By
From the * Department of Clinical Laboratory Science, Insulin-dependent diabetes mellitus (IDDM) is assumed to be a T cell-mediated autoimmune
disease. To investigate the role of Fas-mediated cytotoxicity in pancreatic
Accumulating evidence has elucidated that insulin-dependent diabetes mellitus (IDDM) is a T cell-mediated autoimmune disease (1, 2). Histological examination of the
IDDM pancreas revealed that mononuclear cells infiltrated
into the islet (insulitis) and the infiltrate was mainly composed of T cells (3). The nonobese diabetic (NOD)
mouse is an excellent animal model of human IDDM, and
possesses a similar T cell predominance in the islet infiltrate
(6). The significant role of T cells in IDDM has been extensively studied by using this mouse model. T cell manipulation by an administration of mAb decreased the incidence of diabetes and insulitis (7, 8). Insulitis and diabetes were adoptively transferred into neonatal or irradiated
young NOD by splenic T cells, T cell lines, and T cell
clones from diabetic NOD (9). Possible roles of these
cells are to give an initial damage to Recent studies have exposed that T cell-mediated cytotoxicity comprised two major pathways, perforin- and Fas-based mechanisms (13). Perforin is a protein present in
the cytoplasmic granules of CTLs and secreted to form
pores on target cell membranes. The presence of perforin
in CD8+ T cells in insulitis lesions of NOD mice suggested
Fas-dependent cytotoxicity is a possible molecular mechanism for triggering Mice.
NOD/shi/osa mice were originated from the colony at
Center for Experimental Animals Development (Shionogi, Koka,
Japan) and bred under specific pathogen-free conditions at the Institute of Animal Research (Osaka University Medical School,
Osaka, Japan). They were monitored for the development of diabetes with Tes-Tape (Eli Lilly, Indianapolis, IN) weekly. The incidence of spontaneous diabetes in our colony was 77% in females
and 40% in males by 32 wk of age. MRL-lpr/lpr mice were purchased from Japan SLC (Hamamatsu, Japan). Experiments were
approved by Osaka University Medical School Animal Care and
Use Committee and performed according to Osaka University
Medical School Guideline for the Care and Use of Laboratory
Animals.
Breeding of NOD-lpr/lpr Mice.
MRL-lpr/lpr mice (H-2k; Kk,
I-Ak, I-E+, Dk) were outcrossed to NOD mice (H-2g7; Kd, I-Ag7,
I-E Genotyping and Phenotyping of Fas Allele.
At the N6 generation, heterozygotes for lpr were intercrossed and N6F1 was obtained. Genotype of the Fas allele was determined by PCR with
Takara Ex Taq (Takara Shuzo, Otsu, Japan) and one set of primers, NIL-1, and NIL-4 covering an early transposable element. lpr
type yielded a band of 5.7 kbp and wild type yielded a band of
265 bp. Phenotype was confirmed by flow cytometry and Northern blot analysis. Thymocytes and splenocytes were dispersed into
single cells (106) and stained with Jo2 anti-mouse Fas antibody
(PharMingen) followed by FITC-conjugated anti-hamster IgG
(PharMingen), or a combination of PE-conjugated anti-CD4
(GK1.5; Becton Dickinson) and FITC-conjugated anti-CD8 (YTS
169.4; Cedarlane), or a combination of PE-conjugated anti-B220
(RA3-6B2; GIBCO BRL, Gaitherburg, MD) and FITC-conjugated anti-CD3 (145-2C11; PharMingen). Dead cells were excluded by 1 µg/ml of propidium-iodine (Sigma Chemical Co., St.
Louis, MO) staining. For Northern blotting, total RNA was prepared from tissue using TRIzol (GIBCO BRL) and blotted onto
a nylon membrane. EcoRI fragment of mouse cDNA was labeled
with 32P and used for hybridization as described (21).
Monitoring Spontaneous Development of Diabetes.
After genotyping, female congenic mice were monitored for the development of diabetes with Tes-Tape weekly. Diabetes was diagnosed when Tes-Tape indicated >2+ and hyperglycemia >300 mg/dl
was confirmed by the measurement of blood glucose using Glutest E (Sanwa Kagaku Kenkyusho, Nagoya, Japan).
Adoptive Cell Transfer.
Cell transfer was performed according
to the method of Wicker et al. (22) with slight modification.
Splenocytes from diabetic NOD were isolated in RPMI 1640 medium supplemented with 10% fetal bovine serum. RBCs were
excluded by a lysis with NH4Cl. After washing, numeration, and
viability evaluation, splenocytes (5 × 107) were intravenously injected into sublethally irradiated male recipients. The dose of irradiation was 800 rad, and the age of recipients was between 9 and
13 wk when none of NOD males spontaneously developed diabetes. Development of diabetes was monitored three times a week
by Tes-Tape after transfer.
