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Departments of
*
Microbiology and Immunology and
Pathology, Albert Einstein College of Medicine, Bronx, NY 10461; and
Department of Immunology, IMM23, The Scripps Research Institute, La Jolla, CA 92037
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The principal animal model for the study of MS has been experimental allergic encephalomyelitis (EAE), with which it shares many histopathological and clinical features. EAE is induced by immunization with autoantigens of myelin, including myelin basic protein and proteolipid proteins, in adjuvants, but susceptibility is highly strain dependent (4, 5, 6, 7). Some strains such as SJL/J, B10.PL, and 129/J are highly susceptible, while other strains, such as C57BL and BALB/c, are generally considered less susceptible. The mechanisms responsible for the genetic resistance to the disease are unclear, but involve a complex interaction between genes within the MHC and genes outside of the MHC (8, 9, 10).
Several lines of evidence suggest a genetic link between cytokine phenotype and susceptibility to EAE. A genetic analysis revealed that one of the non-MHC genes linked to EAE susceptibility is on the D11Nds29 (IL4) locus on chromosome 11, in an interval that contains a cluster of genes encoding cytokines such as IL-3, IL-4, IL-5, IL-13, CSF, and IFN regulatory factor 1 (11). In addition, the highly susceptible SJL/J strain is defective in the ability to produce IgE Abs, an isotype known to be IL-4 dependent, as well as less efficient in the ability to produce IL-4 in the course of a primary immune response (12). This defect is thought to relate to a marked deficiency of NK1.1+ T cells, an IL-4-secreting T cell population that appears to be a major source of IL-4 at the initiation of an immune response. Recently, it has been proposed that this T cell population may play an important immunoregulatory role in T cell-mediated autoimmune disorders such as insulin-dependent diabetes mellitus (13, 14).
Studies on the pathogenesis of EAE indicate that sensitization of CD4 T
cells recognizing proteins present within the myelin sheath is critical
to the encephalitogenic process and that cells expressing Th1-type
cytokines, including IL-2, IFN-
, and TNF-
ß, are required for
disease expression, whereas Th2-type cytokines, including IL-4, IL-10
and TGF-ß, are protective (reviewed in Refs. 15 and 16). Additional
studies have shown that shifting the cytokine profile of
myelin-autoreactive T cells from a Th1- to a Th2-type cytokine profile
significantly alters the course of EAE and ameliorates disease
(17, 18, 19, 20, 21). Moreover, studies of TCR transgenic mice, in which all T
cells express a common T cell receptor derived from an encephalitogenic
T cell clone, strongly suggest that it is the cytokine profile, rather
than T cell receptor specificity, that determines an encephalitogenic
or resistant outcome (22).
The validity of the Th1 vs Th2 paradigm in EAE has recently been called
into question, however, by the observation that EAE can be readily
induced in animals in which the genes for IFN- or its receptor, as
well as the genes for LT and TNF, have been inactivated (23, 24, 25). In
addition, MBP-reactive T cells that have been biased toward a Th2-type
cytokine profile have been shown to mediate an EAE-like disease in the
Rag-1-/- mouse and to have no regulatory activity for a
Th1-type response (26). Nevertheless, there is compelling evidence to
support a role for IL-4 as a regulatory cytokine for an inflammatory
pathway mediated by Th1-type cytokines, and evidence that its presence
in the target organ is sufficient to down-regulate autoreactive Th1
clones (27, 28, 29). To address further the role of IL-4 in EAE and, in
particular, whether IL-4 is necessary for genetic resistance to EAE, we
sensitized two strains of mice in which the gene for IL-4 had been
disrupted. We chose the C57BL/6 and BALB/c strains, since C57BL/6
animals are generally considered to generate a Th-1 type immune
response and BALB/c a Th2 type. We used whole guinea pig spinal cord
myelin for sensitization to obviate an effect of bias toward any
particular myelin Ag in the two different strains of mice. The results
support the conclusion that IL-4 is a major cytokine involved in the
regulation of the severity of the acute phase of the disease. These
data add further support to a major role for IL-4 as a regulatory
cytokine for Th1-type responses in EAE.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 and BALB/c IL-4-deficient and wild-type (wt) littermates, as well as SJL/J mice, 6 to 8 wk of age were purchased from The Jackson Laboratories, Bar Harbor, ME. The IL-4-deficient mice were derived from 129 mice with a transgenic disruption of the IL-4 gene, extensively back-crossed into either the C57BL/6 or BALB/c mouse strains.
