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Departments of
* Neurology,
Pathology and Laboratory Medicine, and
Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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. By
contrast, a Th2-type response to MOG35–55 correlated with
disease resistance in IL-12p40-/- mice. Production of
TNF-
by microglia, CNS-infiltrating macrophages, and
CD4+ T cells was detected in wild-type and
IL-12p35-/-, but not in IL-12p40-/-, mice.
In addition, NO production was higher in IL-12p35-/- and
wild-type mice than in IL-12p40-/- mice. These data
demonstrate a redundancy of the IL-12 system in the induction of EAE
and suggest that p40-related heterodimers, such as the recently cloned
IL-23 (p40p19), may play an important role in disease
pathogenesis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-12 is a pleiotropic cytokine that is produced by activated APCs,
such as dendritic cells, monocytes/macrophages, and microglia, in
response to bacterial products and immune signals (2).
IL-12 acts as a proinflammatory stimulus by activating NK cells and is
one of the key factors in the differentiation and expansion of Th1
cells, which produce proinflammatory cytokines such as IFN- and
TNF- (3, 4). CD4+ cells of the
Th1 phenotype play a critical role in the induction of EAE. A role for
IL-12 in the pathogenesis of EAE has been documented by several lines
of evidence. Treatment of encephalitogenic proteolipid protein-reactive
T cells with IL-12 in vitro enhanced their ability to induce EAE
(5). Abs against IL-12 were capable of preventing the
induction of EAE when administered early after the adoptive transfer of
encephalitogenic T cells to recipient animals (5, 6).
Administration of high doses of IL-12 in the otherwise monophasic EAE
model in the Lewis rat induced disease relapse (7).
IL-12 is a heterodimeric cytokine formed by a large (p40) and a small (p35) subunit. These are linked by disulfide bonds in the producer APC to yield bioactive IL-12 (p70). It has been shown that IL-12p40-deficient (-/-) C57BL/6 mice are completely resistant to EAE induced by myelin basic protein (MBP) peptide 86–104 (8). IL-23 (p40p19) has been recently described as a novel cytokine which shares the p40 subunit and several biological functions with IL-12 (9). Because targeted deletion of the IL-12p40 gene eliminates the expression of both IL-12 (p40p35) and IL-23 (p40p19), it is not clear whether the proinflammatory response in EAE is due to IL-12 and/or other p40 heterodimers such as IL-23. The goal of the present study was to determine the role of IL-12p40 and IL-12p35 in EAE induced by the immunodominant myelin oligodendrocyte glycoprotein (MOG) peptide 35–55 (MOG35–55) in the C57BL/6 mouse. We report that IL-12p35-/- mice are susceptible to EAE, while IL-12p40-/- mice are completely resistant. These findings show that IL-12 is not strictly required for the induction of EAE, and suggest a role for other p40-related heterodimers such as IL-23.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Eight- to 10-wk-old homozygous IL-12p35-/- and IL-12p40-/- C57BL/6 mice and their wild-type controls were purchased from The Jackson Laboratory (Bar Harbor, ME). To induce EAE, mice were each injected s.c. with 300 µg of MOG35–55 in CFA containing 4 mg/ml Mycobacterium tuberculosis H37Ra (Difco, Detroit, MI) over two sites at the back. Pertussis toxin (200 ng) was given i.p. on days 0 and 2 postimmunization (p.i.). EAE was scored according to a 0–5 scale (10) as follows: limp tail or waddling gait with tail tonicity, 1; waddling gait with limp tail (ataxia), 2; ataxia with partial limb paralysis, 2.5; full paralysis of one limb, 3; full paralysis of one limb with partial paralysis of second limb, 3.5; full paralysis of two limbs, 4; moribund, 4.5; and death, 5.
Histopathology
On day 21 p.i., mice were extensively perfused, and spinal cords harvested. Five-micrometer sections were stained with Luxol fast blue (myelin stain; Sigma-Aldrich, St. Louis, MO). Slides were assessed in a blinded fashion for inflammation and demyelination as described (11).
