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by NK Cells1
*
Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden;
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037;
Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Osaka University, Osaka, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-/- mice, rescued the defective Th1 responses in
IL-18-/- mice and rendered IL-18-/- mice
susceptible to the induction of autoimmune encephalomyelitis. Thus,
IL-18 can direct autoreactive T cells and promote autodestruction in
the CNS at least in part via induction of IFN- by NK
cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Experimental autoimmune encephalomyelitis (EAE) in C57BL/6 (B6) mice is one of the animal models of MS (3). EAE in B6 mice can be induced by immunization with MOG35–55 peptide in adjuvant (3). Myelin basic protein-specific CD4+ T cells have been shown to transfer EAE in SJL mice (4). Similarly, MOG35–55-specific CD4+ T cells can also transfer EAE in B6 mice (5). EAE is a prototype Th1 cell-mediated disease, although the exact sequence of events as well as molecular mediators of this CNS inflammatory response have not been clearly defined. The induction of EAE, like the induction of many other experimental autoimmune diseases, requires the use of complete adjuvants. Adjuvant contains bacterial Ags that activate innate immunity (6). Therefore, immunization of experimental animals with concoctions of autoantigen and adjuvant may mimic the initial events involved in the development of autoimmune diseases in humans. We hypothesize that infection might participate in driving autoreactivity to autodestruction. The signals from innate immune responses combating infectious agents, e.g., the early production of key cytokines, may also have an instructive role in the development of autoreactive T cells in both MS and EAE. Thus, identification of cells and molecules of innate immunity and the pathways involved in the subsequent development of EAE may shed light on the etiology of MS.
IL-18, originally designated IFN--inducing factor, is a cytokine
produced by activated macrophages and dendritic cells during the innate
immune response (7). IL-18 shares structural features with
the IL-1 family of proteins (8) and shares some of the
biological activities with IL-12 (7, 9). IL-18 is capable
of promoting the production of IFN- by NK and Th1 cells and enhances
NK cell activity (7, 9). Recent studies suggest that not
only is IL-18 essential for the host defense against intracellular
infection, but it also plays a critical role in regulating the
synthesis of inflammatory cytokines (10). This evidence
suggests the possible participation of IL-18 in the development of
autoimmune diseases. Indeed, expression of IL-18 transcripts occurred
with the onset of insulitis in the nonobese diabetic mouse
(11). Neutralizing Abs to IL-18 prevented EAE in rat
(12). However, the nature of IL-18 in the initiation and
maintenance of autoimmunity remains largely elusive.
To identify the contribution of IL-18 in autoimmune disease, we
compared the development of EAE in wild-type (WT) and IL-18-deficient
(IL-18-/-) mice. We show that
IL-18-/- mice are defective in mounting
autoreactive Th1 and autoantibody responses and are resistant to
MOG35–55 peptide-induced encephalomyelitis.
Furthermore, we demonstrate that IL-18 promotes autoreactive Th1 cell
development at least in part via induction of IFN- by NK
cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-18-/- (9),
recombinase-activating gene 1 (RAG1)-/-
(13), and IFN--/-
(14) mice were backcrossed at least 12 times to a B6
background. Mice were housed in specific pathogen-free conditions at
the animal facilities of the Microbiology and Tumor Biology Center,
Karolinska Institute (Stockholm, Sweden), and The Scripps Rodent Colony
(La Jolla, CA). Female mice, 8–10 wk of age at the initiation of the
experiments, were used.
Ags, Abs, and recombinant cytokines
The murine MOG35–55 peptide (M-E-V-G-W-Y-R-S-P-F-S-R-V-V-H-L-Y-R-N-G-K) was synthesized at the Swedish Institute for Infectious Disease Control (Stockholm, Sweden). PK136 clone (anti-NK1.1) (15) was obtained from American Type Culture Collection (Manassas, VA). Mouse IgG (Sigma, St. Louis, MO) was used as the isotype control Ab for anti-NK1.1 Ab. For in vivo depletion of NK1.1+ cells, 100 µg of anti-NK1.1 mAb was injected i.p. into each mouse on day -2 postimmunization (p.i.). Every 5–7 days thereafter, 50 µg of anti-NK1.1 mAb was injected i.p. until the termination of experiments. Depletion efficacy was confirmed by flow cytometry with PE-NK1.1 Ab (PharMingen, San Diego, CA). Recombinant IL-18 was purchased from PeproTech (Rocky Hill, NJ). Each mouse received 1000 ng of IL-18 i.p. daily for 5 consecutive days as previously described (9).