Histological Examination.
Pancreas was fixed on a filter paper
in neutral-buffered formalin, and paraffin-embedded sections were
prepared as maximum plane could be observed. Two nonconsecutive hematoxylin and eosin sections were examined. For transferred mice, sections were scored for insulitis, and the number of
islets was counted by one investigator in a blind fashion. Score of
insulitis was 0, normal; 1, peri-insulitis; 2, mononuclear cell infiltration in <50% of the area of the islet; 3, mononuclear cell infiltration in 50% or more of the area of the islet.
Analysis of Microsatellite Markers.
To examine the extent of
bringing in MRL genes surrounding lpr mutation to the NOD
genetic background, genomes of the N6 backcross used for the
intercross were assessed with locus-specific microsatellite markers.
IDDM susceptibility (Idd) genes with significant evidence of linkage to insulitis and diabetes (23, 24) were assessed similarly. Microsatellite markers were selected from the published data (25)
and the database released by the Whitehead Institute/Massachusetts Institute of Technology Center for Genome Research (Cambridge, MA), and screened for polymorphisms between NOD
and MRL strains. After MapPairsTM (Res. Genetics, Huntsville,
AL) were subsequently used in this study: Idd3, D3Mit270; Idd5,
D1Mit122, and D1Mit318; Idd10, D3Mit10, and D3Mit140;
chromosome 19, D19Mit11, D19Mit34, D19Mit43, D19Mit54, and D19Mit69.
Statistical Analysis.
The Kaplan-Meier method was used for
the calculation of diabetes incidence. Insulitis scores and the
number of islet were compared using the Kruskal-Wallis test.
Genotyping at the Fas locus determined NOD-+/+, NOD-+/lpr, and NOD-lpr/
lpr. They were all maturated, but NOD-lpr/lpr showed marked lymphadenopathy at ~4 mo of age. This is due to
impaired transcription of the Fas gene, defective expression
of Fas antigen, and consequent accumulation of CD4
Female NOD-+/+
and NOD-+/lpr developed spontaneous diabetes after 3 mo of age. The incidence increased with age and reached 68% in NOD-+/+ and 62% in NOD-+/lpr by 10 mo of
age (Fig. 2). This time course is comparable with that in
NOD mice in our colony. In contrast, none of NOD-lpr/lpr
developed diabetes during this observation period.
Prevention of spontaneous diabetes might be due to the distorted cell proportion of immune cells since unusual CD4
Mild to severe insulitis existed
in the pancreas of both genders of NOD-+/+ and NOD-+/lpr, irrespective of the development of diabetes (Fig. 4).
In contrast, mononuclear cells were barely found in and
around the islet of both genders of NOD-lpr/lpr. The severity of insulitis and the number of islets were evaluated in
transferred mice. The average scores of insulitis (mean ± SE) were 2.47 ± 0.15, 2.36 ± 0.19, and 0.02 ± 0.02 in
NOD-+/+, NOD-+/lpr, and NOD-lpr/lpr, respectively
(P <0.01). The number of islets per section was decreased
in NOD-+/+ (9.89 ± 2.78), and NOD-+/lpr (12.3 ± 2.39), compared with that in NOD-lpr/lpr (52.1 ± 10.2) (P <0.01). Most islets of NOD-+/+ and NOD-+/lpr
were inflamed and small in size, indicating the decrease in
number resulted from destruction of the islet. Conversely,
islets of NOD-lpr/lpr remained normal in morphology.
Genetic regions encompassing lpr mutation were assessed in three pairs of the N6
littermates used for producing the intercross. Although the
position of recombination between NOD and MRL strains varied among the pairs (Table 1), either the incidence of
diabetes in NOD-+/+ and NOD-+/lpr or the protection
of insulitis and diabetes in NOD-lpr/lpr did not change
among the F1 intercross of these pairs. Markers linked to
Idd3, Idd5, and Idd10 loci were all homozygous for NOD
alleles.
The dominant role of T cells in the pathogenesis of
IDDM has been strongly suggested by many investigators,
but exact molecular mechanisms have remained elusive.
Recent advances in the understanding of T cell-mediated
cytotoxicity disclosed the possibility that Even in this protocol, insulitis and diabetes were completely prevented in NOD-lpr/lpr, whereas they were rapidly induced in the littermates not homozygous for lpr. This
finding strongly suggests that autoimmune cascade against
pancreatic During the process of backcrossing, we screened H-2g7
(Idd1) homozygotes at the N2 generation and lpr mutation
at each generation. This implies that the prevention of insulitis and diabetes observed in NOD-lpr/lpr might be due
to the absence of other Idd genes or the presence of unknown recessive genes linked to lpr mutation. However, microsatellite marker analysis revealed that other Idd loci significantly linked to insulitis and diabetes were replaced by
the NOD alleles. In addition, either the incidence of diabetes in NOD-+/+ and NOD-+/lpr, or the protection of
insulitis and diabetes in NOD-lpr/lpr did not change
among the intercross with various recombinational positions from the Fas locus. This suggests that lpr mutation itself is responsible for the lack of disease in NOD-lpr/lpr.
