Interferon- as a Mediator of Polyinosinic:Polycytidylic AcideCInduced Type 1 Diabetes
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糖尿病学杂志 2005年第9期
the Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado
ABSTRACT
A number of studies and clinical case reports have implicated interferon (IFN)- as a potential mediator of type 1 diabetes pathogenesis. Administration of polyinosinic:polycytidylic acid (poly I:C), a mimic of viral double-stranded RNA, induces diabetes in C57BL/6 mice expressing the B7.1 costimulatory molecule in islets. We investigated the potential role of IFN- in this disease model. The quantitative correlation between IFN- levels and time to diabetes, diabetes prevention with antieCIFN- antibody, and ability of IFN- itself to induce diabetes are consistent with the hypothesis that poly I:C in this model acts by induction of IFN- in a genetically susceptible host. Numerous recent studies highlight the importance of the innate immune system and toll receptors in determining adaptive immune responses, and we speculate that for type 1 diabetes, viral and other environmental factors may act through induction of IFNs.
Type 1A diabetes results from T-celleCmediated destruction of -cells in the pancreas with evidence of islet-specific autoimmunity (1eC3). Both genetic and environmental factors appear to play an important role in the pathogenesis of type 1A diabetes. Since the concordance for type 1A diabetes is only 40eC50% for monozygotic twins, environmental factors such as toxins, viruses, and certain diets may be involved in the initiation of this disease (4). With the recent increase in the incidence of type 1A diabetes worldwide, many investigators have been searching for environmental factors that could potentially play a role in the pathogenesis of the disease (5).
Viruses have been implicated as an important factor triggering type 1A diabetes in genetically susceptible humans and in many animal models (6). The mechanism of viral infection leading to -cell destruction may be due to its direct or indirect effect on the -cells of the pancreas or directly on lymphoid cells. Furthermore, islet -cells produce a wide range of antiviral responses for host protection that may stimulate an immune-mediated islet destruction (7). There is accumulating evidence implicating the viral induction of the cytokine interferon (IFN)- in the disease process (8eC11). There have been numerous case reports describing IFN- therapy and the appearance of islet autoantibodies, i.e., type 1A diabetes (12). In addition, IFN- can accelerate and induce autoimmune diabetes when expressed as a transgene in islets of mice (13).
Double-stranded RNA is produced during the process of viral replication of both DNA and RNA viruses (14). The viral mimic poly I:C (polyinosinic:polycytidilic acid) is a synthetic double-stranded RNA that stimulates an immune response similar to those observed in viral infections and is specifically recognized by toll-like receptor 3 (7). Furthermore, poly I:C is a potent IFN- inducer that stimulates a variety of cells of the innate immune system, namely dendritic cells, macrophages, T-cells, and NK cells (7). Poly I:C induces diabetes in the BB rat (15,16) and in streptozotocin-treated mice (13). Paradoxically, low-dose poly I:C has been shown to prevent diabetes in NOD mice (17). In "normal" wild-type BALB/c mice, insulin autoantibodies and insulitis were induced following immunization with insulin peptide B:9eC23 and poly I:C (18). Poly I:C has also been shown to induce diabetes in transgenic mice in which -cells express the human costimulatory molecule B7.1 under the control of the rat insulin promoter (RIP) (19).
We have recently shown that diabetes induction with poly I:C in mice expressing the B7.1 molecule in islet -cells is related to genetic background. C57BL/6 mice treated with poly I:C develop diabetes, whereas BALB/c mice are resistant (20). In this current study, we provide evidence that the induction of IFN- by poly I:C is essential for the development of autoimmune diabetes in RIP-B7.1 mice, and this disease induction can be blocked by systemic administration of antibodies to IFN-.