Induction of EAE
Mice were immunized s.c. at four different sites on the flank with an emulsion containing 700 µg/mouse of guinea-pig myelin, prepared according to the method of Norton and Poduslo (30), in CFA. Pertussis toxin (100 ng, Sigma, St. Louis, MO) was given i.v. on days 0, 2, and 7 postimmunization (p.i) to each group of mice.
Anti-IL-12 treatment
Mice were treated daily with 200 µg of a sheep polyclonal Ab (kindly supplied by Dr. G. Trinchieri) against murine IL-12 administered i.p. from day 0 to day 12 p.i.
Clinical evaluation
Animals were assigned to coded groups and monitored on a daily basis for clinical expression of disease. The clinical scores were assigned using the following scale: 1, limp tail; 2, hind limb weakness; 3, complete hind limb paralysis; 4, tetraplegia; 5, death. A clinical index was established by determining the mean (±SD) of the clinical scores of all of the animals sensitized.
Histopathologic evaluation
Under ether anesthesia, mice (n = 2 or 3 per group) were perfused with 20 ml ice-cold 0.1 M phosphate buffer, pH7.4, containing 4% paraformaldehyde and 1% glutaraldehyde. The brain, spinal cords, and optic nerves were removed, dehydrated through a graded series of alcohols, and embedded in epon 812 (Electron Microscopy Sciences, Fort Washington, PA). One-micron sections were prepared and stained with 1% toluidine blue. The extent of inflammation and demyelination was determined on coded samples of lumbar spinal cord tissues as described previously (31). At least five sections per block were evaluated.
Determination of cytokine profiles in the CNS and draining lymph nodes by RT-PCR
Draining lymph nodes, brains, and spinal cords were collected
from individual C57BL/6 wt and IL-4-deficient mice at day 11 p.i.
Total RNA was extracted with Trizol (LTI, Life Technologies,
Gaithersburg, MD), the c-DNA amount was normalized measuring the
hypoxanthine phosphoribosyltransferase (HPRT) expression, and the
IFN-, IL-4, and IL-10 transcripts were analyzed by RT-PCR using
specific primer sequences (Clontech Laboratories, Palo Alto, CA).
Reactions were performed in a programmable thermal controller
(Perkin-Elmer Cetus, Norwalk, CT). After amplification, 10 µl of PCR
product was separated by electrophoresis on 1% agarose gel and
visualized by ethidium bromide staining.
Establishment of MBP-specific short-term lines
C57BL/6 wt and IL-4-deficient mice were immunized with bovine MBP (50 µg/mouse, SIGMA) in CFA s.c. at four different sites on the flank. After 10 days, the draining lymph nodes were removed, and lymph node cells were isolated and cultured in vitro for 4 days in RPMI 1640 containing 10% FBS, 50 µM 2-ME, 1 mM sodium pyruvate, 0.1 M HEPES, 1% nonessential amino acids, and MBP at 50 µg/ml.
Measurement of IL-4- and IFN--secreting MBP-specific T cells by
ELISPOT assay
The number of IL-4- and IFN--secreting MBP-specific T cells
was determined by ELISPOT assay. Briefly, the MBP-specific short-term
lines, isolated from C57BL/6 wt and IL-4 deficient mice, were passed
over Ficoll-Hypaque (Pharmacia, Uppsala, Sweden), washed, added to
anti-IFN-- or anti-IL-4-coated wells of nitrocellulose
plates (Millipore, Bedford, MA) at serial twofold dilutions (2 x
105 to 6 x 103) and cultured for
20 h in the presence of Con A- and CD3-depleted, irradiated
congenic splenocytes. Spots representing IFN-- or IL-4-secreting
cells were developed using biotinylated anti-cytokine Abs and
avidin-peroxidase complex (PharMingen, San Diego, CA), with
3-amino-ethylcarbazole and H2O2 as substrate,
and counted with a dissecting microscope.
