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MediCity Research Laboratory, University of Turku, Turku, Finland, and National Public Health Institute, Turku, Finland
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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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We and others have shown that the mucosal vascular addressin MAdCAM-1
is also constitutively expressed at low levels on pancreatic
vasculature and, in conjunction with the appearance of lymphocyte
infiltrates (insulitis) in pancreatic islets, becomes strongly induced
on islet vessels (8, 9, 10). MAdCAM-1 is one of the two principal vascular
ligands of 
4 integrins (11) and could, in theory, favor
the homing of mucosal effector lymphocytes
(4/ß7high and
4/ß1+) to islets. Such
lymphocytes predominate in islet infiltrates at early stages of the
disease process (12). Functionally, 4 integrins are
important in the development of diabetes both after adoptive cell
transfer and spontaneously in the NOD mouse (13, 14, 15). However,
4 integrins interact not only with MAdCAM-1 but also
with both the inducible endothelial adhesion molecule VCAM-1, which is
expressed on the endothelium and on APCs such as dendritic cells (16),
and the extracellular matrix molecule fibronectin (17). Therefore,
4 integrins are involved not only in lymphocyte homing
but also in lymphocyte interaction with APCs and, consequently, in T
cell activation and in lymphocyte interaction with the extracellular
matrix, making the interpretation of the mechanism underlying the
observed effect more complicated. In contrast, the expression of
MAdCAM-1 is more restricted (to the venules of GALT), and MAdCAM-1
primarily serves as the vascular addressin directing lymphocyte entry
into GALT (7, 11). Therefore, the MAdCAM-1 blockade may have a more
restricted effect, primarily on lymphocyte homing to tissues in which
it is expressed on the vascular endothelium.
To investigate the requirements of MAdCAM-1 for the entry of diabetogenic lymphocytes into the pancreas and for any earlier steps that were possibly involved in diabetes development, we initially blocked the function of MAdCAM-1 using Ab treatment in NOD/SCID mice receiving adoptive cell transfer of diabetogenic lymphocytes. We also treated spontaneously diabetic NOD mice in a similar manner from an early age onwards. The unexpected finding that MAdCAM-1 is not necessary for the development of diabetes after the adoptive transfer of diabetogenic spleen cells but is involved in diabetes development in the spontaneously diabetic NOD mice suggested that MAdCAM-1 may be important in the early steps of diabetes development. Our results imply that MAdCAM-1 may be involved in a step preceding the development of early diabetogenic lymphocytes in NOD mice and may also be involved in the entry of such lymphocytes into the pancreas.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our colony of NOD mice, which was bred and maintained in the animal facilities of the University of Turku (Turku, Finland) under specific pathogen-free conditions, originated from mice purchased from Bomholtgard (Ry, Denmark). In this colony, the cumulative incidence of diabetes by 180 days of age was 66% in females and 40% in males. Our colony of NOD/SCID mice was similarly maintained and originated from NOD/SCID mice that were kindly provided by Dr. M. Atkinson (University of Florida, Gainesville, FL).
Monoclonal Abs
We used the function-blocking mAbs MECA-367 (against MAdCAM-1)
and Fib504 (against ß7 integrins) provided by Dr.
E.C. Butcher (Stanford University, Stanford, CA) to block the function
of the mucosal vascular addressin MAdCAM-1 and the mucosal homing
receptor 4ß7 integrin in vivo. We used mAb
281.2 against mouse syndecan-1 (in adoptive cell transfer experiments
with mesenteric lymph node (MLN) and spleen cells from diabetic donors,
Fig. 1
A) and mAb 9B5
against human CD44 (in all other experiments, Fig. 1, B–D
and Fig. 2C) as
species- and isotype-matched mAbs. We used the following mAbs to
phenotype spleen and Peyer’s patch (PP) T cells: CRL-1911 for
4 integrins, MEL-14 for L-selectin, TIB-217 for CD11a,
TIB-241 for CD44, and TIB-222 for CD25a (American Type Culture
Collection, Manassas, VA) (all grown as hybridoma supernatants and
concentrated by ammonium sulfate precipitation); Fib504 (see above) for
ß7 integrins, and mAb 16A for CD45RB (PharMingen, San
Diego, CA).