To elaborate effective intervention therapies for IDDM,
a better understanding of the pathogenesis is required.
Given the fact that the Fas-FasL system is involved in the
development of autoimmune diabetes, interference of this
molecular mechanism would be a potent therapeutic strategy.
Soluble form of Fas and anti-FasL Ab suppressed Fas-mediated
cytotoxic activity (29, 30). Inhibitors of IL-1 In conclusion, we have shown that autoimmune Address correspondence to Naoto Itoh, Department of Clinical Laboratory Science, School of Allied Health
Sciences, Faculty of Medicine, Osaka University, 1-7 Yamadaoka, Suita, Osaka 565, Japan. Phone: 81-6-879-2584; FAX: 81-6-879-2499; E-mail: nitoh{at}sahs.med.osaka-u.ac.jp Received for publication 21 April 1997 and in revised form 12 June 1997.
We thank Ms. Katsumi Yamamori for excellent histological preparation.
This work was supported by Grants-in-aid by Ministry of Education, Culture and Sciences in Japan, Ministry of Health and Welfare in Japan, and The Japan Medical Association.
Second
Department of Internal Medicine, and § Department of Genetics, Faculty of Medicine, Osaka
University, Suita, Osaka 565, Japan; and
Center for Experimental Animals Development, Shionogi
& Co., Ltd., Koka, Shiga 520-34, Japan
cell destruction, we established nonobese diabetic (NOD)-lymphoproliferation (lpr)/lpr mice lacking Fas. Out
of three genotypes, female NOD-+/+ and NOD-+/lpr developed spontaneous diabetes by
the age of 10 mo with the incidence of 68 and 62%, respectively. In contrast, NOD-lpr/lpr did
not develop diabetes or insulitis. To further explore the role of Fas, adoptive transfer experiments were performed. When splenocytes were transferred from diabetic NOD, male NOD-+/+ and NOD-+/lpr developed diabetes with the incidence of 89 and 83%, respectively, whereas NOD-lpr/lpr did not show glycosuria by 12 wk after transfer. Severe mononuclear cell
infiltration was revealed in islets of NOD-+/+ and NOD-+/lpr, whereas islet morphology
remained intact in NOD-lpr/lpr. These results suggest that Fas-mediated cytotoxicity is required to initiate
cell autoimmunity in NOD mice. Fas-Fas ligand system might be critical
for autoimmune
cell destruction leading to IDDM.
cells for launching
inflammatory process, and/or to secrete cytokines for recruiting and activating other T cells, and/or to put the final
damage to
cells for causing diabetes. Thus, T cells are essentially involved in the pathogenesis of IDDM, yet exact
mechanisms of pancreatic
cell destruction remain obscure.
cell lysis by a perforin-based mechanism (16). However,
one study using transgenic mice expressing glycoprotein of
lymphocytic choriomeningitis virus (LCMV) in
cells,
transfer of perforin-deficient glycoprotein of LCMV-specific T cells failed to prevent insulitis (17). That study indicates that the perforin-independent pathway is required to
initiate autoimmunity against pancreatic
cells.
cell destruction. To address this issue, we established Fas-lacking NOD mice by introducing
lymphoproliferation (lpr) mutation from MRL-lpr/lpr. The
MRL-lpr/lpr mouse carries an insertion of an early transposable element in intron 2 of the Fas gene leading to premature termination of the transcript and defective Fas expression on cell surface (18). Generated NOD-lpr/lpr did
not develop diabetes or insulitis. In addition, splenocyte-transfer did not provoke insulitis or diabetes either. These
results suggest that Fas-mediated cytotoxicity is critical to
initiate
cell autoimmunity in NOD mice. Fas-Fas ligand
(FasL) system might be required in an initial step of autoimmune
cell destruction leading to IDDM.