Ribonuclease protection assay
Following administration of a lethal dose of sodium
pentobarbital, mice (n = 3 per group) were
perfused through the ascending aorta with 20 ml ice-cold PBS. The
spinal cord was then dissected free from the spinal column, and total
RNA was extracted using TRIREAGENT (Molecular Research Center,
Cincinnati, OH). Ribonuclease protection assays (RPA) using the ml-11
multiprobe template set were performed essentially as described (32).
Briefly, [-32P]UTP-labeled antisense RNA transcripts
for TNF-, lymphotoxin (TNF-ß), IL-1 and -ß, IL-3, IL-4, IL-5,
IL-6, and ML32 (large ribosomal subunit protein 32) were generated
using the template sets and T7 RNA polymerase. Ten to 20 µg total RNA
from each sample were allowed to hybridize to the labeled probe for
20 h at 45°C. Single-stranded RNA was digested with an RNase
A/T1 mixture (Ambion Inc., Austin, TX), and the hybrids were analyzed
on denaturing urea/polyacrylamide gels. Protected fragments were
visualized by autoradiography and quantitated using Image QuaNT
(Molecular Dynamics, Sunnyvale, CA). For each sample, a ratio of the
intensity of the cytokine band was obtained using the band for ML32.
Data from different autoradiograms were normalized by setting the value
of the most intense ML32 band as 100%, and the values for other ML32
expressed as a ratio to the most intense band. This was then used as a
correction factor. Control, unsensitized animals taken at random from
these colonies were uniformly negative for cytokine gene expression in
the CNS using this assay system.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In our initial experiments, we tested the effect of inactivation
of the gene for IL-4 in the genetically resistant C57BL/6 strain of
mouse. IL-4 transgenic gene-disrupted (IL-4-/-) mice
and control wt C57BL/6 mice, as well as the susceptible SJL/J strain,
were immunized with an emulsion of guinea pig spinal cord myelin in CFA
(700 µg/mouse) to induce EAE using a direct sensitization protocol
and monitored on a daily basis for clinical expression of disease. The
results of cumulative data for three separate experiments are shown in
Figure 1
, A and B.
In the C57BL/6 IL-4-/- mice disease onset occurred
earlier, was more severe, and involved a greater number of animals than
in either the C57BL/6 wt, or in the susceptible SJL/J strain. As shown
in Table I, the peak CI achieved by the
IL-4-/- animals was 2.6 ± 0.8
(n = 12; 100% incidence of disease), and for
the control C57BL/6 animals was 1.1 ± 1.3
(n = 12; 50% incidence of disease). The
difference in the CI between the two groups was highly significant
(p < 0.005). No mortality data were
incorporated into these indices, but in the C57BL/6 -/- group 4 of 16
immunized mice died, whereas no deaths were recorded in the control
groups.
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, n = 10 per group).
Although disease was consistently more severe in the
IL-4-/- animals, the BALB/c wt mice developed an equally
severe disease such that it was not possible to detect any
statistically significant differences between the two groups. Moreover,
both the BALB/c wt and IL-4-/- mice did not recover
completely and went into a relapse approximately 45 days p.i.
Interestingly, the severity of the relapse was greater in the
IL-4-/- BALB/c mice, with relapses commencing earlier and
persisting for a longer period of time (Fig. 2).
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From these data we conclude that inactivation of the gene for IL-4 exacerbates disease in the C57BL/6 strain of mouse. However, IL-4 is not the sole factor involved in the genetic resistance to EAE, and other mechanisms, such as the protocol of immunization or the Ag used, may be crucial for disease induction in different strains of mice.
