoimmune encephalomyelitis? Int. Immunol., April 1, 2006; 18(4): 537 - 544. [Abstract] [Full Text] [PDF]
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A. S. Paintlia, M. K. Paintlia, I. Singh, and A. K. Singh IL-4-Induced Peroxisome Proliferator-Activated Receptor {gamma} Activation Inhibits NF-{kappa}B Trans Activation in Central Nervous System (CNS) Glial Cells and Protects Oligodendrocyte Progenitors under Neuroinflammatory Disease Conditions: Implication for CNS-Demyelinating Diseases J. Immunol., April 1, 2006; 176(7): 4385 - 4398. [Abstract] [Full Text] [PDF]
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T. Matsuki, S. Nakae, K. Sudo, R. Horai, and Y. Iwakura Abnormal T cell activation caused by the imbalance of the IL-1/IL-1R antagonist system is responsible for the development of experimental autoimmune encephalomyelitis Int. Immunol., February 1, 2006; 18(2): 399 - 407. [Abstract] [Full Text] [PDF]
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G.-X. Zhang, S. Yu, B. Gran, and A. Rostami Glucosamine Abrogates the Acute Phase of Experimental Autoimmune Encephalomyelitis by Induction of Th2 Response J. Immunol., December 1, 2005; 175(11): 7202 - 7208. [Abstract] [Full Text] [PDF]
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K. Miyamoto, C. I. Kingsley, X. Zhang, C. Jabs, L. Izikson, R. A. Sobel, H. L. Weiner, V. K. Kuchroo, and A. H. Sharpe The ICOS Molecule Plays a Crucial Role in the Development of Mucosal Tolerance J. Immunol., December 1, 2005; 175(11): 7341 - 7347. [Abstract] [Full Text] [PDF]
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S. Jun, W. Gilmore, G. Callis, A. Rynda, A. Haddad, and D. W. Pascual A Live Diarrheal Vaccine Imprints a Th2 Cell Bias and Acts as an Anti-Inflammatory Vaccine J. Immunol., November 15, 2005; 175(10): 6733 - 6740. [Abstract] [Full Text] [PDF]
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N. D. Powell, T. L. Papenfuss, M. A. McClain, I. E. Gienapp, T. M. Shawler, A. R. Satoskar, and C. C. Whitacre Cutting Edge: Macrophage Migration Inhibitory Factor Is Necessary for Progression of Experimental Autoimmune Encephalomyelitis J. Immunol., November 1, 2005; 175(9): 5611 - 5614. [Abstract] [Full Text] [PDF]
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M. J. McGeachy, L. A. Stephens, and S. M. Anderton Natural Recovery and Protection from Autoimmune Encephalomyelitis: Contribution of CD4+CD25+ Regulatory Cells within the Central Nervous System J. Immunol., September 1, 2005; 175(5): 3025 - 3032. [Abstract] [Full Text] [PDF]
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 D. J. Mekala, R. S. Alli, and T. L. Geiger IL-10-dependent infectious tolerance after the treatment of experimental allergic encephalomyelitis with redirected CD4+CD25+ T lymphocytes PNAS, August 16, 2005; 102(33): 11817 - 11822. [Abstract] [Full Text] [PDF]
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Z. Illes, H. Waldner, J. Reddy, E. Bettelli, L. B. Nicholson, and V. K. Kuchroo T Cell Tolerance Induced by Cross-Reactive TCR Ligands Can Be Broken by Superagonist Resulting in Anti-Inflammatory T Cell Cytokine Production J. Immunol., August 1, 2005; 175(3): 1491 - 1497. [Abstract] [Full Text] [PDF]
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N. Nath, S. Giri, R. Prasad, M. L. Salem, A. K. Singh, and I. Singh 5-Aminoimidazole-4-Carboxamide Ribonucleoside: A Novel Immunomodulator with Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis J. Immunol., July 1, 2005; 175(1): 566 - 574. [Abstract] [Full Text] [PDF]
