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Departments of
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Molecular Microbiology and Immunology,
Neurology, and
Pathology, University of Southern California School of Medicine, Los Angeles, CA 90033; and
§
DNAX Research Institute of Molecular and Cellular Biology, Inc., Palo Alto, CA 94394
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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 presence of a Th2 environment before Ag encounter in young adult male SJL mice (3) allowed the in vivo induction and adoptive transfer of neuroantigen-specific Th2 cells (5). Male-derived MBP-specific Th2 cells suppressed both the acute and relapse phases of passive EAE, induced by MBP-specific Th1 cells derived from female SJL mice (5). However, it is not clear whether the suppressive effects of neuroantigen-specific Th2 cells require access into the CNS. Partial inhibition of EAE by peripheral injection of Th2 cytokines suggests that cytokine secretion from a peripheral site may be sufficient to reduce an organ-specific Th1-mediated autoimmune disease. This report demonstrates that the adoptive transfer of Th2 cells specific for keyhole limpet hemocyanin (KLH) is not sufficient to suppress Th1-mediated disease in the absence of in vivo-induced activation. Th2-mediated suppression did not eliminate neuroantigen-specific Th1 cells. However, after clinical recovery, both Th1 and Th2 cytokines are secreted in response to neuroantigen. Furthermore, IL-10 appears to be the primary effector of inhibition mediated by in vivo-activated Th2 cells. These data demonstrate the efficacy of inhibiting Th1-mediated autoimmune disease via IL-10 secretion from in vivo-activated Th2 cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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SJL mice were purchased from The Jackson Laboratory (Bar Harbor, ME), Harlan Sprague-Dawley (Indianapolis, IN), or the National Cancer Institute (Frederick, MD). No differences in responses were noted comparing mice obtained from the different vendors. Males were obtained at 4–5 wk of age and used within 2 wk of receipt. Female donors were obtained at 6 wk of age and used within 2 wk of receipt. Female recipients were obtained at 6 wk of age and used between 7 and 10 wk of age. Animals were housed and maintained in the University of Southern California vivarium.
Immunization
Bovine MBP (Sigma, St. Louis, MO) was dissolved in PBS at 2 mg/ml and emulsified with an equal amount of IFA (Difco, Detroit, MI) supplemented with 20 mg/ml of heat-killed Mycobacterium tuberculosis, strain H37Ra (Difco). Females were immunized with a total of 0.4 ml distributed at four sites over the flanks. Males were immunized i.p. with 100 µg of KLH (Calbiochem, La Jolla, CA) dissolved in 0.5 ml of PBS as previously described (3).
Adoptive transfer and challenge
Inguinal, axillary, and brachial lymph nodes were removed and single-cell suspensions were prepared at 10 days post-MBP immunization or at 5 days post-KLH immunization, as previously described (3, 5). T cells from females were cultured with 50 µg/ml of MBP at 4 x 106 cells/ml. T cells from males were cultured with 50 µg/ml of KLH at 2 x 106 cells/ml. T cells from both males and females were cultured in RPMI 1640 medium supplemented with 10% prescreened FCS, 2 mM L-glutamine, 25 µg/ml gentamicin, nonessential amino acids, sodium pyruvate, and 5 x 10-5 M 2-ME and harvested after 4 days incubation at 37°C. In some experiments 3–5 x 107 cells were injected i.p. In the majority of the experiments shown, 2.5 x 107 cells were injected i.v. into naive, syngeneic female recipients. No differences were noted after either injection route. For suppression studies, equal quantities of KLH-specific cells were injected in addition to the MBP-specific Th1 cells (3–5 x 107 cells/recipient via the i.p. route or 2.5 x 107 cells/recipient via the i.v. route). Recipients were immunized subcutaneously immediately after adoptive transfer with 100 µg of KLH in IFA supplemented with 5 µg/ml H37Ra (Sigma).
Clinical evaluation of EAE
Recipients were monitored daily for clinical EAE scores, graded
as follows: 0, no abnormality; 1, loss of tail tone; 2, paralysis of
one hind limb; 3, total paralysis of both hind limbs; 4, quadriplegia;
and 5, moribund. Symptomatic mice were given ready access to food and
water. Cumulative disease scores were determined from day 7 to day 15
post-adoptive transfer. Significance was determined by the Mann-Whitney
U nonparametric statistical analysis. Differences were
considered significant if p 
0.05.
Ag-specific T cell proliferation
Single-cell suspensions were prepared from lymph nodes or spleens. Cells were cultured at 8 x 105 cells/ml in RPMI 1640 medium supplemented with 1% SJL serum, 2 mM L-glutamine, 25 µg/ml gentamicin, nonessential amino acids, sodium pyruvate, and 5 x 10-5 M 2-ME. A total of 2 µCi/well [3H]thymidine (ICN Radiochemicals, Irvine, CA) was added for the last 16–24 h of incubation of a 72-h incubation. [3H]Thymidine incorporation was measured by liquid scintillation spectroscopy.