EAE in the IL-4-deficient C57BL/6 mice is inhibited by Abs to IL-12
To demonstrate that the development of Th1-autoreactive cells was
indeed responsible for the increased susceptibility in the
IL-4-deficient C57BL/6 mice, we tested the effect of anti-IL-12 Abs
on disease expression in these mice. Since IL-12 plays a critical role
in the initiation of Th1-type cytokine responses, we treated the
IL-4-deficient C57BL/6 mice with neutralizing Abs to IL-12, starting on
the same day as the animals were sensitized and continuing through day
12. This treatment resulted in almost complete inhibition of EAE (Fig. 3) and confirmed the importance of
Th1-type T cells in disease expression in the IL-4-deficient
mice.
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To establish that the protection in the genetically resistant
C57BL/6 mice was mediated by a protective Th2 response, the cytokine
profile of T cells responding to MBP was measured by ELISPOT assay on
lymph node cells obtained 10 days after MBP sensitization and
stimulated in vitro with MBP. IFN--secreting T cells were present in
MBP-specific short-term T cell lines from both groups of animals, but
only cultures from the control animals contained a large number of
cells with an IL-4-secreting Th2 phenotype (Fig. 4).
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To explore further the effect of IL-4 on disease severity, we
determined cytokine gene expression in the CNS of affected mice at a
time point coincident with peak expression of disease in both the
C57BL/6 (day 11) and BALB/c (day 15) animals using a multiprobe RPA
system. The results of this assay for one IL-4-/-
and one wt animal for each strain are shown in Figure 5, and cumulative data for three animals
per group expressed as a ratio of the density of the cytokine band to
that for ML32 are shown in Figure 6.
Although the levels of mRNA for most of the proinflammatory cytokines
(IL-1>IL-6>TNF>LT) were higher in the BALB/c than in the C57BL/6
mice, in both strains of mice they were dramatically increased in the
IL-4-/- animals. Interestingly, the two strains of mice
showed differences in their cytokine profiles, with a prominent band
for IL-1 present only in the CNS samples from BALB/c mice and a band
for IL-5 present only in the C57BL/6 animals. The mRNA for IFN-, the
prototypical Th1 cytokine, was readily detected in the BALB/c samples
but not in those from the C57BL/6 animals. Taken together, these
results are consistent with the more severe clinical EAE detected in
the BALB/c animals compared with the C57BL/6.
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, at the peak of disease on day 11,
IFN- expression was present in the lymph nodes of both groups of
sensitized mice. As expected, IL-4 was observed only in the lymph nodes
of the wt C57BL/6 mice. However, in the CNS, only the IL-4-deficient
mice had a detectable signal for IFN-, indicating the presence of
inflammatory cells within the CNS in the IL-4-deficient mice.
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In the C57BL/6 mice, the IL-4-/- mice showed a
markedly enhanced susceptibility to EAE, but, commencing around day 12,
these animals began to recover and, if they survived, were essentially
free of clinical disease by days 18 to 19 (Fig. 1
A).
The interval between onset of symptoms and recovery was similar in the
C57BL/6 IL-4-/- and susceptible SJL mice. These results
indicate that, while IL-4 plays an important role in regulating the
severity of EAE, it is not necessary for development of the recovery
phase of the disease. In other studies (33, 34), it has been suggested
that IL-10 may play a key role in the recovery process. To test for
this, we performed an RT-PCR analysis on RNA from tissues sampled from
the CNS of C57BL/6 IL-4-/- and wt mice sampled at the
height of clinical disease, a time point immediately before the onset
of the recovery phase. In these tissues a strong signal for IL-10 was
readily detected, consistent with a role for this cytokine in the
recovery process (Fig. 7). Moreover, these results further support the
conclusion that IL-10 can be produced in the absence of IL-4,
indicating that it is not formally associated with the Th2 pathway.
Histopathologic features of EAE in the IL-4-deficient BALB/c and C57BL/6 mice
We then investigated whether inactivation of the gene for IL-4 altered the pathologic expression of EAE in these two strains of mice. Specifically, we were interested to know if inactivation of the gene for IL-4 altered either the nature of the cellular infiltrate in the CNS lesions, and/or the distribution of lesions throughout the neuraxis. To answer these questions, histopathologic examination of CNS tissues mice was performed at three time points in the C57BL/6 mice (day 7, day 11, and day 14), and at two time points in the BALB/c mice (day 15 and day 70). These different time points were studied because the kinetics of the disease process differed between the two different strains of mice.
