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Institute of Histology and Embryology (G.P., M.G.), School of Medicine, Second University of Naples, Naples, Italy; Institute of Microbiology (F.N.), University of Milan Bicocca, Monza (Milan), Italy; Department of Cell Biology (F.A.P.), School of Biological Sciences, University of Calabria, Cosenza, Italy; Institute for Inflammation Research (K.B.), IIR7521, National University Hospital Copenhagen, Denmark
Address all correspondence and requests for reprints to: Gianpaolo Papaccio, M.D., 21 via Giuseppe Bonito, 80129 Naples, Italy. E-mail: gpapacc{at}tin.it
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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globulin (HGG). Eleven of
12 mice were protected from the development of diabetes up to the age
of 25 weeks, and the insulitis score was significantly reduced. In
contrast, NOD mice receiving unpulsed splenic DCs showed histological
signs of insulitis and course of type 1 diabetes similar to untreated
NOD mice. Treatment with HGG-pulsed DC was associated with profound
modifications of cytokine secretory capacities within the islets. Thus,
supernatants of islets from these mice contained increased levels of
interleukin (IL)-4, IL-10, and, to a lesser extent, interferon- and
diminished levels of tumor necrosis factor-
compared with controls.
Because exogenous IL-4 and IL-10 exert antidiabetogenic effect in NOD
mice and early blockade of endogenous tumor necrosis factor-
prevents NOD mouse diabetes, these phenomena may be causally related to
the antidiabetogenic effect of HGG-pulsed DC treatment. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, interleukin (IL)-2 and tumor necrosis
factor (TNF)-, Th1 cells stimulate macrophage and cytotoxic T cell
functions, promote IgG2a and IgG3 synthesis, and are involved in
delayed type hypersensitivity (DTH)-responses (1). On the other hand,
Th2 cells, through the production of type 2 cytokines IL-4, IL-5, IL-6,
IL-10, IL-13, down-regulate macrophage and cytotoxic T cell functions,
stimulate IgG1 and IgE production, and play a pathogenetic role in
IgE-mediated allergic reactions (1). Because delayed type hypersensitivity (DTH) responses against relevant autoantigens (autoAg) are involved in the pathogenesis of organ-specific autoimmune diseases such as multiple sclerosis, autoimmune thyroiditis, orchitis, and type 1 diabetes (see Ref. 2 for a review), it has been suggested that a disregulated production of Th1 cytokines either primary or secondary to a defective Th2 cell function, may represent an important pathogenic element in the development of these diseases (2).
Several, but not all, lines of evidences suggest that an altered
Th1/Th2 cell balance may be involved in both human and rodent (BB rat,
NOD mouse) type 1 diabetes (3–5; see Refs. 6, 7, 8 for reviews). These
include, among others, the increased blood levels of TNF-, IL-2, and
IFN- observed in subjects at risk for developing type 1 diabetes,
patients with newly diagnosed disease (9) and (IFN-) acutely
diabetic BB rats (10), the defective production of IL-4 from T cells of
newly diagnosed type 1 diabetic patients (11) and NOD mice (12, 13),
and the presence of IFN- and TNF- mRNA transcripts in the
advanced insulitic lesions of these rodents (14, 15, 16, 17). Moreover, the
progression to overt diabetes in the NOD mouse and/or the BB rat may be
interrupted either by specific antagonists (monoclonal antibody,
soluble receptors, receptor antagonists) of IFN- (18, 19, 20), TNF-
(21), and IL-2 (22), or by exogenously administered type 2 cytokines
such as IL-4 (12, 23) and IL-10 (24).
Understanding the cellular and molecular events responsible for the preferential polarization toward "harmful" Th1 rather than "protective" Th2 responses upon presentation of candidate diabetogenic (auto)Ags to CD4+ T cells from professional MHC class II+ Ag-presenting cells (APC) may help identify new targets of therapeutic intervention in type 1 diabetes. The ultimate events determining whether an Ag polarizes Th0 cells toward either a Th1 or a Th2 phenotype and function is a complex, not completely understood process involving genetic factors, hormonal influences, the cytokine milieu in the microenvironment and the type of APC that present the Ag to CD4+ Th0 cells (1).