Induction of EAE
EAE was induced by s.c. flank and tail base injections of 200 µg of MOG peptide in CFA (Difco, Detroit, MI) containing 500 µg of heat-inactivated Mycobacterium tuberculosis on days 0 and 7, supplemented by i.v. injections of 200 ng of pertussis toxin on day 2 (List Biologic, Campbell, CA). The mice were observed daily for clinical signs of disease and were scored on a arbitrary scale of 0–5, with graduations of 0.5 for intermediate scores (16): 0, no clinical signs; 1, flaccid tail; 2, hind limb weakness or abnormal gait; 3, complete hind limb paralysis; 4, complete hind limb paralysis with forelimb weakness or paralysis; and 5, moribund or deceased. For passively transferred EAE, mice were immunized with MOG35–55 as described above. Fourteen days later, spleen cell suspensions from the immunized mice were cultured for 4 days with 10 µg/ml MOG35–55 (15 U/ml IL-2; PeproTech). After washing them with HBSS, 5 x 107 cells were injected i.v. into recipient mice.
Culture medium
Cells were suspended in DMEM (Life Technologies, Paisley, U.K.) supplemented with 1% (v/v) MEM (Life Technologies), 2 mM glutamine (Flow Laboratories, Irvine, U.K.), 50 IU/ml penicillin, 50 mg/ml streptomycin, and 10% (v/v) FCS (all three from Life Technologies).
Cytotoxicity assay
NK cell-mediated cytotoxicity was assayed using a standard 51Cr release assay (17). Spleen cells were incubated with 51Cr-labeled YAC-1 target cells at the indicated E:T cell ratios. After 4 h of culture, supernatants were counted for 51Cr release in a gamma counter (Packard, Meriden, CT).
Cell isolation, sorting, and transfer
Mononuclear cells (MNC) were obtained by mincing the popliteal and inguinal lymph nodes through a wire mesh. Spleen DX5+ cells were sorted using a FACStarPlus (Becton Dickinson, Mountain View, CA). DX5+ spleen cells were >99% pure upon reanalysis by flow cytometry. Alternatively, NK cells were purified using anti-NK cell (DX5) MicroBeads (Miltenyi Biotech, Auburn, CA) from spleen cells immunized with CFA. After overnight culture, the purified NK1.1+ cells were injected i.v. into recipient mice.
T cell proliferation
MNC (4 x 105) were incubated in 200 µl of culture medium in 96-well round-bottom microtiter plates (Nunc, Copenhagen, Denmark). Ten-microliter aliquots of MOG35–55 peptide or Con A (Sigma) were added to wells at final concentrations of 5, 10, 15, and 20 µg/ml (MOG35–55) and 5 µg/ml (Con A). After 4 days of incubation, the cells were pulsed for 18 h with 10-µl aliquots containing 1 µCi of [methyl-3H]thymidine (sp. act., 42 Ci/mmol; Amersham, Arlington Heights, IL). Cells were harvested onto glass-fiber filters, and thymidine incorporation was measured.
Cytokine induction
CD4+ T cells were purified from spleen
cells of MOG35–55/CFA-immunized mice by magnetic
separation using anti-CD4 Ab conjugated to magnetic beads (Miltenyi
Biotech). T cells were eluted by flushing the magnetic column with PBS
containing 0.5% FCS as recommended by the manufacturer’s protocol.
The CD4+ T cells were cultured in duplicate with
irradiated (3000 rad) B6 spleen cells in 1.5 ml of culture medium
containing 10 µg/ml MOG35–55 peptide. For
cytokine induction, supernatants were collected at 48 h after in
vitro boosting. IFN- and IL-4 were measured by optEIA kits
(PharMingen). The sensitivities of these ELISAs were 31.3 pg/ml for
IFN- and 7.8 pg/ml for IL-4. TNF-
was measured by Quantikine M
Mouse TNF- Immunoassay (sensitivity, 15 pg/ml; R&D Systems,
Minneapolis, MN).