Isolation of CNS cells and flow cytometry
Mononuclear cells (MNCs) from the CNS of
MOG35–55-immunized mice were isolated by Percoll
gradient centrifugation by modification of published methods (12, 13). Briefly, mice were sacrificed and transcardially perfused
with ice-cold GKN solution (2 g/L D-(+)glucose, 0.4 g/L
KCl, 8 g/L NaCl, 3.56 g/L
Na2HPO412H20,
and 0.78 g/L
NaH2PO42H20;
pH 7.4) (14) with 2 U/ml heparin (Sigma-Aldrich). Brains
and spinal cords were removed into GKN/0.02% BSA (w/v), mechanically
dissociated through a 100-µm-cell strainer, and enzymatically
digested by incubation with 250 µg/ml collagenase/dispase and 250
µg/ml DNase I (Roche, Basel, Switzerland) at 37°C for 20–30
min. The digested CNS preparation was washed with GKN/BSA, and the
pellet was fractionated on a 70/37/30% Percoll gradient. MNC
(microglia and infiltrating MNC) and lymphocytes were recovered from
the 37/70 interface, washed, and resuspended in RPMI 1640 with
10% FCS. Pooled cells (1 x 106) were
washed in FACS buffer. After blocking with CD16/CD32 Abs, cells were
incubated with Abs to murine CD4, CD8, CD11b, and CD45, (all from BD
PharMingen, San Jose, CA). Production of TNF- was analyzed by
intracytoplasmic staining of CNS-derived cells with Abs to murine
TNF- (BD PharMingen) after culture for 4 h in the presence of
the protein transport inhibitor brefeldin A. Where indicated, 50
µg/ml MOG35–55 was added to activate
CNS-derived cells for 4 h in vitro. Data were acquired on a
FACSCalibur (BD Biosciences, Mountain View, CA), and data were analyzed
using CellQuest software (BD Biosciences).
MOG-specific T cell proliferation and cytokine production
Suspensions of MNCs from the inguinal and popliteal lymph nodes
or from the spleen were prepared on day 21 p.i. Cells were
cultured at a cell density of 2.5 x 106/ml
in medium containing MOG35–55 at a final
concentration of 25 µg/ml, Con A at 5 µg/ml, or without Ag/mitogen.
Supernatants were collected after 48 h. Quantitative ELISA for
IFN-, IL-2, IL-3, TNF-, IL-4, IL-5, and IL-10 were performed
using paired mAbs according to the manufacturer’s recommendation (BD
PharMingen). Where indicated, brefeldin A was added to cells cultured
with or without MOG35–55 for 48 h during
the last 4 h of culture, and production of cytokines was
determined by intracytoplasmic flow cytometry as described above. For
proliferation, cells were cultured in triplicate wells of microtiter
96-well plates (4 x 105 cells/well) in the
presence or absence of 50 µg/ml MOG35–55 or 5
µg/ml Con A. After 60 h of incubation, the cells were pulsed for
12 h with 1 µCi of [3H]methylthymidine.
Cells were harvested and counts read with a beta counter (Microbeta;
Applied Biosystems, Foster City, CA). The results are expressed as cpm.
Production of the NO metabolite nitrite was measured in the
supernatants using the Griess reagent. One hundred microliters of
supernatants was mixed with an equal volume of Griess reagent. After a
10-min reaction at room temperature, the absorbance at 540 nm was
measured in an automated plate reader. Nitrite concentration was
determined by comparison with a sodium nitrite standard curve in
culture medium.
Statistics
ANOVA was used for the comparison of clinical score, proliferative responses, and cytokine profiles among different groups. All significance tests were two-sided.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To investigate the role of the two IL-12 subunits in the
pathogenesis of EAE, we immunized IL-12p35-/-
and IL-12p40-/- mice on the
H-2b background and their wild-type controls
(C57BL/6 mice) with MOG35–55 in CFA.
IL-12p40-/- mice were completely resistant to
EAE. A representative experiment of three is shown in Fig. 1
. By contrast,
IL-12p35-/- mice developed EAE that was
comparable in time of onset and severity to EAE observed in
wild-type mice.
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Histological analysis of spinal cords harvested from perfused
animals on day 21 p.i. showed typical EAE, with MNC infiltration
and demyelination in wild-type mice. A representative histopathology
picture is shown in Fig. 2. Consistent
with clinical findings, mononuclear cellular infiltration and
demyelination in IL-12p35-/- mice were similar
to those observed in wild-type animals. By contrast,
IL-12p40-/- mice had normal spinal cords
(Fig. 2).
