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Department of Immunology, 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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Cytokines produced by T cells and APCs play a pivotal role in
autoimmune diabetes. In that context, the role of Th2 cytokine IL-10 in
the pathogenesis of this disease has recently been examined. IL-10 has
exhibited paradoxical effects on diabetes of the NOD mouse.
Accordingly, treatment of young NOD mice with recombinant IL-10 (11, 12) and an adoptive transfer of islet-specific T cell clones transduced
with IL-10 cDNA (13) prevented diabetes. These findings demonstrated
that IL-10 is an immunosuppressive factor in IDDM of the NOD mouse. In
contrast, anti-IL-10 mAb treatment of young NOD mice prevented
insulitis (14). BALB/c mice expressing IL-10 transgene in their
insulin-producing ß cells (IL-10-BALB/c mice) of the pancreas did not
develop diabetes, but their offspring (IL-10-NOD mice) from backcrosses
to NOD mice became diabetic at an accelerated rate (15). Similarly, NOD
mice expressing IL-10 transgene in glucagon-producing 
cells of the
pancreas developed accelerated diabetes (16). These findings
demonstrated that IL-10 is an immunostimulatory factor in IDDM of the
NOD mouse.
To determine how the IL-10 participates in these pathogenic anti-islet inflammatory responses, we performed genetic, T cell-depletion, and Ab-blocking studies. First, we verified the role of autoreactive lymphocytes by backcrossing IL-10-BALB/c mice with NOD-scid mice. Next, to identify the role of CD4+ and CD8+ T cells, we depleted IL-10-NOD mice of these cells with mAbs. To identify the role of B cells, we bred the IL-10-NOD mice with NOD-µMT (B cell-deficient) mice. Finally, to examine the contributions of CD40/CD40 ligand (CD40L) as costimulator of diabetes in the IL-10-NOD mice, we blocked its activity with blocking anti-CD40L mAb. The results revealed that IL-10 does not cause dysfunction of ß cells leading to diabetes, and rather modulates the disease process through CD8+ T cells without the participation of B cells and the established CD40-CD40L costimulation pathway.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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NOD/shi mice were part of the rodent breeding colony at The Scripps Research Institute (La Jolla, CA). IL-10-BALB/c mice expressing IL-10 transgene in their islets under the control of human insulin promoter (17) were backcrossed to NOD/shi NOD-scid mice to generate IL-10-NOD or IL-10-NOD-scid mice, respectively. These mice were typed for the transgene’s presence by PCR (17). The scid mutation in IL-10-NOD-scid mice was verified by flow cytometry and an immunodiffusion test. We randomly used N2-N5 backcross generation mice in all the experiments described in this manuscript. We have selected the mice that are IL-10 transgene+ve and I-Ed-ve. Note that the mice were not typed for additional information on MHC class I and class II loci. The kinetics of disease in N7 backcross generation mice were similar to those observed in N2-N5 backcross mice (B. Balasa and N. Sarvetnick, unpublished observations).
B cell-deficient (µMT) NOD mice, carrying their genome-targeted disruption of the membrane exon of the Ig µ-chain gene (µMT) (-/-), were generated by backcrossing C57BL/6-µMT mice onto the NOD background for eight generations, were kindly provided by Drs. Diane Mathis and Christopher Benoist (Illkirch, France). The IL-10-BALB/c mice were backcrossed to NOD-µMT mice to generate experimental animals (mutant -/- as well as +/- and +/+ control littermates). The µMT allele was detected by PCR using genomic DNAs from tails as described (www@jax.org). B cell-deficient IL-10-NOD mice (IL-10-NOD-µMT) (-/-) were further screened by typing their PBLs with two-color flow cytometric using FITC-conjugated anti-B220 mAb and phycoerythrin-conjugated anti-CD3 mAb (PharMingen, San Diego, CA).