Anti-MOG35–55 IgG Abs
Microtiter plates (Nunc) were coated with 100 µl/well of MOG35–55 peptide at a concentration of 5 µg/ml. MOG35–55-specific IgG and IgG isotypes were detected by ELISA using rabbit anti-mouse IgG1, IgG2a, or IgG2b (Dakopatts, Glostrup, Denmark) as previously described (18).
Statistical analysis
Differences between groups were evaluated by ANOVA. Disease incidence and severity were analyzed by Fisher’s exact test and Mann-Whitney U test, respectively.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Given the prominent role of IL-18 in promoting Th1 and NK cell
activities, we determined the involvement of this cytokine in the
development of EAE in WT and IL-18-/- mice.
Subcutaneous immunization of WT mice with 200 µg of
MOG35–55 peptide in CFA on days 0 and 7 and with
pertussis toxin i.v. on day 2 resulted in moderate to severe acute
encephalomyelitis, with clinical signs appearing on or around day 13
and rapid progression thereafter. On day 19 p.i., disease
incidence reached 89% (17 of 19 animals), and the mean severity was
3.8 ± 0.9. Clinical motor defect was present for 10 days and then
spontaneously remitted to leave a mild, chronic, nonrelapsing motor
deficit (approximate disease score, 1.5; Fig. 1
A). In contrast, only 2 of 22
IL-18-/- (11%) mice exhibited clinical signs
of EAE. The signs were mild and started from day 16. The mice were
completely recovered by day 22 (p < 0.01 for
both comparisons of disease incidence and severity with WT mice on day
19 p.i.). This observation is in agreement with a recent study
showing that EAE in rats could be prevented by neutralizing Abs to
IL-18 (12).
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B; p < 0.01 for both comparisons
of disease incidence and severity with transfer cells from WT mice on
day 11). Collectively, IL-18 plays a critical role in the inductive
stage of EAE, but may not be required for the progression of the
disease in the CNS. Generation of encephlitogenic Th1 cells and autoantibodies to MOG35–55 are impaired in IL-18-/- mice
The CNS demyelination is considered an outcome of coordinated
immune attaches initiated from both encephalomyelitis T cells and
pathogenic autoantibodies in MOG-induced EAE (19). We
first assessed Ag-specific spleen cell proliferation and cytokine
induction in MOG35–55-sensitized WT and
IL-18-/- mice. Spleen cells from WT and
IL-18-/- mice proliferated equally well to
MOG35–55 peptide (Fig. 2A), indicating that the
absence of IL-18 did not alter Ag-specific T cell proliferation in this
model. However, compared with WT mice, CD4+ T
cells from IL-18-/- mice produced severely
reduced levels of IFN- and TNF- in response to the
MOG35–55 peptide (Fig. 2B). In
contrast, levels of IL-4 production by CD4+ T
cells were comparable in IL-18-/- and WT mice.
These results indicated that IL-18 is required for autoreactive Th1,
but not for Th2 cell development.
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C).
Because IFN- was shown not to be required for the generation of MOG
induced-EAE (20), the resistance to
MOG35–55-induced EAE could be a result of a more
general malformation of Th1 cells (e.g., production of TNF- and/or
other inflammatory cytokines) and autoantibodies to MOG rather than
only depend on the IFN- producing Th1 cells.
NK cell functions are impaired in MOG35–55-sensitized IL-18-/- mice
Recent studies have suggested that NK cells may regulate the
adaptive immune response, including the development of autoimmune and
hypersensitivity reactions (21, 22). IL-18 can promote NK
cell functions (9). Therefore, we asked whether the
resistance to EAE induction in IL-18-/- mice
could be associated with an altered NK cell function. To explore this
possibility, the killing of YAC-1 cells by NK cells and the production
of IFN- by NK cells were examined. Spleen cells from
MOG35–55-sensitized WT mice could readily kill
YAC-1 target cells. Sorted NK cells from these mice were capable of
producing IFN- (Fig. 3). In contrast,
levels of YAC-1 killing and production of IFN- were significantly
lower in nonimmunized mice (Fig. 3). Therefore, NK cells are activated
quickly after primary immunization with MOG35–55
plus CFA. In contrast, both killing of YAC-1 cells and the production
of IFN- by NK cells were lower in IL-18-/-
mice immunized with MOG35–55 and CFA than in WT
mice (p < 0.05; Fig. 3B).