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On day 21 p.i., cells isolated from the LN and the spleen
strongly proliferated in response to MOG35–55,
without significant differences between wild-type,
IL-12p35-/-, and
IL-12p40-/- mice (not shown). We cultured cells
harvested from the draining lymph nodes and the spleen at day 21
p.i. in the presence or absence of 25 µg/ml
MOG35–55 or 5 µg/ml Con A and measured the
production of IFN-, TNF-, IL-2, IL-3, IL-4, IL-5, and IL-10 by
ELISA in supernatants collected after 48 h of culture. The Th
profile of the cytokine response in the draining lymph node was
different among the three groups (Fig. 3). Similar levels of IFN- were
produced by wild-type and IL-12p35-/- mice in
response to MOG35–55, whereas
IL-12p40-/- mice were defective in
autoantigen-specific production of IFN-. This observation was
confirmed by intracytoplasmic flow cytometry, which showed
MOG35–55-specific production of IFN- by
CD4+ T cells in wild-type and
IL-12p35-/- mice (Fig. 4). IL-2 production was detected only in
response to Con A and was higher in wild-type mice than in
IL-12p35-/- (p < 0.03)
and IL-12p40-/- mice (p
< 0.03). TNF- was below detection limits (not shown). Production of
IL-3 was higher in IL-12p40-/- than in
wild-type (p < 0.01) and
IL-12p35-/- mice (p <
0.01) (data not shown). Higher levels of the Th2-type cytokines IL-5
(p < 0.001) and IL-10
(p < 0.001) were detected in
IL-12p40-/- mice compared with those of both
wild-type and IL-12p35-/- mice (Fig. 3). IL-4
production was below detection limit in all mice (not shown).
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). MOG-specific IFN- production was
higher in wild-type than in IL-12p35-/- mice
(p < 0.05) and was undetectable in
IL-12p40-/- mice. Consistent results were
obtained by intracytoplasmic flow cytometry (Fig. 6). MOG-specific IL-2 production was
higher in wild-type and IL-12p35-/- mice than
in IL-12p40-/- mice (p
< 0.01). TNF- was below detection limits (not shown). Production of
IL-3 was higher in IL-12p40-/- than in
wild-type (p < 0.01) and
IL-12p35-/- mice (p <
0.01)(data not shown). Spleen cells from
IL-12p40-/- mice stimulated with
MOG35–55 or Con A produced higher levels of the
Th2-type cytokines IL-4 and IL-10 than did those of wild-type and
IL-12p35-/- mice (p <
0.01 for all comparisons; Fig. 5). IL-5 production in the spleen was
detected only in response to Con A in
IL-12p40-/- mice (not shown).
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Finally, we determined the levels of NO in the supernatants of the
lymph node and spleen cell cultures. Figs. 3
and 5 show that NO
production was higher in wild-type and
IL-12p35-/- mice than in
IL-12p40-/- mice. This suggests that this
macrophage-derived factor may contribute to the pathogenesis of this
EAE model.
In vivo TNF- production is observed in the CNS of wild-type and
IL-12p35-/- mice
We then focused on the CNS to analyze any differences in the
composition of infiltrating and CNS-resident cells among the three
strains of mice. We performed flow cytometric analysis on CNS MNC
isolated from mice at the peak of clinical disease. In preliminary
experiments, we found that the production of TNF-, a proinflammatory
cytokine involved in the pathogenesis of EAE, was consistently detected
by intracytoplasmic flow cytometric analysis in the CNS of EAE mice.
Therefore, we focused our analysis on the production of this cytokine.