RESEARCH DESIGN AND METHODS
C57BL/6.RIP-B7.1 and BALB/c.RIP-B7.1 (backcross 10) transgenic mice were kindly given by L. Wen (Yale University). These mice are designated BL/6 B7.1 and BALB/c B7.1, respectively. Backcross (BC) mice were created by crossing (C57BL/6-RIP-B7.1 x BALB/c) F1 to BALB/c. The RIP-B7.1 transgene expression was detected by PCR amplification of the B7.1 gene using genomic DNA isolated from tail biopsies. C57BL/6 mice and BALB/c were purchased from The Jackson Laboratory. The mice were housed in a pathogen-free animal colony at the Barbara Davis Center for Childhood Diabetes with approved protocols from the University of Colorado Health Sciences Center Animal Care and Use Committee.
Reagents.
Poly I:C salt was purchased from Sigma-Aldrich. Mouse IFN- was purchased from Research Diagnostics (Flanders, NJ), and rat IgG1 anti-mouse IFN- antibody (clone F18, 6.25 x 104 neutralizing units/mg antibody) was purchased from Cell Sciences (Canton, MA). Insulin peptide B:9eC23 (SHLVEALYLVCGERG) and tetanus toxin (TT) peptide 830eC843 (QYIKANSKFIGIFE) were purchased from SynPep (Dublin, CA). The peptide was >90% high-performance liquid chromatography purified, dissolved in lipopolysaccharide-free sterile saline, and adjusted to a neutral pH.
Disease induction protocol.
Poly I:C was given intraperitoneally on days 1eC5 and 8eC14 (starting at 4 weeks of age) at a concentration of 7.5 e/g body wt. In the group of mice given recombinant mouse IFN-, 10,000 units i.p. were given as per the poly I:C protocol. In the group of mice given anti-mouse IFN- monoclonal antibody and poly I:C, 60,000 units i.p. of anti-mouse IFN- monoclonal antibody was given three times a week during weeks 3 and 4 and subsequently given 80,000 units i.p. three times a week during weeks 5 and 6. This regimen was based on a similar work described by Stewart et al. (21). Poly I:C was given intraperitoneally as per protocol described above. Blood glucose was measured weekly with the Freestyle blood glucose monitoring system (Therasense, Alameda, CA), and the mice were considered diabetic after two consecutive blood glucose values >250 mg/dl.
IFN- measurement.
Mouse IFN- in serum was detected using the enzyme-linked immunosorbent assay kit purchased from PBL Biomedical Laboratories (Piscataway, NJ). The standard provided by the kit is based on the international standard for mouse IFN- provided by the National Institute of Health. The detection range of the assay was 12.5eC500 pg/ml. This kit does not cross-react with mouse IFN- or -.
IFN- response to poly I:C in vitro.
To determine which cell(s) was responsible for the induction of circulating IFN- levels in response to poly I:C in vitro, the following experiment was conducted. BC1 B7.1 and BC1 (without B7.1 transgene) mice (four in each group) were killed 4 h posteCday 6 of poly I:C injections (to mimic the similar peak response seen in serum IFN-, see RESULTS). A separate group of mice without any in vivo exposure to poly I:C was studied as well. Splenocytes and lymphocytes from pancreatic lymph nodes were cultured (1 x 108 cells/ml) in a final volume of 200 e蘬 in a 96-well flat-bottom microtiter plate in RPMI-1640 with 0.5% (heat-inactivated) mouse serum, 1 mmol/l sodium pyruvate, penicillin-streptomycin, and 1% HEPES. Cells were cultured with no stimulus or with poly I:C at a 100-e/ml final concentration. At the end of a 24-h culture period, samples of supernatant were obtained for IFN- analysis. Pancreatic islets were isolated from the BC1 B7.1 mice by collagenase digestion. Pancreatic islets were dispersed in calcium-free HEPES-buffered Earle’s medium containing 1 mmol/l EDTA and 25 e/ml trypsin. Isolated cells were diluted in the calcium-free Earle’s medium buffer and filtered through a 63-e nylon screen to remove cell clumps and undigested material. Islet cells were seeded at a concentration of 2 x 104 cells/200 e蘬 in a 96-well flat-bottom plate with RPMI-1640 medium (Invitrogen) supplemented with 10% heat-activated fetal bovine serum, 1 mmol/l HEPES, 1 mmol/l sodium pyruvate, penicillin-streptomycin, 2 mmol/l L-glutamine, and nonessential amino acids. After an overnight incubation (37°C, 5% CO2), the islet cells were either activated with or without poly I:C at a 100-e/ml final concentration. Supernatant from each well was removed 24 h later for IFN- analysis.