Antibodies
B cell hybridomas secreting mAbs against mouse CD40L (MR1, hamster IgG) were purchased from American Type Culture Collection (ATCC, Manassas, VA). mAbs, generated in the form of ascites fluid, were purified by affinity chromatography on a HiTrap protein G column (Pharmacia Biotech, Piscataway, NJ). The rat IgG2b mAb to mouse CD4 (YTS 191.1.2) and CD8 (YTS 169.4.2.1) molecules were purified from hybridoma cell culture supernatants (18).
Ab treatment of mice
Depletion of T cells. Groups of 1-wk-old pups from IL-10-NOD mice were injected i.p., on alternate days (days 7, 9, and 11), with isotype-matched 500 µg of depleting anti-CD4 (rat IgG2b) or anti-CD8 (rat IgG2b) mAb or control rat IgG in PBS. When test animals were assessed at 5 wk of age, this procedure regularly resulted in >90% depletion of appropriate T cell subsets as determined by FACS analysis (data not shown). This mAb treatment schedule (three injections of 500 µg doses on alternate days) was repeated on 5-wk-old nondiabetic mice because at 3- to 4-wk posttreatment the T cell subset population bounces back. Control mice were injected with PBS or rat IgG (Sigma, St. Louis, MO) only. The results were pooled from two to three separate experiments. To confirm the efficacy of depleting anti-CD4 mAb, we similarly treated female NOD/shi mice.
Treatment of mice with anti-CD40L mAb. Groups of IL-10-NOD mice were injected i.p., starting at 2 to 3 days of age, with 200 µg of the indicated mAb/dose and then at 3-day intervals for 30 days. Survived animals then received three additional 200-µg doses when they were 6 wk of age. We used the same batch of hamster anti-CD40L mAb that was used earlier to prevent diabetes in NOD mice. The current studies were performed in parallel with our previous studies (19). Before its use, the functional activity of anti-CD40L mAb was confirmed by its binding to CD40L on anti-CD3 mAb-stimulated splenocytes by flowcytometry (data not shown). Control mice were injected with hamster IgG. The results were pooled from two to three separate experiments.
CFA or heat-shock protein 65 (hsp65) immunizations. Groups of mice were immunized with 50 µl of CFA-PBS or IFA-PBS (1:1, v/v) emulsion containing 50 µg of hsp65 following the protocol described earlier (20, 21). Control mice were injected with PBS only. In a separate set of experiments, the injections were repeated at 3 wk of age. The results are representative of two or more separate experiments. As a positive control, 1-wk-old female NOD/shi mice were treated with CFA or hsp65 as above.
Assessment of diabetes
Starting at 5 wk of age, the mice were tested for diabetes by weekly or bi-weekly measurements of blood glucose (BG) levels using a one-step Bayer Glucometer Elite (Bayer, Elkhart, IN). Animals were considered diabetic when BG levels were >300 mg/dl. In most instances, the BG levels exceeded 500 mg/dl.
Histologic analysis
Lymphocytic infiltration of the islets was evaluated on hematoxylin and eosin (HE)-stained paraffin sections of pancreas taken at several levels throughout the organ (19). Paraffin-embedded pancreata were stained with an immunoperoxidase method using polyclonal Abs to porcine insulin and synthetic glucagon, followed by a biotinylated secondary Ab and an avidin-biotin complex as described earlier (19).
Lymphocyte proliferation assays
Splenocytes from age-matched individual transgenic (tg) or non-tg mice were cultured at 8 x 105 cells/well in 200 µl of serum-free HL-1 medium supplemented with 100 U/ml penicillin, 100 µg/ml streptomycin, 2 x 10-3 M L-glutamine, and 3 x 10-5 M 2-ME in 96-well flat bottom microculture in the presence of indicated Ags for 5 days. To identify the nature of proliferating cells, we added nondepleting anti-CD4 (YTS 177; IgG2a) or anti-CD8 (YTS 105; IgG2a) mAb (kindly provided by Dr. Joanna D. Davies, The Scripps Research Institute, La Jolla, CA) or control rat IgG (50 µg/ml) to the cultures. The cultures were pulsed with 1 µCi of [3H]TdR/well during the last 18 h of the assay and were later harvested as described (19). [3H]TdR uptake was measured in a ß scintillation counter. The results were expressed as a stimulation index: [(mean cpm with Ag)/(mean cpm without Ag)]. OVA (Sigma) and porcine insulin (Calbiochem, La Jolla, CA) were purchased. Stimulation index values >3 over the background values were considered significant.