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 H. H. van den Broek, J. G. Damoiseaux, M. H De Baets, and R. M. Hupperts The influence of sex hormones on cytokines in multiple sclerosis and experimental autoimmune encephalomyelitis: a review Multiple Sclerosis, June 1, 2005; 11(3): 349 - 359. [Abstract] [PDF]
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M. Wallberg and R. A. Harris Co-infection with Trypanosoma brucei brucei prevents experimental autoimmune encephalomyelitis in DBA/1 mice through induction of suppressor APCs Int. Immunol., June 1, 2005; 17(6): 721 - 728. [Abstract] [Full Text] [PDF]
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 L. U. Buxbaum and P. Scott Interleukin 10- and Fc{gamma} Receptor-Deficient Mice Resolve Leishmania mexicana Lesions Infect. Immun., April 1, 2005; 73(4): 2101 - 2108. [Abstract] [Full Text] [PDF]
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 M. Kleinewietfeld, F. Puentes, G. Borsellino, L. Battistini, O. Rotzschke, and K. Falk CCR6 expression defines regulatory effector/memory-like cells within the CD25+CD4+ T-cell subset Blood, April 1, 2005; 105(7): 2877 - 2886. [Abstract] [Full Text] [PDF]
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D. J. Mekala, R. S. Alli, and T. L. Geiger IL-10-Dependent Suppression of Experimental Allergic Encephalomyelitis by Th2-Differentiated, Anti-TCR Redirected T Lymphocytes J. Immunol., March 15, 2005; 174(6): 3789 - 3797. [Abstract] [Full Text] [PDF]
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J. N. H. Stern, Z. Illes, J. Reddy, D. B. Keskin, M. Fridkis-Hareli, V. K. Kuchroo, and J. L. Strominger Peptide 15-mers of defined sequence that substitute for random amino acid copolymers in amelioration of experimental autoimmune encephalomyelitis PNAS, February 1, 2005; 102(5): 1620 - 1625. [Abstract] [Full Text] [PDF]
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J. N. H. Stern, Z. Illes, J. Reddy, D. B. Keskin, E. Sheu, M. Fridkis-Hareli, H. Nishimura, C. F. Brosnan, L. Santambrogio, V. K. Kuchroo, et al. Amelioration of proteolipid protein 139-151-induced encephalomyelitis in SJL mice by modified amino acid copolymers and their mechanisms PNAS, August 10, 2004; 101(32): 11743 - 11748. [Abstract] [Full Text] [PDF]
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Z. Illes, J. N. H. Stern, J. Reddy, H. Waldner, M. P. Mycko, C. F. Brosnan, S. Ellmerich, D. M. Altmann, L. Santambrogio, J. L. Strominger, et al. Modified amino acid copolymers suppress myelin basic protein 85-99-induced encephalomyelitis in humanized mice through different effects on T cells PNAS, August 10, 2004; 101(32): 11749 - 11754. [Abstract] [Full Text] [PDF]
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A. C. Anderson, J. Reddy, R. Nazareno, R. A. Sobel, L. B. Nicholson, and V. K. Kuchroo IL-10 Plays an Important Role in the Homeostatic Regulation of the Autoreactive Repertoire in Naive Mice J. Immunol., July 15, 2004; 173(2): 828 - 834. [Abstract] [Full Text] [PDF]
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R. Furlan MBP-Specific Experimental Autoimmune Encephalomyelitis in C57BL/6 Mice J. Immunol., July 1, 2004; 173(1): 5 - 5. [Full Text] [PDF]
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B. Greve, L. Vijayakrishnan, A. Kubal, R. A. Sobel, L. B. Peterson, L. S. Wicker, and V. K. Kuchroo The Diabetes Susceptibility Locus Idd5.1 on Mouse Chromosome 1 Regulates ICOS Expression and Modulates Murine Experimental Autoimmune Encephalomyelitis J. Immunol., July 1, 2004; 173(1): 157 - 163. [Abstract] [Full Text] [PDF]