The immunophenotyping results from a typical experiment are shown in
Figs. 7 and 8. The number of cells recovered from the
CNS was greatly increased in EAE-susceptible (wild-type and
IL-12p35-/-) mice compared with that of
resistant mice (IL-12p40-/- mice; Fig. 7E). We found that TNF- was produced by CNS leukocytes
(CD45+) in wild-type and
IL-12p35-/- mice. Among CNS cells, both
microglia (defined as
CD11b+CD45low; Fig. 7, R2)
and infiltrating macrophages (defined as
CD11b+CD45high; Fig. 7, R3)
produced TNF-. After incubation with MOG35–55
for 4 h, a fraction of CD4+ T cells also
produced TNF- in both wild-type and
IL-12p35-/- mice (Fig. 8). Thus, production of
TNF- by CNS APC and T cells correlated with disease
susceptibility.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). An important role for IL-12 in EAE has been suggested by studies in which the disease was enhanced by IL-12 administration or suppressed by its neutralization (5, 6, 8, 15, 16). We previously showed that IL-12 administration mimics the effect of superantigens in inducing and enhancing the severity and frequency of EAE relapses in (PL/J x SJL/J)F1 mice. Conversely, anti-IL-12p40 Abs blocked superantigen-induced, as well as spontaneous relapses of, EAE (6).
Most studies conducted on EAE so far have only addressed the role of IL-12p40 in disease pathogenesis. The recent discovery of the IL-12-related cytokine, IL-23 (p40p19), which shares the p40 subunit and several biological functions with IL-12, suggests that IL-12p40-/- mice are in fact deficient for both cytokines, whereas IL-12p35-/- mice are only IL-12 deficient (9). In addition, neutralizing anti-IL-12 Abs used to suppress EAE were directed to the p40 subunit, suggesting that neutralization of both IL-12 and IL-23 may have been achieved (6). It should be noted that previous studies have characterized the role of IL-12 in different EAE systems, such as adoptive transfer EAE induced with proteolipid protein 139–151 in SJL mice (5); EAE induced by active immunization with whole MBP in (PL/J x SJL/J)F1 (6), SJL, and C57BL/6 mice (8); adoptive transfer EAE induced with MBP87–106 in SJL mice (8); and adoptive transfer EAE induced by a MOG35–55-specific T cell line in C57BL/6 mice (17). None of these studies specifically addressed the role of IL-12p35.
EAE is considered an autoimmune disease mediated by pathogenic, myelin
Ag-reactive Th1 cells (1). These cells produce
proinflammatory cytokines such as IFN-, IL-2, and TNF- upon
activation by specific Ags. Thus far, the key role of IL-12 in EAE
pathogenesis has been considered the induction and expansion of myelin
reactive Th1 cells (8, 15, 18). To determine the relative
strength of Th1 and Th2 responses to MOG35–55 in
our system, we measured cytokine production by peripheral immune cells
in mice immunized with that peptide. We observed a Th1-type response,
with high levels of IFN- and IL-2 production in response to MOG, in
wild-type mice. This observation is consistent with previous reports of
the pathogenic role of Th1 autoreactive cells in this and other EAE
models (8, 19). By contrast, we observed a strong Th2-type
response to MOG in IL-12p40-/- mice. The
production of high levels of IL-4, IL-5, and IL-10 most likely
underlies disease resistance in these mice. Other investigators have
reported increased Th2 responses in IL-12p40-/-
mice, particularly a higher production of IL-4 (20).
Ag-specific Th1 cells have been reported to induce production of IL-4
by mast cells in the spleen by an IL-3-mediated pathway
(21). Our data suggest that IL-4 produced in the spleen of
IL-12p40-/- mice may be partly induced by IL-3.
In the absence of a significant Th1 response to
MOG35–55 in these mice (
Figs. 3–6), it is
possible that IL-3 is produced by Th2 (22) or NK T cells
(23). This is currently under investigation. The
production of high levels of IL-10 (Figs. 3 and 5) is consistent with
the concept of an immunoregulatory circuit in which IL-10 antagonizes
the disease-promoting effects of IL-12 (8).
Interestingly, we found that IL-12p35-/-
mice were able to mount an encephalitogenic proinflammatory response to
MOG35–55. In the draining lymph node, we
did not find significant differences in IFN- production between
wild-type and IL-12p35-/- mice (Figs. 3 and 4).