Cytokine secretion
Single-cell suspensions of lymph nodes or spleens were
resuspended to 4 x 106 cells/ml with 50
µg/ml of Ag in RPMI 1640 medium supplemented with 10% FCS, 2 mM
L-glutamine, 25 µg/ml gentamicin, nonessential amino
acids, sodium pyruvate, and 5 x 10-5 M
2-ME. Cells were cultured for 60–72 h at 37°C and the supernatants
were tested for secreted cytokine by ELISA as per the manufacturers
instructions. Briefly, ELISA plates (Immulon II, Dynatech Laboratories,
Chantilly, VA) were coated with rat anti-mouse IL-4 (11B11),
anti-mouse IL-10 (JES5-2A5), or anti-mouse IFN-
(XMG1.2)
(PharMingen, San Diego, CA). Biotinylated anti-IL-4 (BVD6-24G),
anti-IL-10 (SXC-1), and anti-IFN- (XMG-1.2) were purchased
from PharMingen. Avidin peroxidase and o-phenylenediamine
were obtained from Sigma.
Anti-cytokine treatment
Purified rat anti-mouse IL-10 (JES5-2A5), anti-mouse IL-10R (1B1.2), anti-mouse IL-4 (11B11), and isotype control mAb, anti-ß galactosidase (GL113) mAb were prepared from serum-free culture supernatants by ion exchange chromatography and contained less than 3 IU of endotoxin/mg Ab. The mAbs were kindly provided by Robert Coffman (DNAX, Palo Alto, CA). Recipients were injected i.p. with 1 mg of anti-IL-10, anti-IL-4 mAb, or isotype control mAb. Recipients treated with anti-IL-10R received 0.5 mg i.p.
Histological evaluation
Mice were sacrificed by CO2 inhalation. Brains and spinal cords were removed and fixed by immersion in 75% ethanol and 25% glacial acetic acid and embedded in paraffin. Sections (1 mm) were stained with hematoxylin-eosin or luxol fast blue and read in a blinded fashion.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female, but not young adult male, SJL mice are susceptible to the
active induction of EAE following immunization with either MBP or mouse
spinal cord homogenate (18). In contrast to the induction
of Th1 cells after immunization of female SJL mice, immunization of
male SJL mice results in the preferential induction of Ag-specific Th2
cells (3, 5). MBP-specific Th2 cells derived from male
donors inhibit EAE induced via the adoptive transfer of MBP-specific
Th1 cells derived from female donors (5). To determine
whether Th2 cells reactive to an Ag not expressed in the CNS could
alter EAE, T cells derived from young adult male SJL mice immunized
with KLH were used as a source of non-neuroantigen-specific Th2 cells
(3). T cells derived from female SJL mice immunized with
MBP served as the source of Th1 cells (5). Both
populations proliferated equally to their specific Ag (Fig. 1
) and did not respond to the
heterologous Ag (data not shown). Consistent with previous results
(3, 5), T cells derived from males secreted high levels of
IL-4 and IL-10 but low amounts of IFN- after KLH-induced activation
(Table I). By contrast, no detectable
IL-4, low amounts of IL-10, but high concentrations of IFN- were
secreted following MBP-induced activation of T cells derived from
females (Table I). These data are consistent with the gender-dependent
differential induction of Th1 and Th2 cells in SJL mice after
immunization with a wide variety of protein Ag (3, 5, 18).
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A).
Immunization of the MBP Th1 cell recipients with KLH (M+I group) also
did not alter the clinical course of EAE (Fig. 2A). These
data suggest that in the absence of cognate Ag, Th2 cells are unable to
influence MBP-specific Th1 cell-induced EAE.
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To determine whether Ag deposition at a peripheral site could
induce sufficient activation to suppress CNS disease, recipients were
injected subcutaneously with KLH (M+K+I group) after adoptive transfer
of both cell populations. Recipients of both Th2 and Th1 cells
immunized with KLH were protected from EAE compared with mice which
received MBP-specific Th1 cells only (Fig. 2
B). To examine
the extent of suppression, mice were sacrificed at day 16 post-adoptive
transfer for histological analysis following resolution of the acute
phase in recipients of MBP-specific T cells only. CNS immunopathology
associated with KLH-mediated suppression demonstrated reduced
mononuclear cell infiltrates in both the brain and spinal cord compared
with recipients of MBP-specific Th1 cells only (Fig. 3). Although demyelination was prominent
in the spinal cords of the mice which received MBP-specific Th1 cells
only (Fig. 3), no demyelination was observed within the spinal cords of
the KLH-protected group. These findings are consistent with the reduced
clinical scores (Fig. 2B) and with the ability of
MBP-specific Th2 cells derived from young adult male SJL mice to
suppress EAE (5).