, Db), and F1 were backcrossed in NOD background. At the
N2 generation, H-2 was typed to select breeders homozygous for
H-2g7 since this characteristic MHC haplotype was essential for
insulitis and diabetes (19). Cervical lymphnode was biopsied and
dispersed cells (106) were stained with the following monoclonal
antibodies. SF1-1.1 for Kd and 28-8-6S for Db were purchased
from PharMingen (San Diego, CA) and 14-4-4S for I-E from
Cedarlane (Hornby, Ontario, Canada). 11-4.1 for Kk, H116-32.R7 for I-Ak, and 10-2.16 for I-Ag7 were provided by Dr. M. Hattori (Harvard Medical School, Boston, MA). FITC-conjugated anti-mouse IgG Fc (Cappel, Durham, NC) was used as a
secondary antibody. Flow cytometric analysis was performed on a
FACScan® (Becton Dickinson, Mountain View, CA). lpr mutation
was also screened at each step of backcrossing. Tail was biopsied
and extracted DNA was subjected to PCR with two different
pairs of primers constructed according to the published sequence
(20). The first pair is composed of NIL-1, 5
-CAG CAG GAA
TCC TAT GAG GT-3
and NIL-2, 5
-CTC GCA ACG TGA
ACG GTT CG-3
, yielding a band of 381 bp for the mutated allele. The second pair is composed of NIL-3, 5
-CCT TCA TAA
CTG GTG TCG CA-3
, and NIL-4, 5
-GCA GAG ATG CTA
AGC AGC AG-3
, yielding a band of 346 bp for the mutated allele.
Genotyping and Phenotyping.
CD8
CD3lowB220+ lymphocytes (Fig. 1). Although the phenotype of NOD-lpr/lpr closely resembled a parental strain,
MRL-lpr/lpr, NOD-lpr/lpr did not show high mortality as
MRL-lpr/lpr making it possible to observe them until 10 mo
of age. NOD-+/+ and NOD-+/lpr could hardly be discriminated by the phenotype.
Fig. 1.
Fas mRNA expression in the thymus (A), Fas expression on
thymocytes (B), and two-color flow cytometric analysis of cell surface markers on splenocytes (C) of NOD-+/+ and NOD-lpr/lpr.
[View Larger Version of this Image (35K GIF file)]
Fig. 2.
Cumulative incidence of spontaneous diabetes in
female NOD-+/+ (n = 19),
NOD-+/lpr (n = 18), and
NOD-lpr/lpr (n = 17).
[View Larger Version of this Image (15K GIF file)]
CD8
T cells accumulated in NOD-lpr/lpr. To avoid this influence, we
performed transfer experiments from diabetic NOD to
sublethally irradiated young congenic mice. In a total of
four experiments, 8 of 9 NOD-+/+ (89%) and 10 of 12 NOD-+/lpr (83%) developed diabetes, whereas 0 of 7 NOD-lpr/lpr (0%) became diabetic during 12 wk of observation period (Fig. 3).
Fig. 3.
Cumulative incidence of adoptively transferred
diabetes in male NOD-+/+
(n = 9), NOD-+/lpr (n = 12),
and NOD-lpr/lpr (n = 7).
[View Larger Version of this Image (15K GIF file)]
Fig. 4.
Hematoxylin and eosin staining of pancreatic islets of NOD-+/+ (A) and NOD-lpr/lpr (B) transferred with splenocytes from diabetic NOD. Original magnification was 200.
[View Larger Versions of these Images (173 + 183K GIF file)]
cells were destroyed by perforin- or Fas-based mechanisms. In fact, perforin-deficient LCMV-transgenic mice did not develop diabetes when infected with LCMV, suggesting that perforin-dependent cytotoxicity was crucial to cause diabetes
by eliminating
cells (17). However, they did show insulitis, indicating that triggering islet inflammation required
the perforin-independent pathway, which initially impaired
cells, exposed autoantigens to antigen-presenting cells, and launched an autoimmune cascade to diabetes.
Our observation revealed that the Fas-dependent pathway
might be precisely a complementary mechanism to initiate
cell destruction. NOD mice became completely free of
insulitis by obtaining Fas-disrupting spontaneous mutation of lpr. Of course, there is a possibility that the lack of insulitis in NOD-lpr/lpr is due to the distorted T cell composition that contained unusual CD4
CD8
cells. To avoid
this influence, we performed transfer experiments from diabetic NOD to sublethally irradiated young congenic mice.
cells is blocked at an early stage in Fas-lacking
NOD mice. Transferred autoreactive T cells might initially
damage
cells through Fas-FasL system, and then substantially destroy fragile target cells by other mediators such as
perforin and cytokines. Two groups have reported that
cells can express Fas when stimulated with IL-1 (26, 27).
IL-1 is a cytokine secreted by macrophages, the participation of which has already been proved essential for the onset of diabetes as well as T cells (28).
-converting
enzyme- or CPP32-like proteases blocked Fas-induced
death signaling (31). If we devise a system to deliver one of
these molecules at the site of inflammation, it might be a
new beneficial treatment without systemic harmful effects
for pre- and early stage of IDDM.
cell
destruction is prevented by introduction of Fas-disrupting
lpr mutation into NOD mice. Considering that islet inflammation was nearly completely abrogated, Fas-based cytotoxic mechanism is assumed to be critical in an initial step
of
cell autoimmunity. Since there have been many
cell-specific T cell clones and lines, the analysis of cytotoxic pathways and abilities to induce diabetes of these cells
would provide further evidence concerning the Fas-FasL system in IDDM.
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Copyright © 1997
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