1 First Department of Internal Medicine, Nagoya City University Medical School, Nagoya 467-8601; and 2 Second Department of Anatomy, Osaka City University Medical School, Osaka 545-8585, Japan
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ABSTRACT |
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We assessed T cell
association with acinar cell apoptosis and a preventive effect
of tacrolimus, a T cell suppressant, on the development of chronic
pancreatitis in male Wistar Bonn/Kobori rats. At 15 wk, cellular
infiltrates composed of F4/80-positive cells (monocytes/macrophages),
CD4-positive cells, and CD8-positive cells were extensive in the
interlobular connective tissue and parenchyma. In particular,
CD8-positive cells invaded pancreatic lobules and formed close
associations with acinar cells, some of which demonstrated features of
apoptosis. At 20 wk, CD8-positive cells were still abundant in
the fibrotic tissue formed with loss of acinar cells. Repeated
subcutaneous injection of 0.1 mg · kg1 · day
1 but not
0.025 mg · kg
1 · day
1 of
tacrolimus for 10 wk completely prevented the occurrence of acinar cell
apoptosis, infiltration of CD4- and CD8-positive cells, and
development of pancreatitis at the age of 20 wk, but these maneuvers
did not recover the decreased plasma corticosterone levels, which
may be responsible for the development of disease. We demonstrated that
T cells, possibly CD8-positive cells, are involved in inducing
apoptosis of acinar cells, raising the possibility that
tacrolimus might find clinical application in the treatment of
autoimmune chronic pancreatitis.
autoimmune pancreatitis; acinar cells; apoptosis; corticosterone
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INTRODUCTION |
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HUMAN CHRONIC PANCREATITIS is an irreversible and progressive disease characterized by acinar cell destruction and fibrosis. Causes are various, and cell-mediated autoimmunity might also be involved, as indicated by infiltration of CD4- and CD8-positive cells and high expression of major histocompatibility complex class I and class II antigens by exocrine epithelial cells, which is suggestive of cell-mediated autoimmune reactions (2, 3, 7, 14). Recently, autoimmune pancreatitis has been proposed as an entity in humans as defined by lymphocyte infiltration, autoantibody production, and effectiveness of steroid therapy (13, 29, 31, 37).
Male Wistar Bonn/Kobori (WBN/Kob) rats spontaneously develop chronic pancreatitis and diabetes. The disease starts with edema of the interlobular and intralobular connective tissue with focal infiltration of inflammatory cells, progresses with increasing extent of inflammation and acinar cell injury, and finally exhibits pancreas replacement by granulation composed of fibroblasts, neutrophils, and lymphocytes, resulting in insufficiencies of exocrine and endocrine functions (24, 26, 28). We previously found (11) that in these rats, apoptosis of acinar cells significantly increases at the ages of 15 and 20 wk in parallel with inflammatory cell infiltration, and we proposed that this might profoundly contribute to the development of chronic pancreatitis. It was also noted that acinar cell apoptosis was related to the decreased levels of endogenous corticosterone, and administration of prednisolone considerably alleviated the disease (11), suggesting the involvement of autoimmune mechanisms in this rat model. Autoimmune mechanisms have also been postulated for the animal models of spontaneous diabetes mellitus, such as BioBreeding/Worcester rats, nonobese diabetes (NOD) mice, and MRL/Mp strain mice (8, 17, 20, 21). Furthermore, Vallace et al. (35) demonstrated that the aged major histocompatibility complex class II-deficient mice develop an immune-based chronic pancreatitis with selective loss of exocrine pancreatic function.
It was reported (16, 30) that cytotoxic T cells bearing Fas ligand are capable of inducing apoptotic cell death. In this study, to assess the involvement of cytotoxic T cells in induction of acinar cell apoptosis in male WBN/Kob rats, we immunohistochemically investigated the kinetic and spatial relationships of T cell accumulation with apoptotic acinar cells. We further investigated the in vivo effects of tacrolimus, a potent T cell suppressant, on the induction of acinar cell apoptosis, infiltration of CD4- and CD8-positive T cells, development of chronic pancreatitis, and decreased levels of endogenous corticosterone.