Immunohistology.
A portion of the pancreata obtained from the mice was fixed in 10% formalin, paraffin embedded, and stained with hematoxylin and eosin. Pancreatic sections were microscopically examined for the presence of insulitis. Paraffin-embedded pancreatic sections were stained with polyclonal guinea pig anti-insulin and anti-glucagon antibodies (Linco Research Immunoassay, St. Charles, MO), followed by a peroxidase-labeled antieCguinea pig IgG secondary antibody (Kirkegaard & Perry Laboratories, Gaithersburg, MD). Subsequently, the sections were counterstained with hematoxylin and coverslipped. Pancreatic frozen sections were stained by monoclonal antibodies to mouse CD4 and CD8 (Becton Dickinson, San Diego, CA). A universal peroxidase-conjugated secondary antibody (Dako, Glostrop, Denmark) was used as the detection system
RESULTS
Poly I:C triggers diabetes in BL/6 B7.1 but not in BALB/c B7.1 mice.
We have recently reported that poly I:C, a mimic of viral double-stranded RNA, can induce diabetes in the BL/6 B7.1 model (with islet-induced expression of the costimulatory molecule B7.1), but diabetes induction is decreased when backcrossing the B7.1 transgene onto the BALB/c strain (20). Consistent with prior observations, 78% of the BL/6 B7.1 mice developed diabetes by 20 weeks of age with poly I:C administration (Fig. 1) and 66% of the BC1 B7.1 mice developed diabetes with poly I:C. Only 10% of the BALB/c B7.1 (backcross 10) became diabetic with poly I:C.
C57BL/6 (0/10), BC1 (0/8), and BALB/c (0/8) mice that did not express the B7.1 transgene remained diabetes free with poly I:C when followed up to 40 weeks of age (data not shown).
Peak IFN- after poly I:C stimulation is higher in BL/6 B7.1 mice.
To investigate the differential effects of poly I:C on the induction of diabetes in the various models, we studied the pattern of IFN- expression in the serum of these mice after poly I:C administration at 4 weeks of age. We measured IFN- over time following the 6th day of poly I:C administration. Of note, the IFN- response after the first injection (day 1) of poly I:C in the BC1 B7.1 mice, did not demonstrate any detectable IFN- levels when it was measured at similar times (data not shown). On the 6th day of treatment, serum was taken before the injection of poly I:C (the basal level) and at 1, 2, 4, 6, and 12 h postadministration. IFN- levels appeared to peak earlier in BL/6 B7.1 mice (2 h postinjection) than in BC1 B7.1 and BALB/c B7.1 mice (4eC6 h postinjection). The backcross 1 (BC1), BALB/c, and C57BL/6 mice without the B7.1 transgene (five mice in each group) have a much lower peak IFN- response compared with the similar group of mice with the B7.1 transgene (P < 0.01) (Fig. 2A). The mean peak IFN- levels in the BL/6 B7.1 mice was significantly higher than in the BC1 B7.1 and BALB/c B7.1 (P < 0.01) mice. However, despite a difference in susceptibility to diabetes between BC1 B7.1 and BALB/c B7.1 mice, there was no significant difference in peak IFN- levels, suggesting inherent factors other than IFN- susceptibility that might predispose to diabetes (Fig. 2B).
Lymphoid cells (from spleen) induce higher IFN- than islets in BC1 B7.1 mice.