Statistical analysis
The significance of the data was done by student’s t test (paired or unpaired) and Logrank test using Statview software (Abacus Concepts, Berkeley, CA) as required. A value of p < 0.05 was taken as the level of significance.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c mice expressing IL-10 transgene in their insulin-producing
ß cells (IL-10-BALB/c mice) of the pancreas did not develop diabetes.
However, their offspring (IL-10-NOD mice) from backcrosses to NOD mice
became diabetic at an accelerated rate (15). It is possible that the
expression of IL-10 transgene may compromise ß cell function. In
addition, it was argued that localized production of IL-10 in ß cells
caused the endothelial damage and then necrosis of microcapillaries
that affected many islets (22). To test the hypothesis that
IL-10-accelerated diabetes is an autoimmune phenomenon, we backcrossed
the diabetes-prone IL-10-NOD mice to NOD-scid mice and then
assessed the susceptibility of their offspring to diabetes. As shown in
Table I
, IL-10-NOD-scid mice
(n = 13; 0% incidence; p < 0.0001)
did not develop diabetes over a 12-wk period. The wild-type mice
(IL-10-NOD mice) (n = 12; 92% incidence) readily
developed accelerated diabetes. Additionally, the pancreatic islets
from these mice were completely free of lymphocytic (T and B cell)
infiltration (see Fig. 4a). These results demonstrate that
IL-10 alone does not cause diabetes in NOD mice that are
immunologically compromised.
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It has earlier been shown that young NOD mice exhibit spontaneous
T cell reactivity to islet Ags such as glutamic acid decarboxylase 65
(GAD65) and hsp65 (23, 24, 25). Similarly, we have also observed a
spontaneous T cell reactivity of NOD splenocytes against GAD65 and
hsp65 in vitro (19, 26). Because IL-10-NOD mice developed accelerated
diabetes, we examined whether these mice exhibit an increased T cell
reactivity to islet Ags (GAD65 and hsp65) in lymphocyte proliferation
assays. The results are shown in Table II. The splenocytes from individual tg
IL-10-NOD mice (n = 7) proliferated in vitro against
GAD65 and hsp65 Ags at a higher intensity than those cells from
age-matched non-tg littermates (n = 7). However, the
responses to hsp65 (p = 0.06) and to GAD65
(p = 0.42) between the groups were not
statistically significant. The responses between GAD65 and hsp65 within
each group were also found not statistically significant (for
transgene+ve mice: p = 0.28) (for transgene-ve mice:
p = 0.755). Lymphocytes from neither group of mice
proliferated in response to porcine insulin (mean stimulation
index <2.0). Lymphocyte proliferative responses to islet Ags was
abrogated by the addition of anti-CD4 but not anti-CD8 mAb (not
shown). These data suggest that expression of IL-10 transgene in
pancreatic islets of NOD mice did not enhance the CD4+ T
cell autoreactivity against GAD65 and hsp65.