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MATERIALS AND METHODS |
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Animals. Male WBN/Kob rats were purchased from SLC (Hamamatsu, Japan) and kept in a temperature-controlled room under a constant light cycle. They were allowed free access to water and standard laboratory diet. The study protocol was approved by the Animal Care Committee of Nagoya City University.
Administration of tacrolimus.
Tacrolimus and its placebo were generously donated by Fujisawa (Tokyo,
Japan). WBN/Kob rats at the age of 10 wk were randomly divided into
three groups: 1) a placebo group (n = 7),
2) a low-dose (0.025 mg · kg1 · day
1) group
(n = 6), and 3) a high-dose (0.1 mg · kg
1 · day
1) group
(n = 6). The placebo and tacrolimus dissolved in saline were subcutaneously injected every other day for 10 wk. Body weights were recorded once a week.
Histology.
Animals aged 10, 15, and 20 wk (6 animals/age) were killed with an
overdose of pentobarbital sodium (Abbott Laboratories, North Chicago,
IL). Placebo- (n = 7), low dose of tacrolimus- (n = 6), and high dose of tacrolimus-
(n = 6) treated rats were also killed after 10 wk
treatment in the same manner at 4 PM after blood was drawn from the
abdominal aorta to minimize the influence of circadian rhythm on the
endogenous glucocorticoid levels. Blood was heparinized, and plasma was
kept at 40°C to measure plasma corticosterone levels as described
in Measurement of plasma corticosterone levels.
Scoring of pancreatitis. Histological alterations, including inflammatory cell infiltration, interstitial edema and fibrosis, acinar cell injury, and hemorrhage were graded on a scale of negligible to maximal (0-3), as reported previously (11).
Counting of apoptotic acinar cells and CD4- or CD8-positive T cells. The numbers of TUNEL-positive acinar cells in the placebo (n = 7) and tacrolimus (low dose; n = 6 and high dose; n = 6) groups were counted in 20 blindly selected areas for each animal at 200-fold magnification as reported previously (11). The numbers of CD4- or CD8-positive T cells were counted in the immunohistochemically stained sections derived from the placebo (n = 4) and high dose of tacrolimus (n = 8) groups at 400-fold magnification in the same manner.
Measurement of pancreatic myeloperoxidase activity.
Portions of fresh tissue obtained from the placebo (n = 7) and tacrolimus (low dose; n = 6 and high dose;
n = 6) groups were stored at 40°C. Pancreatic
myeloperoxidase (MPO) activity, an indirect quantitative index of
granulocyte infiltration, was determined by using a minor modification
of the method of Grisham et al. (9). Briefly, pancreatic
tissue was homogenized in 20 mM phosphate buffer (pH 7.4) and
centrifuged at 6,000 g for 20 min at 4°C. The pellet was
then homogenized and sonicated with an equivalent volume of 50 mM
acetic acid (pH 6.0) containing 0.5% (wt/vol) hexadecyltrimethylammonium hydroxide. The MPO activity was determined by measuring the hydrogen peroxide-dependent oxidation of
3,3',5,5'-tetramethylbenzidine and expressed as units per gram wet
weight of pancreas.
Measurement of plasma corticosterone levels. Plasma corticosterone levels in the placebo (n = 7), low-dose (n = 6), and high-dose (n = 6) groups were determined as described previously (34).
Flow cytometric analysis. Thymocytes and peripheral lymphocytes in the placebo (n = 4) and high dose of tacrolimus (n = 8) groups were prepared and stained with both fluorescein isothiocyanate-conjugated mouse anti rat-CD4 and R-phycoerythrin-conjugated mouse anti rat-CD8a MAbs (Becton-Dickinson, Mountain View, CA) as described previously (15). Freshly stained cells were analyzed by single-color or double-color fluorescence distribution in a FACScan flow cytometer (Becton-Dickinson).
Statistics. Data are expressed as means ± SE. Statistical differences among groups were identified using one-way ANOVA. Multiple comparisons were performed using the least significant difference method. Differences were analyzed by the Student's t-test.
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RESULTS |
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Spatial association of T cells with apoptotic acinar cells
during chronic pancreatitis.
At the age of 10 wk, there were no appreciable histological changes in
the pancreas. Infiltration of CD8-positive cells was negligible (Fig.