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D. E. Faunce and J. Stein-Streilein The Authors Respond J. Immunol., July 1, 2004; 173(1): 5 - 6. [Full Text] [PDF]
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H. J. Kim, I. Ifergan, J. P. Antel, R. Seguin, M. Duddy, Y. Lapierre, F. Jalili, and A. Bar-Or Type 2 Monocyte and Microglia Differentiation Mediated by Glatiramer Acetate Therapy in Patients with Multiple Sclerosis J. Immunol., June 1, 2004; 172(11): 7144 - 7153. [Abstract] [Full Text] [PDF]
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A. Skapenko, G. U. Niedobitek, J. R. Kalden, P. E. Lipsky, and H. Schulze-Koops Generation and Regulation of Human Th1-Biased Immune Responses In Vivo: A Critical Role for IL-4 and IL-10 J. Immunol., May 15, 2004; 172(10): 6427 - 6434. [Abstract] [Full Text] [PDF]
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P. Mana, M. Goodyear, C. Bernard, R. Tomioka, M. Freire-Garabal, and D. Linares Tolerance induction by molecular mimicry: prevention and suppression of experimental autoimmune encephalomyelitis with the milk protein butyrophilin Int. Immunol., March 1, 2004; 16(3): 489 - 499. [Abstract] [Full Text] [PDF]
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D. E. Faunce, A. Terajewicz, and J. Stein-Streilein Cutting Edge: In Vitro-Generated Tolerogenic APC Induce CD8+ T Regulatory Cells That Can Suppress Ongoing Experimental Autoimmune Encephalomyelitis J. Immunol., February 15, 2004; 172(4): 1991 - 1995. [Abstract] [Full Text] [PDF]
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Y. Inoue, T. Otsuka, H. Niiro, S. Nagano, Y. Arinobu, E. Ogami, M. Akahoshi, K. Miyake, I. Ninomiya, S. Shimizu, et al. Novel Regulatory Mechanisms of CD40-Induced Prostanoid Synthesis by IL-4 and IL-10 in Human Monocytes J. Immunol., February 15, 2004; 172(4): 2147 - 2154. [Abstract] [Full Text] [PDF]
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X. Zhang, D. N. Koldzic, L. Izikson, J. Reddy, R. F. Nazareno, S. Sakaguchi, V. K. Kuchroo, and H. L. Weiner IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells Int. Immunol., February 1, 2004; 16(2): 249 - 256. [Abstract] [Full Text] [PDF]
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 E. L. Oleszak, J. R. Chang, H. Friedman, C. D. Katsetos, and C. D. Platsoucas Theiler's Virus Infection: a Model for Multiple Sclerosis Clin. Microbiol. Rev., January 1, 2004; 17(1): 174 - 207. [Abstract] [Full Text] [PDF]
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R. S. Klein, L. Izikson, T. Means, H. D. Gibson, E. Lin, R. A. Sobel, H. L. Weiner, and A. D. Luster IFN-Inducible Protein 10/CXC Chemokine Ligand 10-Independent Induction of Experimental Autoimmune Encephalomyelitis J. Immunol., January 1, 2004; 172(1): 550 - 559. [Abstract] [Full Text] [PDF]
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D. Frenkel, Z. Huang, R. Maron, D. N. Koldzic, W. W. Hancock, M. A. Moskowitz, and H. L. Weiner Nasal Vaccination with Myelin Oligodendrocyte Glycoprotein Reduces Stroke Size by Inducing IL-10-Producing CD4+ T Cells J. Immunol., December 15, 2003; 171(12): 6549 - 6555. [Abstract] [Full Text] [PDF]
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C. Weir, C. C. A. Bernard, and B. T. Backstrom IL-5-deficient mice are susceptible to experimental autoimmune encephalomyelitis Int. Immunol., November 1, 2003; 15(11): 1283 - 1289. [Abstract] [Full Text] [PDF]
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M. Khare, M. Rodriguez, and C. S. David HLA class II transgenic mice authenticate restriction of myelin oligodendrocyte glycoprotein-specific immune response implicated in multiple sclerosis pathogenesis Int. Immunol., April 1, 2003; 15(4): 535 - 546. [Abstract] [Full Text] [PDF]