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). These data suggest that the ability
of KLH-specific Th2 cells to suppress EAE was not due to elimination of
MPB-reactive T cells. Although T cells derived from the two groups
proliferated equally in response to MBP (Fig. 4), T cells derived from
the KLH-immunized recipients, receiving both Th1 and Th2 cells,
secreted high levels of IL-4, IL-10, and IFN- following MBP
stimulation (Table II). By contrast, T
cells derived from the recipients of MBP-specific T cells only secreted
high levels of IFN- and only minimal amounts of IL-4 and IL-10
(Table II). Ag-specific IFN- secretion was not diminished in the T
cells derived from MBP-only recipients compared with immunized
recipients of both Th1 and Th2 cells, which is consistent with
equivalent proliferative responses (Fig. 4). By contrast, the
MBP-induced secretion of both IL-4 and IL-10 increased 3- to 4-fold in
immunized recipients of Th1 and Th2 cells compared with mice that
received MBP-specific T cells only. These data suggest that in vivo
activation of MBP-specific T cells was influenced by the presence of a
Th2 response, and that it contrasts with the absence of IL-4 secretion
from T cells derived from mice protected from EAE via the secretion of
IL-10 (17).
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Secretion of Th2 cytokines by MBP-specific T cells following
recovery from acute disease (Table II) suggested that Ag-induced
cytokine secretion from the KLH-specific cells was responsible for EAE
suppression (Fig. 2). To determine whether cytokines were indeed
responsible for EAE suppression, immunized recipients of both cell
populations were treated with anti-IL-4, anti-IL-10, or an
isotype control mAb. A single injection of anti-IL-10 mAb on the
day of adoptive transfer partially reversed the protective effects
(Fig. 5A). This group
exhibited an onset of disease similar to that of the recipients of MBP
cells only. The clinical scores for this group exceeded those of the
group treated with the isotype control mAb. Maximum clinical scores
were significantly different from both the KLH-protected group (M+K+I)
and the group which received MBP cells only (M group)
(p 0.05), suggesting partial amelioration of
suppression. By contrast, treatment with anti-IL-4 mAb resulted in
only a small increase in clinical score (Fig. 5A). To
confirm that in vivo activation-mediated EAE suppression via IL-10 was
not due to a generalized increase in clinical severity following IL-10
inhibition, groups of MBP-specific T cell recipients were treated with
either anti-IL-10 or the isotype control mAb on the day of adoptive
transfer. Neither mAb altered the course of EAE induced by the adoptive
transfer of MBP-specific Th1 cells (Fig. 5B).
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A), two injections of either anti-IL-10 or
anti-IL-10R mAb completely reversed the protective effect (Fig. 5C; Table III). Although the
mean day of onset of clinical disease in the protected group was
delayed 2 days relative to the group which received MBP-specific T
cells only, disease onset in mice treated with anti-IL-10 or
anti-IL-10R was identical to that in mice which received only the
MBP-specific T cells (Fig. 5C; Table III). Similarly, the
maximum clinical scores and cumulative disease scores in protected
recipients treated with either mAb regime were similar to those
recipients of MBP-specific Th1 cells only (Fig. 5C; Table III). In contrast to a single injection of anti-IL-10, preliminary
experiments suggest that a single injection of 500 µg of
anti-IL-10R on the day of adoptive transfer is sufficient to
reverse protection. These data indicate that peripheral activation
results in IL-10 secretion sufficient to inhibit the progression of
EAE. In contrast to immunized recipients (Fig. 3), histological
analysis of the CNS of immunized recipients treated twice with either
anti-IL-10 or anti-IL-10R mAb revealed significant inflammation
and demyelination at day 16 post-transfer, a condition comparable to
that in control recipients receiving MBP T cells only (data not
shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The adoptive transfer of IL-4- and IL-10-secreting lymph node cells from young male SJL mice primed in vivo with MBP resulted in a reduction of both clinical and histological EAE (5). In this model, inhibition of EAE is associated with increased expression of IL-10 mRNA in the CNS of protected mice (5). The passive transfer of anti-IL-10 mAb and the analysis of mice deficient in IL-10 secretion suggested that this cytokine is critical in the regulation of EAE (16). Furthermore, recent analysis of two transgenic models, one in which IL-10 secretion was controlled by the CD2 promoter resulting in IL-10 secretion by T cells, and one controlled by the MHC class II promoter resulting in IL-10 secretion by APC, finds that both support previous data demonstrating that rIL-10 has a protective effect on the progression of EAE (16, 17).