In contrast, a relative deficit in IFN- production was observed in
the spleen (Figs. 5 and 6). Overall, we observed a milder deficit in
Ag-specific IFN- production in IL-12p35-/-
mice than that reported for mice infected with Leishmania
major (24) or immunized with keyhole limpet
hemocyanin (25). Together, these data suggest that
IL-12p35-/- mice mount a weaker Th1 response to
MOG35–55 than do wild-type mice, whereas
IL-12p40-/- mice mount a Th2-type response to
the same peptide that is characterized by a severe deficit in IFN-
production and high production of IL-4, IL-5, and IL-10 (Figs. 3 and 5). Our observation is strongly supported by recent reports that
demonstrated the capacity of IL-12p35-/- mice
to mount partial Th1 responses and thereby survive infection by
M. tuberculosis (26) and Salmonella
enteritidis (27). In the same studies, a severe
deficit in IFN- production by IL-12p40-/-
mice correlated with high susceptibility to bacterial growth and
increased mortality. In addition, IFN- production was impaired in
IL-12p40-/-, but not
IL-12p35-/-, mice in a murine model of cardiac
transplant rejection (28) and hapten-induced colitis
(29). Thus, the level of IFN- production in
IL-12-deficient mice is dependent on experimental variables such as the
type of immunization and/or infection. In the absence of IL-12-mediated
activation of Stat4 via the 
2-chain of the IL-12R (3),
we speculate that IFN- production may be induced by IL-23 through
activation of Stat4 via the heterodimeric receptor for IL-23
(IL-12R1/IL-23R) (30). In addition,
Stat4-independent pathways, such as those activated by IL-18
(NF-
B, p38 mitogen-activated protein kinase, and growth arrest and
DNA damage gene 45) may also be involved (30, 31).
Because IFN- is a key factor in the development of Th1 responses,
but is clearly dispensable in the induction of EAE
(32, 33, 34), we investigated the role of other
proinflammatory cytokines in our experimental model. TNF- was an
obvious candidate because of its involvement in EAE pathogenesis
(35). TNF- production was below detection level in the
periphery. The production of TNF- in the CNS at the single-cell
level was studied by intracytoplasmic staining and flow cytometric
analysis (Figs. 7 and 8). We found that EAE-susceptible (wild-type and
IL-12p35-/-) mice, but not EAE-resistant
(IL-12p40-/-) mice, had high numbers of
TNF--producing cells in the CNS (Figs. 7 and 8). TNF- was
produced by both CNS-resident APC (microglia,
CD11b+CD45low) and
infiltrating APC, such as activated macrophages
(CD11b+CD45high), as
previously reported by Juedes et al. (36) in wild-type
C57BL/6 mice. TNF- production was not impaired in resident microglia
in IL-12p40-/- mice (Fig. 7F), but
much fewer TNF--producing infiltrating macrophages were observed, in
agreement with the Th2-type response observed in the periphery (
Figs. 3–6) and the lack of CNS inflammation (Fig. 2). After a short in vitro
activation with MOG35–55, we also detected
production of TNF- by a small percentage of CNS-infiltrating
CD4+ cells in wild-type and
IL-12p35-/- mice, but not in
IL-12p40-/- mice. The correlation between
TNF- production in the CNS and disease susceptibility in both
wild-type and IL-12p35-/- mice suggests the
involvement of TNF- in EAE pathogenesis. TNF- is produced by both
Th1 cells and APC and is thought to be involved in EAE pathogenesis
through oligodendrocyte cytotoxicity, the up-regulation of the
expression of adhesion molecules, and the induction of chemokine
production (36, 37, 38).
Interestingly, transgenic mice overexpressing IL-23p19 produce a higher
level of TNF- than do wild-type mice, and such overproduction may
contribute to the systemic inflammation and premature death in these
mice (39). We speculate that IL-23 may substitute for
IL-12 in the induction of TNF- and perhaps other aspects of Th1 cell
development in IL-12p35-/- mice. Because
signaling through TNFRI has been shown to correlate with severity of
clinical signs and demyelination in MOG-induced EAE, whereas TNFRII may
play a protective role (38), it will be important to
determine the level of expression of these key receptors in CNS cells
during the course of inflammatory demyelination.