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Cells for adoptive cell transfer were isolated from aseptically removed spleens and MLNs representing GALT by squeezing the organs in glass homogenizers. Red cells were lysed by resuspending the spleen cells in 1 ml of sterile water for 10 s and then washed in 50 ml of RPMI 1640. After counting, 20 x 106 cells from pooled (4, 5, 6, 7, 8) spleens or MLNs derived from diabetic or 6-wk-old NOD female mice were transferred i.v. in 200 µl of RPMI 1640 into the tail vein of age-matched female NOD/SCID mice (aged 4–6 wk). These recipient mice were monitored twice per wk for urinary glucose (Glucotest, Boehringer, Germany), and blood glucose was measured from glucosuric mice. A value of >240 mg/ml (14.3 mM, MediSense, Waltham, MA) was considered diabetic.
Treatment of mice with mAbs
Female NOD and NOD/SCID mice were treated with mAbs to
investigate how MAdCAM-1 and 4ß7
integrins affect the homing of diabetes-causing lymphocytes into the
pancreas as well as possible earlier steps in the disease process. In
adoptive cell transfer experiments, the recipients simultaneously
received two i.p. injections of indicated mAbs (100 µg starting
2 h before the cell transfer) per wk. When cells from diabetic
animals were used, the treatment was administered until diabetes
occurred; when cells from young (6-wk-old) donors were used, the
treatment was administered for 4 wk following the cell transfer. In
experiments investigating the role of MAdCAM-1 and
4ß7 integrins in the development of
spontaneous diabetes and diabetes-causing lymphocytes, female NOD
littermate mice received the indicated mAbs (in 100-µg aliquots)
twice per wk starting at 3 wk of age (or, alternatively at 10 wk of
age). Treatment was continued until 7 mo of age or until diabetes
occurred.
For all in vivo experiments, mAbs were grown as serum-free supernatants of the corresponding hybridomas. Abs were concentrated from supernatants by salt precipitation (2.6 M NH4SO2), dialyzed against PBS, affinity purified in protein G columns (Pharmacia, Uppsala, Sweden) according to the manufacturer’s instructions, dialyzed, concentrated by lyophilization, and adjusted to a final concentration of 1 mg/ml.
Phenotyping of spleen and PP cells from mice treated with mAbs
To investigate how the MAdCAM-1 and
4ß7 integrin blockade affect the
phenotype of T cells during longstanding mAb treatment, female NOD mice
that received mAbs starting at 3 or 10 wk of age and remained
diabetes-free were killed at 7 mo of age. Spleen and PP cell
suspensions were prepared from the pooled spleens or PPs of each group
and were stained for flow cytometry using a FACScan (Becton Dickinson,
San Jose, CA). The stainings were performed essentially as described
previously (18) using biotinylated
(N-hydroxysuccinimide biotin; Calbiochem, La Jolla,
CA) mAbs against indicated cell surface markers. Briefly, the cells
were incubated with the biotinylated mAbs and washed. They were
subsequently incubated with streptavidin-conjugated phycoerythrin
(Becton Dickinson) as a second-step reagent that was used in
combination with directly FITC-conjugated TIB-207 (anti-CD4) or
Lyt2.2 (anti-CD8, PharMingen), washed, and fixed in
paraformaldehyde. The staining of cells gave similar results in three
different long-term treatment experiments in which the cells of three
to five mice per treatment group were pooled each time before
phenotyping.
Histochemistry and grading of islet infiltrates
For the morphologic analysis of PPs and other lymphoid organs, NOD mice that received longstanding mAb treatment (from 3 or 10 wk of age) and remained nondiabetic were killed at 7 mo of age; their PPs (and other lymphoid organs) were pooled within treatment groups (three or more mice per group in each experiment), treated for routine histology, and stained with hematoxylin and eosin.
To study the effect of mAb treatment on the development of lymphocytic
infiltrates in pancreatic islets, NOD mice were treated from 2 wk of
age (all females) or from 1 wk of age without knowledge of the sex
(MECA-367 group: four males plus one female; 9B5 group: three males
plus two females) with anti-MAdCAM-1 or a control mAb (as explained
above) until 7 wk of age. The mice were killed after 5 wk (at 12 wk of
age). Islets in routinely processed and hematoxylin and eosin-stained
sections of each pancreas were graded accordingly: 0 = no
insulitis, 1 = peri-islet insulitis, 2 = insulitis occupying
50% of the islet area, 3 = insulitis occupying >50% of the
islet area. Mean insulitis values represent the frequency of islets in
these categories. A total of 35 to 60 islets were analyzed from each
pancreas. The results from the two experiments were similar and were
pooled.