In an attempt to resolve the relative roles of IL-4 and IL-10 in inhibition of EAE, as well as to determine whether the activation of Th2 cells specific for a non-neuroantigen at a peripheral site could alter the course of EAE, Th2 cells specific for KLH were induced in young adult male SJL mice (3, 5, 18). These T cells were cultured in vitro and cotransferred with similarly activated EAE-inducing neuroantigen-specific Th1 cells. In the absence of activation by cognate Ag, Th2 cells were unable to influence the induction, progression, or severity of EAE. These results suggested that without in vivo activation, Th2 cells could not antagonize the function of adoptively transferred encephalitogenic Th1 cells, even though it has been suggested that Th1 and Th2 cells with different Ag specificities can interact in vivo (5, 27, 28). For example, activation of Th2 cells during parasitic infection alters the Th1 response to heterologous Ag such as mycobacteria and viruses (23, 24). Consistent with these data, activation of the Th2 cells by immunization with the cognate Ag was efficient in suppressing the Th1-mediated EAE.
The possibility of clonal deletion of MBP-specific Th1 cells was
excluded by demonstrating the retention of Ag-specific proliferation in
the KLH-protected and control groups after remission. However,
examination of the Ag-specific cytokine secretion following MBP-induced
activation showed that the MBP-specific T cells derived from the
KLH-immunized groups secreted both Th1- and Th2-type cytokines, i.e.,
high IL-4, IL-10, and IFN-. These data contrast with the MBP-induced
secretion of the T cells derived from the control group which was
predominantly a Th1 type of cytokine profile. These data suggest that
the cytokine secretion profile by MBP-specific T cells recovered
following KLH-induced protection resulted from the in vivo activation
of KLH-specific Th2 cells, most likely via secretion of IL-4
(21). The data cannot exclude a primary effect of IL-10;
however, analysis of transgenic mice demonstrated that IL-10 can
prevent EAE in the absence of a preferential induction of Th2 cells
(17). Effector CD4+ T cells appear
to be irreversibly committed to one given type (29);
therefore, the altered cytokine secretion profile exhibited by the
MBP-specific cells in a KLH-induced Th2 cytokine environment may
reflect cytokine secretion by a mixture of the adoptively transferred
Th1 cells and in vivo-activated MBP-specific T cells derived from naive
T cells of the recipients.
Partial inhibition of the protective effect induced by transfer and in vivo activation of the KLH-specific Th2 cells by a single injection of anti-IL-10 suggested that activation induced a significant amount of IL-10 or that an additional mediator was participating in EAE suppression. However, two injections of either anti-IL-10 or anti-IL-10R reversed protection. The possibility that another mediator also participates in EAE suppression induced by the peripheral activation of Th2 cells cannot be ruled out. However, the data support the previous reports suggesting that IL-10 plays a dominant role in suppression of EAE (17, 18). Protection required in vivo activation of the transferred population and, interestingly, treatment with a neutralizing anti-IL-4 mAb did not alter protection. The inability of anti-IL-4 to prevent protection suggests that Th2 cell proliferation is not required, implying that secretion of IL-10 is not dependent upon continued proliferation. In addition, a number of studies have demonstrated that IL-10 can be induced in the absence of ongoing Th2 responses (30, 31). For example, IL-4-deficient mice recovering from EAE had high levels of IL-10 mRNA in the CNS (9), which correlates with the reduction of both EAE severity (5) and disease remission (1). Recent studies have shown that in vitro-generated regulatory T cells (21, 32, 33) are capable of secreting large amounts of IL-10 and/or TGF-ß, but not IL-4. This suggests the possibility that a regulatory T cell population indeed may be the source of IL-10. Although the mechanism of IL-10-mediated inhibition is unclear, the loss of blood brain barrier integrity during EAE may allow IL-10 to access the CNS. Alternatively, IL-10 may modify or prevent EAE by inhibiting the loss of blood brain barrier integrity (34). Both of these possibilities are consistent with the reduced CNS inflammation associated with protection. These data provide evidence that peripheral activation of IL-10-secreting cells can suppress a Th1-mediated autoimmune disease via the secretion of IL-10. Therefore, these data support the concepts that either activation of a preexisting Th2 regulatory population or direct peripheral administration of IL-10 may be viable approaches to ameliorate or modify human autoimmune disease.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Stephen A. Stohlman, University of Southern California School of Medicine, 1333 San Pablo Street, MCH 142, Los Angeles, CA 90033. E-mail address:
3 Abbreviations used in this paper: EAE, experimental allergic encephalomyelitis; PLP, proteolipid protein; MBP, myelin basic protein; KLH, keyhole limpet hemocyanin.
Received for publication June 23, 1999. Accepted for publication September 21, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and interleukin-10. J. Exp. Med. 183:2559.This article has been cited by other articles:
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