Finally, another mechanism of CNS inflammatory damage in both wild-type
and IL-12p35-/-mice may relate to the
production of NO by CNS-infiltrating macrophages as well as
CNS-resident microglia. Indeed, we found that
MOG35–55 induced the production of significant
amounts of NO in lymph node and spleen cell cultures of EAE-susceptible
wild-type and IL-12p35 mice (Figs. 3 and 5). In contrast, NO production
was negligible in IL-12p40-/- mice. Therefore,
even though both toxic and protective roles have been demonstrated for
NO in EAE (40), NO production by CNS-infiltrating MNCs in
this EAE model may contribute to inflammatory demyelination in both
wild-type and IL-12p35-/- mice. This may occur
by direct toxicity to oligodendrocytes as well as by enhancing the
toxicity of TNF- (Figs. 7 and 8) (40, 41).
The observation of typical MOG35–55-induced EAE
in IL-12p35-/- mice indicates that IL-12 plays
a dispensable rather than an obligatory role in the induction of EAE.
This is consistent with the emerging view that IL-12 is one of several
factors involved in the induction of Th1 responses and that its role
can be at least partly substituted by other factors (4, 42, 43). One interesting candidate for such a role is IL-23
(p40p19), an IL-12-related heterodimer, which can induce Th1
differentiation of naive T cell precursors, at least in humans
(9, 44). Although it was not the goal of this study to
characterize the role of IL-23 in EAE, and certain important reagents
are not yet available for this purpose, our report suggests a possible
role for IL-23 and/or other IL-12-related heterodimers in EAE, which
will require further investigation. Consistent with the present report,
we recently observed that mice deficient for IL-12R1 (3, 30), and therefore unresponsive to both IL-12 and
IL-23, are completely resistant to EAE,
whereasIL-12R2-/- mice, which maintain
responsiveness to IL-23 (30), develop early and severe
EAE. In addition, spleen cells of
MOG35–55-immunized
IL-12R2-/- mice showed increased expression
of IL-23p19 mRNA compared with that of wild-type mice, suggesting that
IL-23 may indeed contribute to EAE pathogenesis (G.-X. Zhang, B. Gran,
J. Li, S. Yu, I. Siglienti, M. Kamoun, and A. M. Rostami,
unpublished data).
In summary, we observed typical EAE in mice defective for IL-12p35 and complete disease resistance in the absence of IL-12p40. This suggests that pathogenic, MOG-specific autoreactivity can develop in the absence of IL-12 and that other p40 heterodimers such as IL-23 may compensate for the lack of IL-12. Because IL-12 has clearly been shown to expand pathogenic Th1 cells (4) and to exacerbate EAE (5, 6, 7), our study does not refute the role of this cytokine in organ-specific autoimmunity, but rather demonstrates a degree of redundancy in its function which had not been previously recognized.
Note.
After submission of this manuscript for publication, Becher et al. (45) reported that, similar to the results shown in this study, IL-12p35-/- mice are susceptible to MOG35–55-induced EAE, while IL-12p40-/- mice are resistant.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Abdolmohamad Rostami, Department of Neurology, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, PA 19104. E-mail address: rostamia{at}mail.med.upenn.edu
3 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; MBP, myelin basic protein; MNC, mononuclear cell; p.i., postimmunization.