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H. H. Hofstetter, C. L. Shive, and T. G. Forsthuber Pertussis Toxin Modulates the Immune Response to Neuroantigens Injected in Incomplete Freund's Adjuvant: Induction of Th1 Cells and Experimental Autoimmune Encephalomyelitis in the Presence of High Frequencies of Th2 Cells J. Immunol., July 1, 2002; 169(1): 117 - 125. [Abstract] [Full Text] [PDF]
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R. Lang, R. L. Rutschman, D. R. Greaves, and P. J. Murray Autocrine Deactivation of Macrophages in Transgenic Mice Constitutively Overexpressing IL-10 Under Control of the Human CD68 Promoter J. Immunol., April 1, 2002; 168(7): 3402 - 3411. [Abstract] [Full Text] [PDF]
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M. Jansson, V. Panoutsakopoulou, J. Baker, L. Klein, and H. Cantor Cutting Edge: Attenuated Experimental Autoimmune Encephalomyelitis in Eta-1/Osteopontin-Deficient Mice J. Immunol., March 1, 2002; 168(5): 2096 - 2099. [Abstract] [Full Text] [PDF]
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G.-X. Zhang, H. Xu, M. Kishi, D. Calida, and A. Rostami The Role of IL-12 in the Induction of Intravenous Tolerance in Experimental Autoimmune Encephalomyelitis J. Immunol., March 1, 2002; 168(5): 2501 - 2507. [Abstract] [Full Text] [PDF]
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S. Ehlers, J. Benini, H.-D. Held, C. Roeck, G. Alber, and S. Uhlig {alpha}{beta} T Cell Receptor-positive Cells and Interferon-{gamma}, but not Inducible Nitric Oxide Synthase, Are Critical for Granuloma Necrosis in a Mouse Model of Mycobacteria-induced Pulmonary Immunopathology J. Exp. Med., December 17, 2001; 194(12): 1847 - 1859. [Abstract] [Full Text] [PDF]
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C. D. Pack, A. E. Cestra, B. Min, K. L. Legge, L. Li, J. C. Caprio-Young, J. J. Bell, R. K. Gregg, and H. Zaghouani Neonatal Exposure to Antigen Primes the Immune System to Develop Responses in Various Lymphoid Organs and Promotes Bystander Regulation of Diverse T Cell Specificities J. Immunol., October 15, 2001; 167(8): 4187 - 4195. [Abstract] [Full Text] [PDF]
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A. C. M. Johansson, A.-S. Hansson, K. S. Nandakumar, J. Backlund, and R. Holmdahl IL-10-Deficient B10.Q Mice Develop More Severe Collagen-Induced Arthritis, but Are Protected from Arthritis Induced with Anti-Type II Collagen Antibodies J. Immunol., September 15, 2001; 167(6): 3505 - 3512. [Abstract] [Full Text] [PDF]
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S. M. Liva and R. R. Voskuhl Testosterone Acts Directly on CD4+ T Lymphocytes to Increase IL-10 Production J. Immunol., August 15, 2001; 167(4): 2060 - 2067. [Abstract] [Full Text] [PDF]
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A. Ito, B. F. Bebo Jr., A. Matejuk, A. Zamora, M. Silverman, A. Fyfe-Johnson, and H. Offner Estrogen Treatment Down-Regulates TNF-{{alpha}} Production and Reduces the Severity of Experimental Autoimmune Encephalomyelitis in Cytokine Knockout Mice J. Immunol., July 1, 2001; 167(1): 542 - 552. [Abstract] [Full Text] [PDF]
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A. J. Slavin, R. Maron, and H. L. Weiner Mucosal administration of IL-10 enhances oral tolerance in autoimmune encephalomyelitis and diabetes Int. Immunol., June 1, 2001; 13(6): 825 - 833. [Abstract] [Full Text] [PDF]