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A) and 33 mice (of which 7
mice were transgene+ve) with hsp65 (Fig. 1B). Control mice
were injected with PBS only (Fig. 1A, n =
10; Fig. 1B, n = 12). The mice were
monitored for diabetes by measuring their BG levels at weekly
intervals. Surprisingly, neither of these treatments protected
IL-10-NOD mice from accelerated diabetes. The incidence of diabetes in
CFA-treated mice (11 of 15; 73% incidence) did not differ
significantly from those of PBS-treated mice (9 of 10; 90% incidence)
(p = 0.6246). Additionally, the incidence of
diabetes in hsp65-treated mice (5 of 7; 71.4% incidence) did not
differ significantly from those of PBS-treated mice (11 of 12; 91.7%
incidence) (p = 0.6425). In a separate set of
experiments, injection of two doses of CFA or hsp65 at 1 wk and 3 wk of
age did not block diabetes in IL-10-NOD mice (data not shown). As a
positive control, we treated young (1-wk-old) NOD mice either with CFA
or hsp65. The mice were monitored for a period of 28 wk. Both CFA
(n = 8; 6 of 8 mice) or hsp65 (n = 8; 6
of 8 mice) treatments effectively blocked insulitis and diabetes,
demonstrating the effectiveness of these treatments in modulation of
the disease (data not shown). In agreement with the established
findings in the literature, histologic examination of the pancreata
from protected NOD mice showed peri-insulitis but not insulitis (not
shown). Taken together, CFA and hsp65 treatments failed to block
accelerated diabetes in IL-10-NOD mice.
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Recent studies employing NOD-µMT (B cell-deficient) mice
(7, 28) and B cell-depleted (anti-IgM-treated) NOD mice (8) have
demonstrated that B cells are necessary as APCs for the initiation of
insulitis and diabetes. Because IL-10 has immunostimulatory effects on
B cells (29), we hypothesized that B cells play a role in the
initiation and perpetuation of accelerated diabetes in IL-10-NOD mice.
To test this hypothesis, we backcrossed the IL-10-BALB/c mice with
NOD-µMT mice to generate IL-10+ve B cell-deficient (-/-)
(n = 16), heterozygous (+/-) (n = 17),
and wild-type (+/+) (n = 13) mice. The results appear
in Figure 2A. Surprisingly,
the IL-10-NOD-µMT mice (-/-) readily developed accelerated diabetes
(14 of 16 mice; 87.5% incidence). The incidence and kinetics of
disease in these IL-10-NOD-µMT mice were not statistically
significant from those of heterozygous (13 of 17 mice; 76.5%
incidence) and wild-type (10 of 13 mice; 76.9% incidence) littermate
controls (p = 0.4786 vs wild-type +/+ mice;
p = 0.1953 vs heterozygous +/- mice). As expected,
non-tg µMT (-/-) mice did not develop diabetes (not shown).
Therefore, the B lymphocytes as APCs are not required for the
initiation of accelerated diabetes in IL-10-NOD mice.
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B depicts the results of treating these
mice with anti-CD40L mAb or control hamster IgG starting when the
mice were 2 to 3 days old and injected at 3-day intervals for 30 days.
Surprisingly, the diabetes developed in anti-CD40L-treated mice
reaching a cumulative incidence of 86% (12 of 14) at 11 wk of age.
These results did not differ (p = 0.3206) from
those of control hamster IgG-treated mice (9 of 11; 82% incidence).
The islets from these treated groups exhibited insulitis (not shown).
Thus, anti-CD40L mAb did not block accelerated diabetes of
IL-10-NOD mice. Treatment of IL-10-NOD mice with depleting anti-CD8 mAb retards diabetes but not insulitis
The islets of Langerhans in IL-10-NOD mice are infiltrated with many more CD4+ T cells and very few CD8+ T cells (15). The natural course of diabetes in the NOD mouse requires the participation of both CD4+ and CD8+ T cell as the depletion of CD4+ (30, 31) and CD8+ (32) T cell subsets with corresponding mAb completely retarded insulitis. It is established that IL-10 possesses differential effects on T cell subsets via direct and indirect mechanisms (33, 34, 35).