Received for publication June 17, 2002. Accepted for publication October 10, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2 subunit expression by endogenous IL-12: a critical step in the differentiation of pathogenic autoreactive T cells. J. Exp. Med. 189:969. production and type 1 cytokine responses. Immunity 4:471.[Medline]
upon activation by anti-CD3 or CD1. J. Immunol. 159:2240.1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. 168:5699. gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J. Immunol. 156:5.[Abstract]
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 M Krakauer, P Sorensen, M Khademi, T Olsson, and F Sellebjerg Increased IL-10 mRNA and IL-23 mRNA expression in multiple sclerosis: interferon-{beta} treatment increases IL-10 mRNA expression while reducing IL-23 mRNA expression Multiple Sclerosis, June 1, 2008; 14(5): 622 - 630. [Abstract] [PDF]
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D. Luger, P. B. Silver, J. Tang, D. Cua, Z. Chen, Y. Iwakura, E. P. Bowman, N. M. Sgambellone, C.-C. Chan, and R. R. Caspi Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category J. Exp. Med., April 14, 2008; 205(4): 799 - 810. [Abstract] [Full Text] [PDF]
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K. Kreymborg, R. Etzensperger, L. Dumoutier, S. Haak, A. Rebollo, T. Buch, F. L. Heppner, J.-C. Renauld, and B. Becher IL-22 Is Expressed by Th17 Cells in an IL-23-Dependent Fashion, but Not Required for the Development of Autoimmune Encephalomyelitis J. Immunol., December 15, 2007; 179(12): 8098 - 8104. [Abstract] [Full Text] [PDF]
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E. Smith, A. Zarbock, M. A. Stark, T. L. Burcin, A. C. Bruce, P. Foley, and K. Ley IL-23 Is Required for Neutrophil Homeostasis in Normal and Neutrophilic Mice J. Immunol., December 15, 2007; 179(12): 8274 - 8279. [Abstract] [Full Text] [PDF]
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 M. Oukka Interplay between pathogenic Th17 and regulatory T cells Ann Rheum Dis, November 1, 2007; 66(suppl_3): iii87 - iii90. [Abstract] [Full Text] [PDF]
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F. Annunziato, L. Cosmi, V. Santarlasci, L. Maggi, F. Liotta, B. Mazzinghi, E. Parente, L. Fili, S. Ferri, F. Frosali, et al. Phenotypic and functional features of human Th17 cells J. Exp. Med., August 6, 2007; 204(8): 1849 - 1861. [Abstract] [Full Text] [PDF]
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 K. S. Shindler, E. Ventura, T. S. Rex, P. Elliott, and A. Rostami SIRT1 Activation Confers Neuroprotection in Experimental Optic Neuritis Invest. Ophthalmol. Vis. Sci., August 1, 2007; 48(8): 3602 - 3609. [Abstract] [Full Text] [PDF]
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P. Thakker, M. W. Leach, W. Kuang, S. E. Benoit, J. P. Leonard, and S. Marusic IL-23 Is Critical in the Induction but Not in the Effector Phase of Experimental Autoimmune Encephalomyelitis J. Immunol., February 15, 2007; 178(4): 2589 - 2598. [Abstract] [Full Text] [PDF]
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 Y. Li, N. Chu, A. Hu, B. Gran, A. Rostami, and G.-X. Zhang Increased IL-23p19 expression in multiple sclerosis lesions and its induction in microglia Brain, February 1, 2007; 130(2): 490 - 501. [Abstract] [Full Text] [PDF]
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J. Xu and P. D. Drew Peroxisome Proliferator-Activated Receptor-{gamma} Agonists Suppress the Production of IL-12 Family Cytokines by Activated Glia J. Immunol., February 1, 2007; 178(3): 1904 - 1913. [Abstract] [Full Text] [PDF]
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 Y. Wada, R. Lu, D. Zhou, J. Chu, T. Przewloka, S. Zhang, L. Li, Y. Wu, J. Qin, V. Balasubramanyam, et al. Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor Blood, February 1, 2007; 109(3): 1156 - 1164. [Abstract] [Full Text] [PDF]
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T. Touil, D. Fitzgerald, G.-X. Zhang, A. Rostami, and B. Gran Cutting Edge: TLR3 Stimulation Suppresses Experimental Autoimmune Encephalomyelitis by Inducing Endogenous IFN-beta J. Immunol., December 1, 2006; 177(11): 7505 - 7509. [Abstract] [Full Text] [PDF]
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K. S Shindler, Y. Guan, E. Ventura, J. Bennett, and A. Rostami Retinal ganglion cell loss induced by acute optic neuritis in a relapsing model of multiple sclerosis Multiple Sclerosis, September 1, 2006; 12(5): 526 - 532. [Abstract] [PDF]