Collectively, these data suggest that NK cell functions were reduced in
the autoantigen-sensitized IL-18-/-
mice.
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To explore whether the resistance to EAE induction in
IL-18-/- mice could be attributed to the
defective NK functions observed above, we first injected IL-18 to WT
and IL-18-/- mice. IL-18 injection enhanced the
severity of EAE as well as the production of IFN- and TNF- in WT
mice (Table I, groups 1 and 2). IL-18
injection could break the resistance to EAE induction and restore the
defective Th1 response in IL-18-/- mice (Table I, groups 4 and 5). However, when host NK1.1+
cells were depleted by administration of anti-NK1.1 mAb, the
effects of IL-18 injection were abrogated in both WT and
IL-18-/- mice (Table I, groups 3 and 6). This
suggested that the effects of IL-18 are dependent on the presence of NK
cells. Notably, the role of NK cells appeared critical at the time of
primary immunization, because depletion of NK1.1+
cells after primary immunization had no detectable effect (data not
shown). When WT mice were treated with anti-NK1.1 mAb, EAE
development was suppressed. This was associated with a reduced
production of IFN- and TNF- (Table I, group 9).
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directs autoreactive Th1 cell development
Early production of IFN- by NK cells has been suggested to
promote subsequent Th1 responses during host defense against infections
(23, 24). It is not known whether this mechanism operates
an autoimmune process. In the current model the defective
MOG35–55-reactive Th1 responses in the
IL-18-/- mice could be attributed to the direct
absence of IL-18, the reduced IFN- production by NK cells as a
consequence of the absence of IL-18, or both. Despite normal
development of NK cells, NK cell activity with respect to cytotoxicity
and production of IFN- is severely impaired in
IL-18-/- mice (6) (Fig. 3). Thus,
IL-18-/- mice provide a very useful model for
functional NK cell deficiency. RAG1-/- mice
have normal NK cells, but no NK T cells (13). To address
whether NK cell-derived IFN- can influence autoreactive Th1 cell
responses, we purified NK cells (activated by
MOG35–55 and CFA) from
RAG1-/- or
RAG1/IFN--/- (double-mutant) mice and
transferred the NK cells to IL-18-/- mice at
the time of immunization with MOG35–55 and CFA.
IL-18-/- mice that received
107 NK cells from RAG1-/-
mice before immunization with MOG35–55/CFA
developed EAE at a similar magnitude as control WT mice (Table I, group
7). In contrast, no development of EAE was observed after transfer of
NK cells from RAG1/IFN--/- mice (Table I,
group 8). The mice were killed on 25 days p.i., and
CD4+ T cells were purified from local lymph
nodes. Transfer of 107 NK cells from
RAG1-/- mice largely rescued the impaired
IFN- and TNF- production by CD4+ T cells
from IL-18-/- mice (Table I, groups 4 and 7).
In contrast, transfer of 107 NK cells from
RAG1/IFN--/- mice to
IL-18-/- mice had no detectable effect on
cytokine production by T cells. IL-4 production was not significantly
altered by reconstitution of NK cells (data not shown). Transfer of NK
cells after induction of disease had no detectable effect (data not
shown). Taken together, these results provide in vivo evidence that
IFN- production by activated NK cells can promote autoreactive Th1
responses during the initiation stage of autoimmune responses.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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by NK cells (7, 9). In this study
we have focused attention on IL-18 in the pathogenesis of MOG-induced
EAE in B6 mice, a murine model for MS. IL-18 gene disruption converts
susceptible B6 mice to a state of high resistance to disease induction,
while IL-18 administration enhances the severity of the disease. These
results suggest that IL-18 is critical for the development of
MOG-induced EAE. An impaired capacity of NK cells to release IFN-
during the point of primary immunization, due to the absence of IL-18,
appears to be a major mechanism underlying the resistance to EAE
induction. Thus, our study suggests that IL-18 links the innate immune
response involving NK cells to the generation of destructive
autoimmunity.