In this study, we addressed whether treatment of IL-10-NOD mice with
depleting rat IgG2b mAb to CD4 and CD8 molecules would block insulitis
and diabetes. The results are shown in Figure 3A. Anti-CD4 mAb treatment did
not block diabetes because IL-10-NOD mice (21 mice were treated, of
which 9 mice were transgene+ve; n = 9) developed
diabetes at 5 to 9 wk of age (89% incidence) closely resembling that
of PBS (control)-treated mice (n = 8; 88% incidence)
(p = 0.572). Similar results were obtained in
control rat IgG-treated mice (data not shown). However, efficacy of the
anti-CD4 mAb was verified by blocking diabetes in female
NOD/shi mice because treated young NOD mice failed to
develop insulitis and diabetes over a 32-wk period (data not shown). In
ontrast, depleting anti-CD8 mAb treatment completely
prevented accelerated diabetes (16 mice were treated; 11 were
transgene+ve; n = 11; 0% incidence) even at 17 wk of
age (anti-CD4 group vs anti-CD8 group, p =
0.0003; anti-CD8 group vs PBS group, p = 0.0002).
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, B–D. Irrespective of the treatments employed,
IL-10-NOD mice showed extensive lymphocytic infiltration in their
islets. These findings demonstrate that anti-CD8 mAb treatment, as
opposed to its effectiveness on insulitis in NOD mice (32), did not
abolish lymphocytic infiltration into the islets of IL-10-NOD mice
(Fig. 4). However the islets from these
mice contained significant numbers of insulin-positive ß cells. On
the other hand, HE sections of pancreata from anti-CD4 mAb-
and PBS-treated mice showed extensive lymphocytic infiltration
accompanied by complete or near to complete loss of insulin-positive
ß cells (Fig. 4). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A critical role for CD8+ T cells in acceleration of
diabetes in IL-10-NOD mice emerged from experiments showing that
depleting anti-CD8 but not anti-CD4 mAb effectively abrogated
the disease (Fig. 3A). However, anti-CD4 and
anti-CD8 mAb-treated IL-10-NOD mice developed severe insulitis
(Fig. 4d). It is apparent that the lymphocytic infiltrate in
anti-CD8 mAb-treated mice may be nonpathogenic because these mice
failed to develop diabetes. On the other hand, the lymphocytic
infiltrate in anti-CD4 mAb-treated mice may be of pathogenic nature
because these mice developed diabetes. These findings contrast with
earlier reports demonstrating that similar treatments inhibited both
insulitis and diabetes in NOD mice (30, 31, 32). Furthermore, abrogation of
B cells as APCs in the disease process of IL-10-NOD mice (Fig. 2A) is in complete contrast to the earlier results showing
that B cells are necessary for the initiation of disease in NOD mice
(7, 8, 28). Thus, the differential effectiveness of depleting mAb to
CD4 and CD8 molecules on diabetes and insulitis and the abrogation of a
requirement for B cells as APCs in the disease process suggest a
fundamental difference in the mechanisms of disease development in
IL-10-NOD and NOD mice. In support of the current findings, elsewhere
it was shown that IL-10 could prime the CD8+ T cells
against P815 tumor cells in anti-CD4 mAb-treated mice (36).
Certainly, the proinflammatory IL-10 plays a critical role during very
early stages of autoimmune process via CD8+ T cell pathway.
In that regard, CD8+ T cells are implicated in the disease
process of IDDM patients (37, 38, 39).
We demonstrated here that CD8+ T cells are critical for accelerated diabetes, but the precise mechanisms by which the proinflammatory IL-10 accelerates disease in IL-10-NOD mice are currently not known. It is possible that IL-10 may act as a chemoattractant (40) and a differentiation factor (41, 42, 43) for CD8+ T cells. The chemotactic activity of IL-10 should be tested by adoptive transfer of Ag-inexperienced CD8+ T cells from 3-wk-old NOD mice into IL-10+-NOD-scid and IL-10--NOD-scid mice. We are currently testing this possibility. Alternatively, IL-10 may induce the differentiation of and/or cytotoxic potential in islet Ag-specific CD8+ T cells. Therefore, we are currently breeding IL-10-NOD-scid mice (N6 backcross) with TCR tg RAG-2-deficient 8.3-NOD mice expressing an islet-specific monoclonal CD8+ T cell repertoire (44).