In C57BL/6 animals sampled on day 7, when no clinical signs were
detected in any of the animals, the IL-4-deficient mice showed small
perivascular infiltrates of mononuclear and polymorphonuclear cells
around venules in the anterior fissure of the spinal cord, particularly
in the lumbar region. In contrast, no inflammation was noted in any of
the samples taken from the C57BL/6 mice (Table I). At day 11 in the
C57BL/6 mice (height of disease), sections of the lumbar region of the
spinal cord from the IL-4-/- animals showed areas of
submeningeal and perivascular inflammation, particularly at the root
entry zones, that consisted of focal accumulations of lymphocytes,
macrophages, and an occasional polymorphonuclear cell. Primary
demyelination was also evident in these inflamed areas of the cord
(Fig. 8A). In the wt
animals, only an occasional inflammatory cell was detected that was not
associated with any appreciable evidence of demyelination (Fig. 8B). Comparisons were then made between the
distribution of lesions throughout the neuraxis in the C57BL/6
IL-4-/- animals and clinically involved SJL/J mice. No
differences were noted in either the distribution of the lesions, or in
the cellular profile of the inflammatory infiltrate, in these two
groups of animals (data not shown). Thus, inactivation of the gene for
IL-4 led to a more intense inflammatory response within the spinal cord
(Table I) but did not lead to an altered distribution of lesions in the
CNS, nor did it change the nature of the cellular infiltrate in the
C57BL/6 strain. The only evidence that the absence of IL-4 in the
C57BL/6 mice altered the pathologic picture typical of EAE was the
reduced presence of plasma cells in the later stages of the disease
(day 14, data not shown).
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, A and B, and
Table I). Interestingly, however, although no differences were detected
in the nature of the inflammatory infiltrate found in the
IL-4-/- and the wt animals, distinct differences in the
profile of the inflammatory infiltrates were observed between the
C57BL/6 animals and the BALB/c animals. As noted above, the
inflammatory infiltrate at the height of the disease in C57BL/6 animals
resembled that found in SJL/J mice and consisted of small lymphocytes,
blast cells, and macrophages, with relatively few polymorphonuclear
cells. However, in the BALB/c animals, the inflammatory infiltrate at
the height of disease contained large numbers of polymorphonuclear
cells. These cells were intensely osmiophilic and exhibited numerous
extended cellular processes, suggesting that they were in a highly
activated state. Large numbers of inflammatory cells had invaded
adjacent areas of the cord, and many demyelinated axons were present in
these lesioned areas of the cord (Fig. 9A). Evidence
of Wallerian degeneration was also occasionally detected (Fig. 9A). These data suggest that the underlying
pathogenetic mechanisms involved in EAE induction in C57BL/6 mice and
in BALB/c mice differ, perhaps reflecting differences in the cytokine
profiles of the inflammatory infiltrates present in the CNS, as noted
in the RPA results presented above. At the day 70 time point, lumbar
spinal cord sections from both the IL-4-/- and wt animals
showed little evidence of active ongoing inflammation. However, white
matter areas of the cord contained many large chronically demyelinated
lesions containing large lipid-laden macrophages. Small focal areas of
remyelination were noted. No significant differences were noted between
the IL-4-/- and wt animals (Table I).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-1, TNF, and LT in spinal
cord tissues. In the BALB/c strain we were not able to detect a
difference in the clinical expression of the disease due to the high
level of susceptibility to EAE that we found in this strain of mouse
following our induction protocol. However, we found that the absence of
IL-4 in this strain of mouse increased the severity of the relapses,
the severity of the inflammatory response, and the level of
proinflammatory cytokines in the CNS. These data support the conclusion
that IL-4 plays a major role in regulating the effects of inflammatory
events mediated by proinflammatory cytokines in the CNS, the target
organ of the autoimmune attack. In contrast, inactivation of the gene
for IL-4 had little to no effect on the time point at which animals
started to recover from the acute episode of the disease, indicating
that the effects of IL-4 on the inductive and recovery phases in EAE
could be dissociated.