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J Kawanokuchi, T Mizuno, H Takeuchi, H Kato, J Wang, N Mitsuma, and A Suzumura Production of interferon-{gamma} by microglia Multiple Sclerosis, September 1, 2006; 12(5): 558 - 564. [Abstract] [PDF]
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Y. Komiyama, S. Nakae, T. Matsuki, A. Nambu, H. Ishigame, S. Kakuta, K. Sudo, and Y. Iwakura IL-17 Plays an Important Role in the Development of Experimental Autoimmune Encephalomyelitis J. Immunol., July 1, 2006; 177(1): 566 - 573. [Abstract] [Full Text] [PDF]
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 W. Hu, T. Dehmel, J. Pirhonen, H.-P. Hartung, and B. C. Kieseier Interleukin 23 in acute inflammatory demyelination of the peripheral nerve. Arch Neurol, June 1, 2006; 63(6): 858 - 864. [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. Kihara, S. Ishii, Y. Kita, A. Toda, A. Shimada, and T. Shimizu Dual phase regulation of experimental allergic encephalomyelitis by platelet-activating factor J. Exp. Med., September 19, 2005; 202(6): 853 - 863. [Abstract] [Full Text] [PDF]
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P. G. Bannerman, A. Hahn, S. Ramirez, M. Morley, C. Bonnemann, S. Yu, G.-X. Zhang, A. Rostami, and D. Pleasure Motor neuron pathology in experimental autoimmune encephalomyelitis: studies in THY1-YFP transgenic mice Brain, August 1, 2005; 128(8): 1877 - 1886. [Abstract] [Full Text] [PDF]
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 Y. Osorio and H. Ghiasi Recombinant Herpes Simplex Virus Type 1 (HSV-1) Codelivering Interleukin-12p35 as a Molecular Adjuvant Enhances the Protective Immune Response against Ocular HSV-1 Challenge J. Virol., March 15, 2005; 79(6): 3297 - 3308. [Abstract] [Full Text] [PDF]
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E. Bettelli and V. K. Kuchroo IL-12- and IL-23-induced T helper cell subsets: birds of the same feather flock together J. Exp. Med., January 18, 2005; 201(2): 169 - 171. [Abstract] [Full Text] [PDF]
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C. L. Langrish, Y. Chen, W. M. Blumenschein, J. Mattson, B. Basham, J. D. Sedgwick, T. McClanahan, R. A. Kastelein, and D. J. Cua IL-23 drives a pathogenic T cell population that induces autoimmune inflammation J. Exp. Med., January 18, 2005; 201(2): 233 - 240. [Abstract] [Full Text] [PDF]
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N. Ghilardi, N. Kljavin, Q. Chen, S. Lucas, A. L. Gurney, and F. J. de Sauvage Compromised Humoral and Delayed-Type Hypersensitivity Responses in IL-23-Deficient Mice J. Immunol., March 1, 2004; 172(5): 2827 - 2833. [Abstract] [Full Text] [PDF]
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C. A. Murphy, C. L. Langrish, Y. Chen, W. Blumenschein, T. McClanahan, R. A. Kastelein, J. D. Sedgwick, and D. J. Cua Divergent Pro- and Antiinflammatory Roles for IL-23 and IL-12 in Joint Autoimmune Inflammation J. Exp. Med., December 15, 2003; 198(12): 1951 - 1957. [Abstract] [Full Text] [PDF]
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T. Nagai, O. Devergne, T. F. Mueller, D. L. Perkins, J. M. van Seventer, and G. A. van Seventer Timing of IFN-{beta} Exposure during Human Dendritic Cell Maturation and Naive Th Cell Stimulation Has Contrasting Effects on Th1 Subset Generation: A Role for IFN-{beta}-Mediated Regulation of IL-12 Family Cytokines and IL-18 in Naive Th Cell Differentiation J. Immunol., November 15, 2003; 171(10): 5233 - 5243. [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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G.-X. Zhang, S. Yu, B. Gran, J. Li, I. Siglienti, X. Chen, D. Calida, E. Ventura, M. Kamoun, and A. Rostami Role of IL-12 Receptor {beta}1 in Regulation of T Cell Response by APC in Experimental Autoimmune Encephalomyelitis J. Immunol., November 1, 2003; 171(9): 4485 - 4492. [Abstract] [Full Text] [PDF]
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G.-X. Zhang, B. Gran, S. Yu, J. Li, I. Siglienti, X. Chen, M. Kamoun, and A. Rostami Induction of Experimental Autoimmune Encephalomyelitis in IL-12 Receptor-{beta}2-Deficient Mice: IL-12 Responsiveness Is Not Required in the Pathogenesis of Inflammatory Demyelination in the Central Nervous System J. Immunol., February 15, 2003; 170(4): 2153 - 2160. [Abstract] [Full Text] [PDF]
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