Labeling of cells before in vivo transfer
For the early detection of lymphocytes that have homed into the pancreas of NOD/SCID recipients after the transfer of GALT cells from young (6-wk-old) donors, we labeled the cells before transfer with the fluorescent dye DiI (Molecular Probes, Leiden, the Netherlands). Briefly, DiI (1 mM in DMSO) was added in a 1:200 dilution to cells that had been adjusted to 10 million/ml in RPMI 1640. The cells were incubated at 37°C for 10 min, washed in RPMI 1640, and adjusted to 100 million/ml before transfer into NOD/SCID recipients. Starting at 2 h before cell transfer, recipients were simultaneously treated with the mAbs MECA-367 against MAdCAM-1 or 9B5 (control mAb) to investigate the involvement of MAdCAM-1 in the homing of GALT lymphocytes from young donors into the pancreas. Mice were killed at various timepoints after cell transfer (1, 3, 5, 7, and 14 days), and cryocut sections from each pancreas (three per group) were viewed under fluorescence microscopy (Olympus, Tokyo, Japan).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To investigate the role of MAdCAM-1 in the homing of
diabetogenic lymphocytes into the pancreas, we transferred spleen and
MLN cells from diabetic NOD mice to female NOD/SCID mice receiving
simultaneous Ab treatment. Treatment with the anti-MAdCAM-1 Ab
MECA-367 did not affect the development of diabetes (Fig. 1
A) or insulitis (data not shown) in the recipients,
indicating that the MAdCAM-1 blockade did not prevent the homing
of transferred cells to the pancreas. However, since the
transferred cells were from overtly diabetic donors, many of the
transferred effector cells were obviously already primed against islet
Ags due to the established disease. Therefore, we also transferred MLN
lymphocytes from young donors to NOD/SCID mice receiving Ab treatment
to study the potential requirement of MAdCAM-1 in the
pancreatic homing of mucosal cells from an earlier phase of disease
pathogenesis. In these transfers, anti-MAdCAM-1 treatment
significantly reduced the incidence of diabetes, delayed the onset of
diabetes (p < 0.02, 
2 test),
and inhibited the formation of inflammatory infiltrates in islets (Fig. 1, B–C).
Due to a relatively long time lag before the formation of easily
detectable inflammatory infiltrates in these transfers, we also
labeled MLN cells from young donors with the fluorescent dye
DiI to trace the first cells which home into the pancreas after
transfer. At 7 days after the transfer, fluorescent cells were
frequently detected perivascularly and periductally in the pancreata of
recipients treated with a control Ab, whereas only sporadic fluorescent
cells were detected in the pancreata of recipients treated with
anti-MAdCAM-1 Ab (Fig. 1D). This finding
indicates that the homing of early developing diabetogenic cells into
the pancreas depends, in part, upon MAdCAM-1.
MAdCAM-1 affects the size of GALT and is required for the development of diabetes
Under physiologic conditions, MAdCAM-1 is expressed preferentially
on the high endothelial venules of organized mucosal lymphoid tissues
and is required for the entry of lymphocytes into GALT (5, 7). To test
how longstanding anti-MAdCAM-1 treatment affects GALT and the
development of diabetogenic effector lymphocytes, we treated NOD mice
continuously with i.p. injections of MECA-367 or a control mAb in two
sets of experiments and followed the development of diabetes until 7 mo
of age. In the first set of experiments, the treatment was started at
21 days of age, when there are no lymphocyte infiltrates in pancreatic
islets. In the second set, the treatment was started at 10 wk of age
with preexisting infiltrates in islets. The size and appearance of the
spleen, MLNs, and PLNs were comparable in all animals. However, PPs
were much smaller and contained much fewer lymphocytes in the group of
animals that had received anti-MAdCAM-1 treatment from 3 wk of age
compared with PPs in other groups of mice (Fig. 2A).