In short, the early participation of IL-10 in the disease process provoked rapid pathogenic autoimmunity (15, 16) and anti-IL-10 mAb treatment abrogated insulitis in young NOD mice (14). In contrast, the later participation of IL-10 in the disease process protected NOD mice from destructive autoimmunity (11, 12, 13, 16). These paradoxes evidently relate to the period in which the immune system of the NOD mouse perceives high levels of IL-10. Presumably, as the current study shows, the presence of IL-10 during early stages of IDDM favors the generation of effector CD8+ T cells leading to acceleration of diabetes, whereas its presence during late stages of IDDM inhibits the generation of pathogenic CD4+ Th1 cells and concurrently promotes the development of CD4+ Th2 cells as shown elsewhere (12). Thus, our results demystify the biphasic requirement for the participation of IL-10 in the disease process.
Similarly, other cytokines, such as TNF-, also exhibited paradoxical
effects on IDDM of the NOD mouse. Systemic injection of TNF-
accelerated (45) or retarded (46) diabetes in young and adult NOD mice,
respectfully. Additionally, anti-TNF- mAb treatment in young NOD
mice prevented diabetes (46). It is possible that the early presence of
TNF- may induce the generation of islet-specific CD8+ T
cells to accelerate diabetes because TNF- modulates the generation
of CD8+ CTLs (47). Conversely, higher levels of TNF- in
adult NOD mice may abrogate priming of pathogenic CD4+ Th1
cells via inhibiting the Fc
RII-dependent presentation of islet Ags
by dendritic cells as suggested (48, 49). Therefore, individual
cytokines can produce opposing effects depending upon the timing of
their participation in the disease process.
Noticeably, IL-10-NOD mice did not respond to several of the treatments
tested here. In that context, the failure of CFA or hsp65 treatments to
protect IL-10-NOD mice (Fig. 1, A and B) contrasts with
their effectiveness in protecting NOD mice from diabetes (20, 21, 25).
Two possibilities can be entertained for these apparent discrepancies:
1) the treated IL-10-NOD mice may have developed diabetes before their
immune system had an opportunity to shape a hsp65-specific regulatory
CD4+ T cell repertoire of Th2 phenotype; or 2) the results
may be related to the differential requirement for CD4+ T
cells in regulating the autoimmune process of NOD and IL-10-NOD mice.
In NOD mice, such protection is presumably mediated by regulatory
CD4+ T cells (20), whereas in IL-10-NOD mice such
protection may not be possible because of the inability of
CD4+ T cells to mitigate the CD8+ T cell
activity. Consequently, the hsp65-specific T cell reactivity may not
participate in the IL-10-induced pathogenic autoimmunity tested here;
thus, exactly which islet Ags drive the pathogenic islet-reactive T
cells remains a daunting task.
Elimination of a requirement for CD40-CD40L costimulation in the
disease process of IL-10-NOD mice is not expected (Fig. 2, Aand B). However, further testing of costimulatory
pathways (B7/CD28 and ICAM-1/LFA-1) by blocking mAb to B7-1
(n = 5; 5/5), B7-2 (n = 9; 8/9), B7-1 +
B7-2 (n = 7; 6/7), ICAM-1 (n = 9; 8/9),
and LFA-1 (n = 7; 6/7) molecules also failed to retard
diabetes in IL-10-NOD mice (B. Balasa and N. Sarvetnick, unpublished
data). Nevertheless, our results directly contrast with earlier results
showing that the blockade of these pathways with a corresponding mAb
effectively abrogated diabetes in NOD mice (19, 50, 51). Consequently,
a differential requirement for costimulation in the genesis of diabetes
in NOD and IL-10-NOD mice has emerged. We hypothesize that these events
may be related to the generation of very high affinity, relatively
costimulation-independent effector CD8+ T cells in
IL-10-NOD mice. Identification of MHC class I-restricted T cell
epitopes of islet Ags would resolve this issue. In that context, very
recent studies have showed that purified MHC class I and peptide
complexes activate naive CD8+ T cells independently of the
CD28/B7 and LFA-1/ICAM-1 costimulatory interactions (52). Therefore,
several factors, such as the concentration of MHC-peptide complexes,
TCR affinity, and the cytokine milieu in the islet environment during
pathologic states may dictate the likelihood of bypassing
costimulation.