Myelin sheath destruction in MS and MOG-induced EAE appears to be a
coordinated immunological attack initiated by both Th cells and
autoantibodies (19). Factors that determine the
differentiation of naive T cells into either Th1 (IL-2, IFN-,
TNF-), or Th2 (IL-4, IL-10) phenotypes would be expected to have an
impact on the development of autoimmune responses. The most clearly
defined factors determining Th subset differentiation from naive
CD4+ T cell precursors are cytokines present at
the initiation of the immune response at the stage of ligation of the
TCR (25). A number of inflammatory mediators are
released promptly during the innate immune responses. For example,
virus/bacterial stimuli activate macrophages and subsequently NK cells
of the innate immune response to produce IL-12 and IFN-,
respectively, which may drive the development of Th1 cells from naive
Ag-specific T cells (23, 24). Beside its ability to
produce IFN-, NK cells may produce a variety of other
immunoregulatory mediators, including TGF-ß, TNF-, TNF-ß,
GM-CSF, macrophage inflammatory protein-1, IL-1, IL-3, IL-5, IL-8,
and IL-10 (21, 26). These soluble factors may also affect
in different ways the development of autoimmune diseases.
Although NK cell numbers are normal in IL-18-/-
mice (9), NK cell functions with regard to cytotoxicity
and production of IFN- are reduced in
MOG35–55/CFA-immunized mice (Fig. 3). A critical
question arises as to whether the failure to mount Th1 responses to MOG
in IL-18-/- mice is due to the defective NK
cell functions, the deficiency in IL-18, or both. IL-18 could not
directly drive Th1 development in in vitro experiments
(27), indicating that additional factors in vivo are
required for the development of Th cells. In the present study, IL-18
injection restored the MOG35–55-specific Th1 and
autoantibody responses (data not shown). This restoration was abrogated
when NK cells were depleted by administration of anti-NK1.1 mAb in
IL-18-/- mice, indicating that the action of
IL-18 in promoting the generation of strong MOG-specific Th cells was
dependent on NK cells in this model. Furthermore, transfer of NK cells
from RAG1-/- mice, but not from
RAG1/IFN--/-(double-mutant) mice, rescued
the defective Th1 responses in IL-18-/- mice
and converted IL-18-/- mice so that they were
susceptible to EAE induction. Collectively, these data demonstrate that
IL-18 favors the differentiation of naive T cells into autoreactive Th1
cells. This effect is largely dependent on IFN- production by NK
cells and cannot be compensated by other soluble factors, such as
IL-12, in this system. Therefore, the present study provides in vivo
supportive evidence for a role of NK cells in directing Th1 responses
not only in the host defense against infections, but also in the
generation of an autoimmune disease.
It has been demonstrated that NK cells could critically influence the
initial differentiation of naive T cells into effector cells in
response to foreign Ag, but not the secondary activation of Ag-specific
T cells (21). This salient feature of NK cells is also
well reflected in the current model, in which no detectable effects
were seen upon depletion of NK cells or transfer of NK cells to
IL-18-/- mice after induction of disease.
Because most cytokines produced by NK cells can also be produced by
other cell types, our study suggests that the timing of IFN-
released by NK cells in regulating the autoreactive T cell response is
critical and is indispensable by cytokines produced by other cells.
Our results suggests that defective NK cell function in
IL-18-/- mice underlies the failure of the
development of autoreactive Th1 cells and the resistance to EAE
induction. These results seem at odds with a recent study showing that
anti-NK1.1 mAb treatment enhanced the
MOG35–55-reactive Th1 cell response and the
development of EAE (22). Currently, there is no clear
explanation for this apparent discrepancy. It is noticeable that in
that study induction of disease followed shortly after the
administration of anti-NK1.1 mAb. Anti-NK1.1 mAb cross-link with
NKR-P1 and trigger IFN- release by the NK cells before the actual
depletion of the cells (28). In our hands, depletion of
NK1.1+ cells 2 days prior to immunization
resulted in reduced disease development as well as Th1 responses (Table I, group 9). Determination of whether the timing and dose of Ab
administration are responsible for these contrasting results requires
further investigation.
Previous studies have demonstrated that EAE can be induced by
IFN--independent pathways as well (20). However, those results do
not exclude a disease-promoting role for IFN-, including IFN-
produced by NK cells. The present results support the idea of an
important role for IFN- produced by NK cells in the course of
disease development in the present model. It might be that Th1
differentiation is crucial, but that the relevant effector cytokine is
T1 cytokines other than (in additional to) IFN-.