B cells, macrophages, and dendritic cells (DCs) are professional APC
capable of capturing, processing and presenting Ag to
CD4+ T cells, therefore allowing initiation of
immune responses. While the contribution of B cells and macrophages to
IDDM has been thoroughly studied (see Ref. 25 for a review), relatively
little is known about the contribution of DCs. Both in the BB rat and
the NOD mouse, DCs are the first to accumulate around the islets
(26, 27, 28). In prediabetic BB rats, insulitis starts with the
accumulation of DC in the periphery of the islets, followed by
macrophages after DCs have formed clusters with infiltrating T cells
(26). In the NOD mice, the lymphocytic infiltrate is well organized
around a network of DCs that, rather than resident macrophages, seem to
be the primary APC in the early diabetogenic pathways in these mice
(27, 28, 29, 30). That DCs may participate to diabetes development in these
animals also concurs with the observations that DCs from diabetes-prone
BB rats exposed in vitro to macrophage-derived factors
display a greater accessory activity than DC from Wistar/Furth rats
(29), and that these cells (and macrophages) are the first and major
producers of TNF- in pancreatic islets in NOD mice (30). However,
other studies suggest that DCs may play an antidiabetogenic roles in
type 1 diabetes development; for example, our recent observation that
detection and/or persistence of DCs in the islet infiltrate correlates
with type-2 cytokine production in the NOD (31). In
vivo studies with transferred DC have yield conflicting results.
Thus, whereas Clare-Saltzer et al. (32) successfully
prevented NOD mouse diabetes by DC transfer, Ludewig et al.
(33) found that transgenic mice expressing the lymphocytic
choriomeningitis virus glycoprotein under the control of the rat
insulin promoter developed diabetes after adoptive transfer with DC
that constitutively expressed a cytotoxic T cell epitope of the virus
glycoprotein. To gain more insights into the effects of DC transfer in
experimental type 1 diabetes, we performed this study where NOD mice DC
pulsed in vitro with human globulin (HGG), which is not
involved in the diabetogenic process, were transferred to syngeneic
recipients. The data demonstrate that in vitro HGG-pulsed DC
exerted powerful immunomodulatory effects in vivo skewing
the T cell-dependent immune response toward a Th2 profile and
preventing both insulitis and diabetes in these mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Blood glucose measurement
Blood glucose levels were tested weekly using the hexokinase
method (Roche Molecular Biochemicals, Mannheim, Germany).
Mice were considered to be diabetic when their fasting blood glucose
levels exceeded 12 mmol/liter on two consecutive determinations.
Treatment with silica
Five-week-old female NOD mice (n = 18) were treated ip with
silica (Sigma, St. Louis, MO) every fifth day (200 mg/kg
body weight) for 30 days and killed on weeks 10 (n = 6), 15
(n = 6) or 20 (n = 6) (silica-treated group), respectively.
This treatment clears phagocytes and makes the detection of DCs easier
(34).
Preparation of antigen-presenting cells
The method of Crowley et al. was used (35). Briefly,
after collagenase digestion, splenic cells were separated into low and
high density fractions on gradient of BSA (Bovuminar Cohn fraction V
powder; Fluka Chemical Co., Milan, Italy). Low density
cells were cultured for 2 h in medium with 10% FCS, and the
nonadherent cells were removed by vigorous pipetting. The same
procedure was repeated with a shorter (1 h) incubation without FCS.
After overnight culture, nonadherent cells contained at least 90% DCs
as assessed by morphology (presence of cytoplasmic processes, strong
Ia-b immunoreactivity), absence of CD3, CD4, CD8 markers, thin
perinuclear positivity for EBM-11 Ab and acid phosphatase, and presence
of CD10, CD34, and MIDC-8 markers (35). Under electron microscopy, the
cells showed a relatively electrolucent cytoplasm, blunt processes
generally devoid of organelles, smooth-surfaced vesicles (lysosomes),
and an eccentrically positioned nucleus, lined with a rim of
heterochromatin.