Our findings suggest that there is more than one cellular pathway to ß cell destruction, and that under the right (or wrong) circumstances, the microenvironment of the islet may help elicit a rapid and deadly CD8+ T cell response. Counterregulation of such T cell responses by host balancing factors is much less likely than for CD4+ T cell responses, thus negating circumvention of the disease. Because CD4+ T cells and B cells are unnecessary here, the disease process quickens dramatically. That is, the period of damage; release of ß cell Ags; Ag capture, processing and presentation; priming of CD4+ cells; migration back to the islet, and subsequent diversification of the response all take time—in the NOD mouse an interval of several weeks (23, 24, 53, 54).
From the foregoing results, we conclude that IL-10-accelerated diabetes is a private interaction between CD8+ T cells and ß cells as the well-described costimulation pathways and B lymphocytes are dispensable. Our findings shed light on the complex regulatory circuits between cytokines and T cell subsets that lead to spontaneous disease, demonstrating how sensitive this system is to perturbation of the islet microenvironment.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Nora Sarvetnick, Mail code: IMM-23, Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address:
3 Abbreviations used in this paper: NOD, nonobese diabetic; BG, blood glucose; CD40L, CD40 ligand; hsp65, heat-shock protein 65; IDDM, insulin-dependent diabetus mellitus; tg, transgenic; HE, hematoxylin and eosin; GAD65, glutamic acid decarboxylase 65; µMT, B cell-deficient.
Received for publication April 10, 1998. Accepted for publication June 10, 1998.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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cells accelerates autoimmune insulitis and diabetes in non-obese diabetic mice. Int. Immunol. 6:1927. 4 in the spontaneous development of autoimmune diabetes in nonobese diabetic mice. Proc. Natl. Acad. Sci. USA 91:12604. and ineterleukin 1. Proc. Natl. Acad. Sci. USA 87:968.. J. Exp. Med. 179:1109.This article has been cited by other articles:
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  B. Ciric, M. El-behi, R. Cabrera, G.-X. Zhang, and A. Rostami IL-23 Drives Pathogenic IL-17-Producing CD8+ T Cells J. Immunol., May 1, 2009; 182(9): 5296 - 5305. [Abstract] [Full Text] [PDF]
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 D. V. Serreze, C. Wasserfall, E. W. Ottendorfer, M. Stalvey, M. A. Pierce, C. Gauntt, B. O'Donnell, J. B. Flanagan, M. Campbell-Thompson, T. M. Ellis, et al. Diabetes Acceleration or Prevention by a Coxsackievirus B4 Infection: Critical Requirements for both Interleukin-4 and Gamma Interferon J. Virol., January 15, 2005; 79(2): 1045 - 1052. [Abstract] [Full Text] [PDF]
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 Q.-S. Mi, D. Ly, P. Zucker, M. McGarry, and T. L. Delovitch Interleukin-4 but not Interleukin-10 Protects Against Spontaneous and Recurrent Type 1 Diabetes by Activated CD1d-Restricted Invariant Natural Killer T-Cells Diabetes, May 1, 2004; 53(5): 1303 - 1310. [Abstract] [Full Text] [PDF]