Thus, the PPs in this group resembled PPs in mice that are genetically
deficient for ß7 integrins (19). In our mice, PPs lacked
T cells expressing high levels of CD8, and the relative number of CD4 T
cells of the memory cell phenotype
(CD44highCD45RBlow) (Fig. 2B)
was clearly increased. Anti-MAdCAM-1 treatment that was initiated at 3
wk of age also resulted in an almost complete reduction in the
development of diabetes (p < 0.01 compared
with the rat IgG2a control mAb 9B5) (Fig. 2C). A
similar treatment started at 10 wk of age neither affected the size and
cellular composition of PPs (data not shown) nor interfered with the
development of diabetes. Treatment with a mAb against ß7
integrins was ineffective at all ages. This lack of effectiveness may
reflect the fact that 4/ß7 and the mAbs
against it control lymphocyte homing to PPs less effectively than
MAdCAM-1 and mAb MECA-367 (18, 20). Anti-MAdCAM-1 treatment also
significantly reduced lymphocyte infiltration in the pancreatic islets
(Fig. 3).
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The homing of early developing diabetogenic effector lymphocytes
to the pancreas was partly dependent upon MAdCAM-1, which could explain
why the anti-MAdCAM-1 treatment started at 3 wk of age inhibited
the development of diabetes. To determine whether diabetogenic cells
were simply kept outside the pancreas during the MAdCAM-1 blockade or
if the development of diabetogenic effector lymphocytes was also
compromised, we transferred spleen cells from those NOD female mice
treated with mAbs to NOD/SCID recipients (21). The recipients of spleen
cells derived from anti-MAdCAM-1-treated mice became diabetic with
a significantly longer time lag (mean 6.2 wk vs 4.3 wk) than the
recipients of spleen cells derived from the control mAb-treated mice
(Fig. 4A; p <
0.01 for the difference in the proportion of diabetic mice at 4 wk
posttransfer, 2 test). In the spleen, the expression of
CD44 and CD11a and the expression of 4 integrins was
lower among the CD4 T cells of mice treated with anti-MAdCAM-1 mAb
than among the CD4 T cells of control mice (Fig. 4B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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4 integrins, which are involved in a variety of
cell to cell interactions during immune responses (13, 14), the
function of MAdCAM-1 is restricted to the homing of lymphocytes. This
specificity may explain the differences in the effect of the MAdCAM-1
blockade when compared with the blockade of 4 integrins:
while the MAdCAM-1 blockade was effective only if started before the
onset of insulitis and not when delayed until insulitis was present or
when given after the adoptive transfer of cells from diabetic donors,
the blockade of 4 integrins was effective
against both the development of spontaneous diabetes in NOD mice and
the transfer of diabetes by spleen cells from overtly diabetic mice
(15, 16, 17). Therefore, MAdCAM-1 is exclusively involved in an
early phase of diabetes pathogenesis in NOD mice.
As naive lymphocytes become activated in secondary lymphoid organs
(such as GALT, PLNs, and the spleen) with the help of professional APCs
that have captured and processed antigenic material, lymphocyte homing
to secondary lymphoid organs is critical for the development of immune
responses (22). A primary hypothesis behind our work was that we should
be able to inhibit diabetogenesis by inhibiting lymphocyte homing into
those lymphoid organs in which the priming of putative diabetogenic
lymphocytes occurs. Since environmental factors have been implicated in
diabetes pathogenesis (1, 2, 3, 4), we hypothesized that lymphocyte homing
to, and, consequently, priming in the GALT may play a role in diabetes
pathogenesis. The results of the long-term MAdCAM-1 blockade
experiments supported the idea that GALT may initially be an important
site for the priming of diabetogenic lymphocytes. Furthermore, the
adoptive transfer of diabetes with spleen cells isolated from
anti-MAdCAM-1-treated mice suggested that these spleen cells had
not acquired a diabetogenic potential equal to that of spleen cells of
normal NOD mice. Since MAdCAM-1 is not involved in lymphocyte entry
into the spleen (23), this observation indicates that anti-MAdCAM-1
treatment probably interfered with a step in the development of
diabetogenic lymphocytes that is proximal to their accumulation in the
spleen. Such a step could involve a mechanism in which MAdCAM-1 is
required, i.e., lymphocyte homing to lymph nodes, especially to those
in the gut region. That MAdCAM-1 is essential for lymphocyte entry into
PPs was evidenced by the fact that the MAdCAM-1 blockade reduced the
size of PPs and the relative numbers of naive lymphocytes in PPs. The
reduced traffic of naive lymphocytes via PPs may, in turn, have reduced
the chances of naive lymphocytes to become primed and, consequently, to
develop into activated and/or Ag-experienced lymphocytes. This
possibility was supported by the finding that both the expression of
the memory markers CD44 and CD11a and the expression of
4 integrin (very late activation Ag-4) in the spleen
were lower among the CD4 T cells of anti-MAdCAM-1-treated than of
control mice. This lower expression may reflect a reduced number of
available Ag-experienced (memory) lymphocytes and could be due to the
reduced frequency of Ag-confrontations by naive lymphocytes in GALT. In
NOD mice, these changes seem to be associated with a remarkable
inhibition in the development of diabetes and of the diabetogenic
potential of spleen cells.