Ag-pulsing of APC
The adherent cells of the low-density fraction of spleen were
cultured overnight in medium RPMI 1640, supplemented with 10% FCS,
penicillin, streptomycin, sodium pyruvate, and L-glutamine (Fluka Chemical Co.) with or without 100 µg/ml of HGG
(Sigma). The nonadherent DCs were then collected.
Immunizations
To induce a primary response, 8-week-old female NOD mice (n =
10) received an iv injection with 3 x 105
HGG-pulsed syngeneic DCs. Control mice were either injected with
unpulsed DCs (n = 10) or were left untreated. (n = 5). Five
days later, all mice received an iv boost of 100 µg of soluble HGG.
For assays, all mice were bled days 8 and 21 after the antigen boost.
To elicit a secondary response, all groups of mice received an
injection of 100 µg HGG iv 1 month after the initial challenge and
were bled 8 days later.
Ag-specific antibodies
The levels of Ag-specific antibodies (Abs) were determined by
solid-phase ELISA, using polyclonal goat antimouse IgG reagent
(Roche Molecular Biochemicals) or rat mAbs directed
against mouse IgG1 or IgG2a (36). Ab titers were calculated based on
linear regression analysis of the optical densities. Results are
expressed as titers determined using the midpoint of the titration
curves relative to an internal standard.
Cytokine profiles
Islets (500/dish) belonging to untreated NOD controls (15 weeks
old) as well as to HGG-pulsed DC-treated animals (see above) were
obtained from pancreases (37). Briefly, islets were isolated by ductal
injection of collagenase (Sigma). After incubation for 45
min at 37 C, the islets were enriched by centrifugation on a Ficoll
density gradient (Ficoll 400, Pharmacia & Upjohn, Uppsala,
Sweden) and by handpicking. The islets were resuspended in Ca
2+ and Mg 2+ free HBSS
(Life Technologies, Inc., Paisley, UK) in the presence of
2.5 mg/ml trypsin (Roche Molecular Biochemicals) and
dissociated into single cells followed by 18 h of culture at 37 C,
5% CO2 in enriched RPMI-1640 (Life Technologies, Inc.), containing 4 mmol/liter glucose and
supplemented with 25 mg/liter ampicillin, 120 mg/liter penicillin, 270
mg/liter streptomycin (Sigma), 1 mmol/liter sodium
pyruvate, 2 mmol/liter L-glutamine, 24 mmol/liter
NaHCO3, 1 mmol/liter HEPES (Sigma),
and 10% FCS (Roche Molecular Biochemicals). Different
protease inhibitors were added to the supernatants, which were then
used for measurement of IL-2, IFN-, TNF-, IL-4, and IL-10 levels
following centrifugation for 5 min at 2,000 rpm to eliminate cell
debris. These cytokines were measured by commercially available
solid-phase ELISA kits (PharMingen, San Diego, CA),
according to the manufacturer’s instructions. The amounts of cytokine
present was determined from the standard curves from purified
recombinant cytokines. Values are expressed as U/ml.
Histological analysis of insulitis
Pancreases were fixed in Bouin’s solution and embedded in
paraffin, and serial sections (5 µm thick) were stained with
hematoxylin-eosin for general morphology. For semiquantitative
evaluation of infiltration, sections containing 6 or more islets were
selected and at least 50 islets per pancreas were evaluated. The degree
of cellular infiltration was scored from 0 to 5 as follows: score
1 = infiltrates in small foci at the islet periphery; score 2=
infiltrates surrounding the islets (peri-insulitis); score 3=
intraislet infiltration < 50% of the islet, without islet
derangement; score 4= extensive infiltration, =50% of the islet, cell
destruction and prominent cytoarchitectural derangement; score 5= islet
atrophy because of ß cell loss. The evaluation was carried out by two
observers. A third and blinded observer scored the slides. Results are
expressed as mean insulitis score (IS) ± SD.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). The disease
occurred with similar clinical appearance, incidence and kinetics in
the NOD mice injected with Ag-unpulsed DCs (Fig. 1). In contrast,
the cumulative rate of diabetes was markedly diminished in mice treated
with HGG-pulsed DCs (P = 0.018 by Logrank (MantelCox)
vs. untreated control mice). Treatment with HGG-pulsed DCs,
as well as with unpulsed DCs, was well tolerated as the mice showed a
general appearance and behavior, similar to the untreated mice. In
addition, the body weights of the mice from the three groups were
comparable throughout the study period (not shown); at the end, the
mean (±SD) body weights were 25.5 (2.8), 25.2
(2.3), and 25.4 (3.2) in untreated mice (n = 2) and in mice
treated with HGG-pulsed DCs (n = 11) and unpulsed DCs (n =
3).