Studies of the genetic susceptibility and resistance to EAE have
indicated that the major susceptibility determinant is found within the
MHC locus, but non-MHC loci also exert a significant influence (8, 9).
Of interest is the observation that each of the non-MHC-linked loci
that have been identified has been found to be associated with genes
encoding cytokines or cytokine receptors (11). Our findings would
support the hypothesis that a predisposition to biasing the cytokine
profile of autoreactive T cell clones toward a protective Th2 type may
be one of the major determinants of genetic resistance to EAE.
Consistent with this thesis are the observations that one of the few
strains genetically highly susceptible to the induction of EAE, SJL/J
mice, are defective in their ability to produce IL-4 in the course of a
primary immune response to protein Ags, a defect that may be associated
with the absence of a minor population of NK 1.1+
TCR-ß+ T cells (12, 35, 36). The B10.S strain is also
resistant to EAE, and its T cells have been found to be unable to
generate IFN- in response to MBP, unless stimulated in vitro with
IL-12 (37), a cytokine that is known to predispose cells to
differentiation along the Th1 pathway (38). IL-4 has been shown to play
a pivotal role in the commitment of naive T cells to the Th2 pathway,
both by positively selecting for growth of such cells (39, 40) and by
inhibiting responsiveness of Th1 T cell precursors to IL-12. In the
circumstance in which both IL-4 and IL-12 are present, IL-4 appears
generally to be epistatic to IL-12 and induces a permanent commitment
to the Th2 pathway (38).
Our results using IL-4-/- mice consistently revealed a marked dissociation between susceptibility to induction of EAE and recovery from the disease. While the absence of IL-4 profoundly increased the susceptibility to EAE, it did not affect the ability of IL-4-/- mice to recover. A similar lack of an effect on recovery has also recently been shown in the susceptible PL/j mouse following inactivation of the gene for IL-4 (41). The IL-4-deficient C57BL/6 mice that recovered from EAE showed high levels of IL-10 mRNA in the CNS, similar to what has been reported in the susceptible SJL/J mice. Thus, IL-4 is essential for protection against EAE, but it is not necessary for recovery. From a therapeutic perspective, it will be important to establish which cytokines are necessary and sufficient for recovery from EAE, the most likely candidates at present being IL-10 and TGF-ß (33, 34). Although IL-10 has been characterized as a cytokine released from lymphocytes committed to a Th2 pathway, that association is not invariant in light of the present findings of IL-10 production in the absence of IL-4. Several studies have shown that IL-10 can be induced by IL-12 in the course of Th1 responses, forming part of a negative feedback loop that controls the production of IL-12, the activation state of macrophages and, in general, the inflammatory process (42, 43).
In summary the present results demonstrate that a genetic trait, the loss of the IL-4 gene, is unequivocally associated with an increased susceptibility to EAE in two different strains of mice. As such, these data lend further support to the conclusion that the ability to bias the differentiation of autoreactive T cell clones to the production of IL-4 could be a general mechanism by which the immune system regulates immune responses against self Ag to prevent the outcome of T cell-mediated autoimmune diseases. We believe these and other recent findings on EAE raise several fundamental questions that urgently need to be clarified in multiple sclerosis. These include whether IL-4 plays a similar determinative role in genetic or acquired resistance to human, T cell-mediated, autoimmune diseases and, more generally, to what extent mechanisms governing induction and recovery from EAE in experimental animal models are faithful reflections of those involved in human autoimmune disease.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Marika Falcone, Department of Immunology, IMM23, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, CA 92037.
3 Abbreviations used in this paper: MS, multiple sclerosis; CNS, central nervous system; EAE, experimental allergic encephalomyelitis; RPA, ribonuclease protection assay; LT, leukotriene; MBP, myelin basic protein; wt, wild type; p.i., postimmunization; ML32, large ribosomal subunit protein 32; CI, clinical index.