The current study provides evidence that IL-18 can interplay with NK
cells and direct autoreactive T cells to a strong Th1 phenotype, and
links innate immune responses to the autoimmune responses. In a more
physiological context, one may envisage an intracellular bacterial or
virus infection that induces monocytes/macrophages to promptly produce
IL-18, which, in turn, independently or in synergy with IL-12 activates
NK cells. These cytokine-activated NK cells may provide a unique
endogenous milieu promoting downstream adaptive responses.
Subsequently, NK cells may promote autoaggression via control of
autoreactive T and B cells. This may be achieved by the production of
IFN- and/or other inflammatory mediators during the initial
activation phase of these cells. Because progression of MS may be
associated with successive rounds of activation of myelin-reactive Th1
cells (such as in epitope spreading) (4), selective
targeting of IL-18 may prevent the development of such neo-generated
autoimmune responses and may therefore provide a therapeutic
alternative for MS.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Fu-Dong Shi, Department of Immunology, IMM-23, The Scripps Research Institute, 10555 North Torrey Pines Road, La Jolla, CA 92037.
3 Abbreviations used in this paper: MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; MNC, mononuclear cells; WT, wild type; RAG, recombinase-activating gene; p.i., postimmunization.
Received for publication April 14, 2000. Accepted for publication July 5, 2000.
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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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C. N. Baxevanis, A. D. Gritzapis, and M. Papamichail In Vivo Antitumor Activity of NKT Cells Activated by the Combination of IL-12 and IL-18 J. Immunol., September 15, 2003; 171(6): 2953 - 2959. [Abstract] [Full Text] [PDF]
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A. Ito, A. Matejuk, C. Hopke, H. Drought, J. Dwyer, A. Zamora, S. Subramanian, A. A. Vandenbark, and H. Offner Transfer of Severe Experimental Autoimmune Encephalomyelitis by IL-12- and IL-18-Potentiated T Cells Is Estrogen Sensitive J. Immunol., May 1, 2003; 170(9): 4802 - 4809. [Abstract] [Full Text] [PDF]
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C. Deng, C. Radu, A. Diab, M. F. Tsen, R. Hussain, J. S. Cowdery, M. K. Racke, and J. A. Thomas IL-1 Receptor-Associated Kinase 1 Regulates Susceptibility to Organ-Specific Autoimmunity J. Immunol., March 15, 2003; 170(6): 2833 - 2842. [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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J. A. Gracie, S. E. Robertson, and I. B. McInnes Interleukin-18 J. Leukoc. Biol., February 1, 2003; 73(2): 213 - 224. [Abstract] [Full Text] [PDF]
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 A. Matejuk, J. Dwyer, A. Zamora, A. A. Vandenbark, and H. Offner Evaluation of the Effects of 17{beta}-Estradiol (17{beta}-E2) on Gene Expression in Experimental Autoimmune Encephalomyelitis Using DNA Microarray Endocrinology, January 1, 2002; 143(1): 313 - 319. [Abstract] [Full Text] [PDF]
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E. Esfandiari, I. B. McInnes, G. Lindop, F.-P. Huang, M. Field, M. Komai-Koma, X.-q. Wei, and F. Y. Liew A Proinflammatory Role of IL-18 in the Development of Spontaneous Autoimmune Disease J. Immunol., November 1, 2001; 167(9): 5338 - 5347. [Abstract] [Full Text] [PDF]
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F.-D. Shi, M. Flodstrom, S. H. Kim, S. Pakala, M. Cleary, H.-G. Ljunggren, and N. Sarvetnick Control of the Autoimmune Response by Type 2 Nitric Oxide Synthase J. Immunol., September 1, 2001; 167(5): 3000 - 3006. [Abstract] [Full Text] [PDF]
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 M. Neighbors, X. Xu, F. J. Barrat, S. R. Ruuls, T. Churakova, R. Debets, J. F. Bazan, R. A. Kastelein, J. S. Abrams, and A. O'Garra A Critical Role for Interleukin 18 in Primary and Memory Effector Responses to Listeria monocytogenes That Extends Beyond Its Effects on Interferon {gamma} Production J. Exp. Med., August 6, 2001; 194(3): 343 - 354. [Abstract] [Full Text] [PDF]
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) mice
immunized with MOG35–55 in CFA on day 7 p.i. as well
as from native WT (
) and IL-18-/- mice (
). NK cell
effectors were tested against YAC-1 target cells. B,
IFN-