In our experiments, the MAdCAM-1 blockade was effective against diabetes only if started before the age at which inflammatory infiltrates appear in the pancreas. This finding suggests that MAdCAM-1 only interferes with an early step in disease development. We propose that this step may be the breakage of self-tolerance during Ag-confrontation following lymphocyte homing into lymphoid organs. Since MAdCAM-1 directs lymphocyte homing, especially into GALT, our results emphasize the potential role of GALT as one of these lymphoid tissues. This is of potential interest in elucidating the mechanisms by which environmental factors, many of which primarily elicit an immune response in GALT, may be involved in triggering the breakage of self-tolerance in type 1 diabetes (3).
If lymphocytes activated in the GALT are involved in the early phases of diabetes development in NOD mice, the constitutive expression of MAdCAM-1 on pancreatic blood vessels may also enable their homing to the pancreas. In our experiments, the MAdCAM-1 blockade selectively inhibited the pancreatic homing of MLN lymphocytes from young (6-wk-old) NOD mice; however, inhibition was not observed for spleen cells from overtly diabetic mice. This finding implies that when the autoimmune response against B cells becomes diversified via intramolecular and intermolecular epitope spreading (24, 25, 26), the relative importance of lymphocytes derived from GALT declines; it would also explain why the anti-MAdCAM-1 blockade was without an effect when applied after the timepoint when the tolerance toward B cells was broken (27) or after the full repertoire of diabetogenic lymphocytes was developed, i.e., in adoptive spleen cell transfers.
In cell transfer experiments, the additional priming of donor cells may occur in the recipients in a manner that is similar to their previous priming in immunocompetent donor mice. In particular, this possibility may be important in transfer experiments in which disease development is slow (i.e., when transferring cells from young donors). Therefore, to demonstrate that the MAdCAM-1 blockade may, in fact, also inhibit the homing of the presumably mucosa-associated and already primed cells that are present in the GALT of young donors, we used labeled cells to detect pancreas-infiltrating cells at the earliest possible timepoint. By doing so, we could observe an accumulation of GALT cells from young donors in the pancreas by day 7 posttransfer; this accumulation was decreased during the MAdCAM-1 blockade. We believe that at this timepoint, most of the cells that have already accumulated in the pancreas were primed in the donor, and that the decrease consequently represents an effect that the MAdCAM-1 blockade had on lymphocyte interaction with the pancreatic endothelium.
Our results demonstrate that MAdCAM-1 is required at an early step in the pathogenesis of diabetes in the NOD mouse, namely for the homing of naive lymphocytes to lymphoid tissues and for their subsequent homing into the pancreas. In addition, our results suggest that GALT may be important as a site in which the breakage of self-tolerance toward B cells may occur. This breakage could involve an immune response elicited by environmental factors derived from the gut (3). This observation may have implications for understanding the pathogenesis of diabetes both in the NOD mouse and in humans (1, 2, 3, 26, 27) and for directing efforts to prevent the progression of human diabetes to a clinical disease.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Sirpa Jalkanen, MediCity Research Laboratory, Tykistökatu 6, FIN-20520 Turku, Finland. E-mail address:
3 Abbreviations used in this paper: NOD, nonobese diabetic; IDDM, insulin-dependent diabetes mellitus; GALT, gut-associated lymphoid tissue; MAdCAM-1, mucosal addressin cell adhesion molecule-1; MLN, mesenteric lymph node; PLN, peripheral lymph node; PP, Peyer’s patch.
Received for publication October 8, 1997. Accepted for publication February 10, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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4 in the spontaneous development of autoimmune diabetes in nonobese diabetic mice. Proc. Natl. Acad. Sci. USA 91:12604.4/ß7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 74:185.[Medline]
4 integrins and vascular cell adhesion molecule-1. J. Clin. Invest. 93:1700.
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), a mAb against ß7 integrins (Fib504; 
), a
mAb against MAdCAM-1 (MECA-367; 
), or both Fib504 and MECA-367
(