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Ag-pulsed DCs modulate cytokine secretion in pancreatic
islets
The production of type 1 proinflammatory cytokines by islet
infiltrating mononuclear cells is known to be associated with and
mediate the diabetogenic potential of these cells (6, 7). We therefore
tested whether HGG-pulsed DCs modulated the cytokine secretory capacity
of islets. Two groups of NOD mice were created that were either
untreated or injected with HGG-pulsed DCs as described. At the age of
15 weeks, at a time when most of our female NOD mice suffer from
insulitis, the euglycemic mice were killed and their pancreata
specimens collected and processed as described in Materials and
Methods.
As shown in Fig. 2, HGG-pulsed DCs
greatly modified the contents of cytokines in the islet supernatants
with significantly (by Student’s t test) larger amounts of
IL-4 (P < 0.001) and IL-10 (P <
0.001) and reduced levels of TNF- (P < 0.001) than
in supernatants of islets from untreated control mice (Fig. 2). There
was also a slight increase in the levels of the type 1 cytokine IFN-
(P < 0.05) (Fig. 2) but no difference in the content
of IL-2.
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, mice treated
with HGG-pulsed DCs exhibited strong humoral responses, the
concentrations of anti-HGG-specific IgG being significantly higher than
those of control mice. The isotypes and subclass composition of these
Abs, both for primary and secondary responses, are also illustrated in
Table 1. Mice primed with HGG-pulsed DC produced larger amounts of
anti-HGG-specific IgG1, but not IgG2a, both in the primary and
secondary responses.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our results demonstrate for the first time that a single iv injection
with Ag-pulsed DCs into 5-week-old, prediabetic NOD mice prevented
development of clinical and histological signs of diabetes in these
animals up to the age of 25 weeks. Simultaneously, intrapancreatic
cells from these mice secreted more IL-4 and IL-10 and less TNF-
in vitro compared with intrapancreatic cells obtained from
control NOD mice. This apparent polarization toward a type 2 cytokine
phenotype was not complete, however, as in vitro production
of IFN- from these cells was significantly higher in the group
receiving HGG-pulsed DCs. The impact of treatment on the cytokine
secretory capacity may have been even higher than appreciated since
treatment with Ag-pulsed DCs markedly reduced the numbers of islet
infiltrating mononuclear cells. Thus, on a per cell basis, these few
intrapancreatic mononuclear cells of the Ag-pulsed DC-treated mice,
most likely secreted severalfold higher amounts of IL-4, IL-10, and
IFN- than the more numerous mononuclear cells infiltrating the
pancreas of the control mice.
Because early blockade of endogenous TNF- suppresses NOD mouse
diabetes (23), as does treatment with IL-4 (12) or IL-10 (21), the
above changes in the intrapancreatic cytokine profile may be causally
related to the antidiabetogenic effect of the treatment. With the well
proven pathogenic role of endogenous IFN- in NOD mouse diabetes
(18, 19, 20), it is unclear whether the increased levels of this cytokine
may have limited the efficacy of Ag-pulsed DC treatment. However,
exogenously administered IFN- does not influence the natural course
of the disease in these animals (39), and it suppresses its appearance
in the BB rats (40), and IFN- secreting suppressor T cells exist in
the NOD mouse (41). It is possible, therefore, that the induction of
IFN- in the islets has played little or no role in the preventive
efficacy of Ag-pulsed DCs or might even have augmented their
efficiency. Presensitized NOD mice injected with HGG-pulsed DCs had
increased blood levels of Ag-specific IgG1, but not IgG2a, prototypical
subclasses of type 2 and type 1-dependent cytokine responses,
respectively. This fits in with the hypothesis that, the injection of
Ag-pulsed DCs induces a predominant type 2 cytokine. It is difficult to
explain the partial discrepancy between our data and those of De Becker
et al. (42) and Sornasse et al. (43), showing
that injection of similar amounts of HGG-pulsed DC induced specific
IgG1 as well as IgG2a Abs in BALB/c and DBA/2 mice. One possibility is
that Ab induction depends on strain-related differences between BALB/c
and DBA/2 mice and NOD mice. This may in turn be secondary to the
particular H2 class I and II region of the NOD mouse compared with that
of BALBc and DBA/2 mice (see Refs. 44, 45 for reviews). In fact, the
H2 system plays a major role in the regulation of immune responses in
mice, including the cytokine secretory capacity. This is clinically
mirrored by the highly variable sensitivity with which different
strains of mice respond to experimentally induced infectious,
autoimmune, and neoplastic diseases (44, 45).