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N. S. Ostlie, P. I. Karachunski, W. Wang, C. Monfardini, M. Kronenberg, and B. M. Conti-Fine Transgenic Expression of IL-10 in T Cells Facilitates Development of Experimental Myasthenia Gravis J. Immunol., April 15, 2001; 166(8): 4853 - 4862. [Abstract] [Full Text] [PDF]
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A. E. Juedes and N. H. Ruddle Resident and Infiltrating Central Nervous System APCs Regulate the Emergence and Resolution of Experimental Autoimmune Encephalomyelitis J. Immunol., April 15, 2001; 166(8): 5168 - 5175. [Abstract] [Full Text] [PDF]
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O. S. Targoni, J. Baus, H. H. Hofstetter, M. D. Hesse, A. Y. Karulin, B. O. Boehm, T. G. Forsthuber, and P. V. Lehmann Frequencies of Neuroantigen-Specific T Cells in the Central Nervous System Versus the Immune Periphery During the Course of Experimental Allergic Encephalomyelitis J. Immunol., April 1, 2001; 166(7): 4757 - 4764. [Abstract] [Full Text] [PDF]
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D. Huang, J. Wang, P. Kivisakk, B. J. Rollins, and R. M. Ransohoff Absence of Monocyte Chemoattractant Protein 1 in Mice Leads to Decreased Local Macrophage Recruitment and Antigen-Specific T Helper Cell Type 1 Immune Response in Experimental Autoimmune Encephalomyelitis J. Exp. Med., March 19, 2001; 193(6): 713 - 726. [Abstract] [Full Text] [PDF]
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D. J. Cua, B. Hutchins, D. M. LaFace, S. A. Stohlman, and R. L. Coffman Central Nervous System Expression of IL-10 Inhibits Autoimmune Encephalomyelitis J. Immunol., January 1, 2001; 166(1): 602 - 608. [Abstract] [Full Text] [PDF]
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A. Weishaupt, S. Jander, W. Bruck, T. Kuhlmann, M. Stienekemeier, T. Hartung, K. V. Toyka, G. Stoll, and R. Gold Molecular Mechanisms of High-Dose Antigen Therapy in Experimental Autoimmune Encephalomyelitis: Rapid Induction of Th1-Type Cytokines and Inducible Nitric Oxide Synthase J. Immunol., December 15, 2000; 165(12): 7157 - 7163. [Abstract] [Full Text] [PDF]
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A. G. Castro, M. Neighbors, S. D. Hurst, F. Zonin, R. A. Silva, E. Murphy, Y.-J. Liu, and A. O'Garra Anti-Interleukin 10 Receptor Monoclonal Antibody Is an Adjuvant for T Helper Cell Type 1 Responses to Soluble Antigen Only in the Presence of Lipopolysaccharide J. Exp. Med., November 20, 2000; 192(10): 1529 - 1534. [Abstract] [Full Text] [PDF]
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A. G.S. van Halteren, B. Mosselman, B. O. Roep, W. van Eden, A. Cooke, G. Kraal, and M. H. M. Wauben T Cell Reactivity to Heat Shock Protein 60 in Diabetes-Susceptible and Genetically Protected Nonobese Diabetic Mice Is Associated with a Protective Cytokine Profile J. Immunol., November 15, 2000; 165(10): 5544 - 5551. [Abstract] [Full Text] [PDF]
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H. Sasaki, L. Hou, A. Belani, C.-Y. Wang, T. Uchiyama, R. Muller, and P. Stashenko IL-10, But Not IL-4, Suppresses Infection-Stimulated Bone Resorption In Vivo J. Immunol., October 1, 2000; 165(7): 3626 - 3630. [Abstract] [Full Text] [PDF]
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E. M. Benkhart, M. Siedlar, A. Wedel, T. Werner, and H. W. L. Ziegler-Heitbrock Role of Stat3 in Lipopolysaccharide-Induced IL-10 Gene Expression J. Immunol., August 1, 2000; 165(3): 1612 - 1617. [Abstract] [Full Text] [PDF]