Received for publication October 28, 1997. Accepted for publication January 22, 1998.
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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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D. Sewell, Z. Qing, E. Reinke, D. Elliot, J. Weinstock, M. Sandor, and Z. Fabry Immunomodulation of experimental autoimmune encephalomyelitis by helminth ova immunization Int. Immunol., January 1, 2003; 15(1): 59 - 69. [Abstract] [Full Text] [PDF]
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G. T. Tran, N. Carter, X. Y. He, T. S. Spicer, K. M. Plain, M. Nicolls, B. M. Hall, and S. J. Hodgkinson Reversal of experimental allergic encephalomyelitis with non-mitogenic, non-depleting anti-CD3 mAb therapy with a preferential effect on Th1 cells that is augmented by IL-4 Int. Immunol., September 1, 2001; 13(9): 1109 - 1120. [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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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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R. B. Fritz and M.-L. Zhao Regulation of Experimental Autoimmune Encephalomyelitis in the C57BL/6J Mouse by NK1.1+, DX5+, {{alpha}}{{beta}}+ T Cells J. Immunol., March 15, 2001; 166(6): 4209 - 4215. [Abstract] [Full Text] [PDF]
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V. T. Nguyen and E. N. Benveniste IL-4-Activated STAT-6 Inhibits IFN-{gamma}-Induced CD40 Gene Expression in Macrophages/Microglia J. Immunol., December 1, 2000; 165(11): 6235 - 6243. [Abstract] [Full Text] [PDF]
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A. Elhofy, I. Marriott, and K. L. Bost Salmonella Infection Does Not Increase Expression and Activity of the High Affinity IL-12 Receptor J. Immunol., September 15, 2000; 165(6): 3324 - 3332. [Abstract] [Full Text] [PDF]
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 C. Newton, S. McHugh, R. Widen, N. Nakachi, T. Klein, and H. Friedman Induction of Interleukin-4 (IL-4) by Legionella pneumophila Infection in BALB/c Mice and Regulation of Tumor Necrosis Factor Alpha, IL-6, and IL-1beta Infect. Immun., September 1, 2000; 68(9): 5234 - 5240. [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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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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A. Elhofy and K. L. Bost Limited Interleukin-18 Response in Salmonella-Infected Murine Macrophages and in Salmonella-Infected Mice Infect. Immun., October 1, 1999; 67(10): 5021 - 5026. [Abstract] [Full Text] [PDF]
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 J. Suttles, D. M. Milhorn, R. W. Miller, J. C. Poe, L. M. Wahl, and R. D. Stout CD40 Signaling of Monocyte Inflammatory Cytokine Synthesis through an ERK1/2-dependent Pathway. A TARGET OF INTERLEUKIN ()-4 AND IL-10 ANTI-INFLAMMATORY ACTION J. Biol. Chem., February 26, 1999; 274(9): 5835 - 5842. [Abstract] [Full Text] [PDF]
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J. F. Rowell and D. E. Griffin The Inflammatory Response to Nonfatal Sindbis Virus Infection of the Nervous System Is More Severe in SJL Than in BALB/c Mice and Is Associated with Low Levels of IL-4 mRNA and High Levels of IL-10-Producing CD4+ T Cells J. Immunol., February 1, 1999; 162(3): 1624 - 1632. [Abstract] [Full Text] [PDF]
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, n = 12); and
two separate experiments for SJL mice (
, n = 12).
The IL-4-/- animals developed a more severe disease that
commenced earlier than that found in either C57BL/6 wt animals or the
susceptible SJL/J animals. Note also that disease onset to recovery
time period was similar in the IL-4-/- and SJL/J mice.
B. Percent incidence of disease for the same group of
animals shown in (A). All
IL-4-/- animals developed clinical signs of disease,
whereas only 80% of susceptible SJL/J, and 43% of resistant C57BL/6
wt mice developed clinical disease.
). In this group, three
of four of the animals were completely protected with only one
developing mild clinical signs, whereas the control group of
IL-4-/- animals injected with an equal volume of PBS
developed severe clinical disease (