The efficacy of Ag-pulsed DC transfer to prevent type 1 diabetes development in NOD mice complements and extends a previous study by Clare-Salzler et al. (32). Those authors also reduced the incidence of diabetes in NOD mice by transferring naive, unpulsed DCs obtained from pancreatic, but not cervical, axillary, or inguinal lymph nodes and spleens of syngeneic euglycemic animals (32). Because the course of the disease was also not influenced by transferring unpulsed splenic DCs in our study, these findings underscore the importance of Ag-pulsing in allowing splenic DCs to acquire antidiabetogenic property in vivo. However, it remains unknown how pulsing splenic DCs with an Ag in vitro modifies them so to counteract diabetogenic pathways.
The antidiabetogenic effect of Ag-pulsed DCs in the NOD mouse also contrast with a recent study by Ludewig et al. (33), showing that transgenic mice expressing the lymphocytic choriomeningitis virus glycoprotein under the control of the rat insulin promoter develop autoimmune diabetes within 21 days after the injections with 3 or 4 doses (104 to 105) of bone marrow-derived DC constitutively expressing an epitope for cytotoxic T cells of the virus glycoprotein. It may be that the different type of Ag expressed by the transferred DCs, that is a "nondiabetogenic" Ag in our study and a diabetogeic Ag in that by Ludewig et al. dictates whether anti- or pro-diabetogenic response is provoked by Ag-pulsed DCs. If the above is correct, pulsing DCs with Ag irrelevant to the diabetogenic process, such as HGG in our study, would lead these DCs to stimulate T cells that are not related to the diabetogenic process, and which may then polarize committed diabetogenic T cells toward a less harmful functional phenotype.
DCs have received much attention as a promising target of immunotherapy (38). The observation that graft survival could be prolonged by DC depletion has fostered studies aimed at blocking the function of these cells (38). On the other hand, transfer of DCs pulsed with tumor peptides has resulted in eradication of experimental tumors (38). Hence, if our results can be applied to the clinical setting, therapeutical protocols based on DC transfer might be considered for the treatment of immunoinflammatory/autoimmune diseases provided that DCs are pulsed with Ags irrelevant to the disease process. Autotransfusing Ag-pulsed DC into subjects with type 1 prediabetes or newly diagnosed type 1 diabetes might then be a cheap and relatively easy form of immunotherapy for the prevention/treatment of the disease.
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Footnotes |
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Received October 18, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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antibody. Endocrinology 138:281–288 gene expression in pancreatic islet-infiltrating
mononuclear cells correlates with autoimmune diabetes in nonobese
diabetic mice. J Immunol 154:4874–4882[Abstract]
and interleukin-6 in autoimmune
insulin-dependent diabetes in NOD/Whei mice. J Clin Invest 87:739–742
. J Autoimmun 4:237–248[CrossRef][Medline]
on insulin-dependent diabetes mellitus in NOD mice. I The early
development of autoimmunity and the diabetogenic process. J Exp Med 180:995–1004 in pancreatic islets in the nonobese diabetic mouse. J
Immunol 160:3585–3593 (IFN-). Clin Exp Immunol 109:149–156:1997[CrossRef][Medline]
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