1A). At 15 wk, inflammation
had developed but was uneven among the lobules. In the inflamed
portions, a large number of CD8-positive cells infiltrated in the
interlobular connective tissue and further invaded the parenchyma,
making contact with acinar cells (Fig. 1B). At 20 wk, the
acinar tissue was destroyed, leaving ductular structures embedded in
fibrous tissue, in which CD8-positive cells were still abundant (Fig.
1C).
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Preventive effect of 10-wk treatment with tacrolimus on acinar cell
apoptosis and the development of pancreatitis.
There was a small but significant decrease in body weight in the rats
treated with the high dose (0.1 mg · kg1 · day
1) of
tacrolimus compared with those in placebo and low-dose groups (Table
1). The pancreas weight, on the other
hand, showed a significant increase. In H-E-stained sections,
inflammatory cell infiltration, destruction of acini, and proliferation
of connective tissue were evident in the placebo group (Fig.
4A). In contrast, no
inflammatory changes or injuries were apparent in any lobules of the
pancreas treated with the high dose of tacrolimus (Fig. 4C).
Histological scores revealed that tacrolimus dose-dependently
suppressed the development of chronic pancreatitis (Table 1).
Consistent with this, pancreatic MPO activity was significantly
decreased by the high dose of tacrolimus (Table 1). Histologically,
TUNEL-positive acinar cells were apparent in the placebo group, whereas
these positive cells were extremely rare in the high-dose group (Fig. 4B and 4D). The effect was also confirmed by
numerical analyses (Table 1).
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Effect of tacrolimus treatment on the plasma corticosterone levels. Plasma corticosterone levels did not significantly differ among the placebo, low-dose, and high-dose groups (187.8 ± 5.0, 172.8 ± 9.4, and 221.6 ± 16.8 ng/ml, respectively).
Effects of tacrolimus treatment on the infiltrated T cells in the pancreas and T cell subsets in the thymus and peripheral blood. In the immunostained pancreatic sections, both CD4- and CD8-positive T cells were evident in the placebo group, whereas the positive cells were almost absent in the high-dose tacrolimus group. Quantitative analyses of CD4- and CD8-positive cells revealed that a high dose of tacrolimus significantly decreased the numbers of both CD4- and CD8-positive cells compared with the placebo (CD4, 0.03 ± 0.01 vs. 3.73 ± 1.13; CD8, 0.04 ± 0.02 vs. 5.50 ± 1.24; P < 0.05 for both). Flow cytometric analyses revealed that a high dose of tacrolimus did not alter the proportions of CD4- and CD8-positive cells in the thymus and peripheral blood compared with the placebo treatment (data not shown).
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DISCUSSION |
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We have demonstrated here that T cells, in particular CD8-positive cells, infiltrated deeply into the pancreatic parenchyma in aging male WBN/Kob rats and made a close association with apoptotic acinar cells, whereas F4/80-positive cells (monocytes/macrophages) and CD4-positive cells, although abundant like CD8-positive cells, less frequently invaded the acini. Because cytotoxic T cells bear Fas ligands that participate in apoptotic cell death (16, 30), CD8-positive cells infiltrating into the acini are most probably involved in the observed acinar cell apoptosis. This interpretation was supported by the present finding that tacrolimus, a potent suppressant of T cell proliferation, cytotoxic T cell generation, and T cell-derived cytokine production (18, 19), completely prevented the occurrence of acinar cell apoptosis, infiltration of both CD4- and CD8-positive cells, and development of chronic pancreatitis.
It has been documented that cell-mediated autoimmune mechanisms are involved in the development of chronic pancreatitis in humans (2, 7), and Bedossa et al. (3) demonstrated large numbers of CD8-positive cells infiltrating areas of inflammation in human chronic pancreatitis. It was described that 82 and 66% of a series of 93 patients with chronic pancreatitis, respectively, expressed major histocompatibility complex class I and class II immunoreactivity in exocrine epithelial cells, suggesting that an unknown antigen may trigger a cell-mediated autoimmune reaction (3, 14). More recently, Okazaki et al. (29) reported that CD8- and CD4-positive cells were increased in the peripheral blood with a Th1-type immune response involvement in autoimmune chronic pancreatitis in humans (29). Consistent with these findings, we confirmed that CD8- and CD4-positive cells contribute to autoimmunity in the present model.