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S. C. Wilcoxen, E. Kirkman, K. C. Dowdell, and S. A. Stohlman Gender-Dependent IL-12 Secretion by APC Is Regulated by IL-10 J. Immunol., June 15, 2000; 164(12): 6237 - 6243. [Abstract] [Full Text] [PDF]
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E. Mizoguchi, A. Mizoguchi, F. I. Preffer, and A. K. Bhan Regulatory role of mature B cells in a murine model of inflammatory bowel disease Int. Immunol., May 1, 2000; 12(5): 597 - 605. [Abstract] [Full Text] [PDF]
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D. A. Young, L. D. Lowe, S. S. Booth, M. J. Whitters, L. Nicholson, V. K. Kuchroo, and M. Collins IL-4, IL-10, IL-13, and TGF-{beta} from an Altered Peptide Ligand-Specific Th2 Cell Clone Down-Regulate Adoptive Transfer of Experimental Autoimmune Encephalomyelitis J. Immunol., April 1, 2000; 164(7): 3563 - 3572. [Abstract] [Full Text] [PDF]
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E. H. Tran, E. N. Prince, and T. Owens IFN-{gamma} Shapes Immune Invasion of the Central Nervous System Via Regulation of Chemokines J. Immunol., March 1, 2000; 164(5): 2759 - 2768. [Abstract] [Full Text] [PDF]
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A. E. Juedes, P. Hjelmstrom, C. M. Bergman, A. L. Neild, and N. H. Ruddle Kinetics and Cellular Origin of Cytokines in the Central Nervous System: Insight into Mechanisms of Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis J. Immunol., January 1, 2000; 164(1): 419 - 426. [Abstract] [Full Text] [PDF]
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S. A. Stohlman, L. Pei, D. J. Cua, Z. Li, and D. R. Hinton Activation of Regulatory Cells Suppresses Experimental Allergic Encephalomyelitis Via Secretion of IL-10 J. Immunol., December 1, 1999; 163(11): 6338 - 6344. [Abstract] [Full Text] [PDF]
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S. Trembleau, G. Penna, S. Gregori, H. D. Chapman, D. V. Serreze, J. Magram, and L. Adorini Pancreas-Infiltrating Th1 Cells and Diabetes Develop in IL-12-Deficient Nonobese Diabetic Mice J. Immunol., September 1, 1999; 163(5): 2960 - 2968. [Abstract] [Full Text] [PDF]
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Y. Dong, W. M. Rohn, and E. N. Benveniste IFN-{gamma} Regulation of the Type IV Class II Transactivator Promoter in Astrocytes J. Immunol., April 15, 1999; 162(8): 4731 - 4739. [Abstract] [Full Text] [PDF]
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 S. Kim, S. M. Liva, M. A. Dalal, M. A. Verity, and R. R. Voskuhl Estriol ameliorates autoimmune demyelinating disease: Implications for multiple sclerosis Neurology, April 1, 1999; 52(6): 1230 - 1230. [Abstract] [Full Text] [PDF]
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H. L. Weiner Oral tolerance with Copolymer 1 for the treatment of multiple sclerosis PNAS, March 30, 1999; 96(7): 3333 - 3335. [Full Text] [PDF]
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D. J. Cua, H. Groux, D. R. Hinton, S. A. Stohlman, and R. L. Coffman Transgenic Interleukin 10 Prevents Induction of Experimental Autoimmune Encephalomyelitis J. Exp. Med., March 15, 1999; 189(6): 1005 - 1010. [Abstract] [Full Text] [PDF]
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W. Ma, W. Lim, K. Gee, S. Aucoin, D. Nandan, M. Kozlowski, F. Diaz-Mitoma, and A. Kumar The p38 Mitogen-activated Kinase Pathway Regulates the Human Interleukin-10 Promoter via the Activation of Sp1 Transcription Factor in Lipopolysaccharide-stimulated Human Macrophages J. Biol. Chem., April 20, 2001; 276(17): 13664 - 13674. [Abstract] [Full Text] [PDF]
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