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S. Kommajosyula, S. Reddy, K. Nitschke, J. R. Kanwar, M. Karanam, and G. W. Krissansen Leukocytes infiltrating the pancreatic islets of nonobese diabetic mice are transformed into inactive exiles by combinational anti-cell adhesion therapy J. Leukoc. Biol., October 1, 2001; 70(4): 510 - 517. [Abstract] [Full Text] [PDF]
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A. La Cava, B. Balasa, A. Good, K. van Gunst, N. Jung, and N. Sarvetnick H-2D End Confers Dominant Protection from IL-10-Mediated Acceleration of Autoimmune Diabetes in the Nonobese Diabetic Mouse J. Immunol., July 15, 2001; 167(2): 1066 - 1071. [Abstract] [Full Text] [PDF]
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 S. Kawamoto, Y. Nitta, F. Tashiro, A. Nakano, E. Yamato, H. Tahara, K. Tabayashi, and J.-i. Miyazaki Suppression of Th1 cell activation and prevention of autoimmune diabetes in NOD mice by local expression of viral IL-10 Int. Immunol., May 1, 2001; 13(5): 685 - 694. [Abstract] [Full Text] [PDF]
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B. Balasa, A. La Cava, K. Van Gunst, L. Mocnik, D. Balakrishna, N. Nguyen, L. Tucker, and N. Sarvetnick A Mechanism for IL-10-Mediated Diabetes in the Nonobese Diabetic (NOD) Mouse: ICAM-1 Deficiency Blocks Accelerated Diabetes J. Immunol., December 15, 2000; 165(12): 7330 - 7337. [Abstract] [Full Text] [PDF]
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C. Vizler, N. Bercovici, A. Heurtier, N. Pardigon, K. Goude, K. Bailly, C. Combadiere, and R. S. Liblau Relative Diabetogenic Properties of Islet-Specific Tc1 and Tc2 Cells in Immunocompetent Hosts J. Immunol., December 1, 2000; 165(11): 6314 - 6321. [Abstract] [Full Text] [PDF]
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B. Balasa, K. Van Gunst, N. Jung, D. Balakrishna, P. Santamaria, T. Hanafusa, N. Itoh, and N. Sarvetnick Islet-Specific Expression of IL-10 Promotes Diabetes in Nonobese Diabetic Mice Independent of Fas, Perforin, TNF Receptor-1, and TNF Receptor-2 Molecules J. Immunol., September 1, 2000; 165(5): 2841 - 2849. [Abstract] [Full Text] [PDF]
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O. T. M. Chan and M. J. Shlomchik Cutting Edge: B Cells Promote CD8+ T Cell Activation in MRL-Faslpr Mice Independently of MHC Class I Antigen Presentation J. Immunol., February 15, 2000; 164(4): 1658 - 1662. [Abstract] [Full Text] [PDF]
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 R. A. Terkeltaub IL-10: An "Immunologic Scalpel" for Atherosclerosis? Arterioscler Thromb Vasc Biol, December 1, 1999; 19(12): 2823 - 2825. [Full Text] [PDF]
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W. S. Gallichan, B. Balasa, J. D. Davies, and N. Sarvetnick Pancreatic IL-4 Expression Results in Islet-Reactive Th2 Cells That Inhibit Diabetogenic Lymphocytes in the Nonobese Diabetic Mouse J. Immunol., August 1, 1999; 163(3): 1696 - 1703. [Abstract] [Full Text] [PDF]
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H. Noorchashm, Y. K. Lieu, N. Noorchashm, S. Y. Rostami, S. A. S. Greeley, A. Schlachterman, H. K. Song, L. E. Noto, A. M. Jevnikar, C. F. Barker, et al. I-Ag7-Mediated Antigen Presentation by B Lymphocytes Is Critical in Overcoming a Checkpoint in T Cell Tolerance to Islet {beta} Cells of Nonobese Diabetic Mice J. Immunol., July 15, 1999; 163(2): 743 - 750. [Abstract] [Full Text] [PDF]
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