Neonatal thymectomy or intrathymic injection of islet tissue prevents
spontaneous diabetes mellitus in BioBreeding/Worcester rats and NOD
mice, suggesting that thymus-dependent, cell-mediated autoimmune
destruction of pancreatic -cells is responsible for their
development of diabetes mellitus (8, 20, 21). Indeed, diabetes requires both CD4- and CD8-positive cells, homing of the
latter to the pancreas being mediated by CD4-positive cell-dependent processes in NOD mice (23, 33). CD8-positive cells cause
the initial
-cell injury that sheds and loads
-cell autoantigens onto antigen-presenting cells, thus activating diabetogenic
autoreactive CD4-positive cells (1). Furthermore, Fas
mediation was demonstrated for
-cell injury in NOD mice by
Chervonsky et al. (5). We could not analyze the expression
of Fas antigen and Fas ligand in the pancreas because antibodies
against them are not commercially available for rats. The mechanism of
acinar cell apoptosis induced by T cells in the present model
remains to be elucidated.
The immunosuppressant tacrolimus, isolated from the fermentation of a
strain of Streptomyces tsukubaensis (18, 19),
has been demonstrated to attenuate the development of several kinds of
autoimmune disease such as diabetes (4, 27), myocarditis (10), and glomerulonephritis (25) in
experimental animals. This agent is already applied in clinics for the
treatment of inflammatory bowel diseases (6). However,
tacrolimus has not been tried in the treatment of the animal model of
chronic pancreatitis. The high dose used here, 0.1 mg · kg1 · day
1, is
equivalent to that employed for immunosuppressive therapy in humans
(22) and gave satisfactory results in the present model of
chronic pancreatitis as demonstrated by marked improvement in
histological scores. In addition, treatment with tacrolimus not only
prevented infiltration of macrophages and neutrophils but also
prevented infiltration of T cells, as demonstrated by pancreatic MPO
activity and immunohistochemistry.
To elucidate another possible mechanism by which tacrolimus prevented
acinar cell apoptosis, we focused our attention on the plasma
corticosterone levels, since a decrease in endogenous corticosterone proved to be responsible for the induction of acinar cell
apoptosis in the present model (11). We confirmed
that the plasma corticosterone levels were not altered by tacrolimus
treatment, suggesting that prevention of acinar cell apoptosis
by tacrolimus may not be related to endogenous corticosterone levels.
We further investigated the effect of tacrolimus on the T cell subsets
in the thymus and peripheral blood, since it was reported that
tacrolimus (1 mg/kg) alters the thymocyte populations in Lewis rats
(36). However, we found that there were no differences in
the T cell subsets between placebo and high dose of tacrolimus groups.
This discrepancy may be explained by the differences of dosage and
animals. On the other hand, tacrolimus was reported to suppress
activations of nuclear factor-B and intracellular adhesion
molecule-1, resulting in the reduced accumulation of leukocytes in
ischemia-reperfusion injury of the rat heart (32).
One might speculate that tacrolimus exerted protection by the same
mechanism. However, we do not believe that this is the case for this
model since CD8-positive cells frequently invaded the acini and closely
adhered to the apoptotic acinar cells, suggesting that CD8-positive
cells play a key role in the induction of acinar cell
apoptosis. We speculate that prevention of T cell infiltration by tacrolimus resulted in reduced acinar cell apoptosis,
leading to disappearance of monocytes/macrophages or neutrophils.
The present study demonstrated the efficacy of tacrolimus for suppression of chronic pancreatitis in male WBN/Kob rats and also raised the possibility of clinical use for chronic pancreatitis. Caution is necessary, however, in this context, because a combination of an innocuous dose of caerulein and tacrolimus was reported to induce pancreatic injury (12). The model of spontaneously occurring chronic pancreatitis employed here, at least in part, reflects autoimmune chronic pancreatitis in humans and thus is useful for exploration of the pathogenesis and effective maneuvers for this disease.
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FOOTNOTES |
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Address for reprint requests and other correspondence: T. Yamada, First Dept. of Internal Medicine, Nagoya City Univ. Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan (E-mail: yamtmaki{at}med.nagoya-cu.ac.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 15 December 2000; accepted in final form 10 September 2001.
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