The mean IFN- production from four BC1 B7.1 mouse splenocytes stimulated in vivo with poly I:C and subsequently in vitro was 68.6 pmol/l. This was higher (P < 0.05) when compared with the mean production from lymphocytes (pancreatic lymph nodes) or islets (44.3 and 19.4 pg/ml, respectively) (Table 1). In contrast, cells that were not stimulated in vivo had a much lower mean IFN- induction with in vitro poly I:C stimulation alone (spleen 28.6, lymphocytes 19.9, and islets <12.5 pg/ml). In BC1 B7.1 mice that were given poly I:C in vivo but not in vitro, splenocytes, lymphocytes, and islet induction of IFN- were (mean) 17.8, <12.5, and <12.5 pg/ml, respectively. In BC1 mice without the B7.1 transgene, only splenocytes stimulated in vivo and in vitro induced any detectable IFN- (14.4 pg/ml). Of note, all four mice in each group had detectable IFN-, except the B7.1-negative group of splenocytes given poly I:C in vivo and in vitro (mean 14.4 pg/ml), in which two of the four mice had detectable levels.
Peak IFN- after poly I:C stimulation is higher in diabetic mice and correlates to age of onset of diabetes.
A total of 50 BC1 B7.1 mice were divided according to phenotype as diabetes or no diabetes by 40 weeks of age, and the peak IFN- levels were compared for these two groups (Fig. 3). The mean peak IFN- levels were significantly (P < 0.001) higher in the group that progressed to diabetes compared with the nondiabetic group. BC1 B7.1 mice were divided into "high" IFN- responders (rise in IFN- 25 pg/ml from the basal level) and "low" IFN- responders (rise of <25 pg/ml from basal level), and diabetes incidence was compared (Fig. 4). By life-table analysis, an IFN- response of >25 pg/ml is highly predictive of diabetes development (positive predictive value 82%). Finally, the peak IFN- levels were compared with the time to onset (age) of diabetes in the poly I:CeCtreated BC1 B7.1 mice. There was a significant inverse correlation (r = eC0.58, P < 0.01) between the age of onset of diabetes with the peak IFN- levels (Fig. 5). These data taken together suggest that the mechanism of diabetes induction with poly I:C in the B7.1 model may involve IFN-.
Neutralizing IFN- after poly I:C induction prevents diabetes in BL/6 B7.1 and BC1 B7.1 mice.
Administration of a monoclonal antibody to IFN- prevented diabetes in all BL/6 B7.1 mice treated with poly I:C (Fig. 6). A similar effect was observed in the BC1 B7.1 mice, whereby only 1 of 12 mice developed diabetes when the monoclonal antibody was coadministered with poly I:C.
Recombinant mouse IFN- induces diabetes in BC1 B7.1 mice.
To further support the role of IFN- in the induction of diabetes in this B7.1 model, recombinant mouse IFN- was administered to BC1 B7.1 mice. Of the 10 BC1 B7.1 mice, 4 developed diabetes in a similar time period when compared with the survival curve using poly I:C alone (P = 0.12 for the IFN- group compared with the poly I:C group) (Fig. 7).
CD4- and CD8-positive staining in islets of poly I:CeCinduced diabetic mice.
Lymphocytic infiltration of the islets (insulitis) is a hallmark of autoimmune type 1A diabetes. Poly I:CeCtreated mice displayed the characteristic CD4 and CD8 T-cell infiltrate in the islets of the pancreas at the time of diabetes onset (Fig. 8A and B). The pancreas in mice that developed diabetes after the administration of recombinant mouse IFN- also showed a similar pattern of insulitis (Fig. 8C and D). In contrast, mice that were given monoclonal antibody to IFN- to block poly I:C disease induction showed no evidence of CD4 and CD8 infiltration when killed at the age of 30 weeks (Fig. 8E and F). Interestingly, mice that did not develop diabetes with poly I:C administration when studied at 40 weeks of age did not show any evidence of insulitis (Fig. 8G and H), suggesting an "all or none" phenomenon in this model of poly I:CeCinduced diabetes.
DISCUSSION
Viruses are considered important environmental agents that may initiate -cell destruction in genetically susceptible individuals (6). The double-stranded RNA viral mimic poly I:C has been extensively used in various experimental models to mimic part of the pathophysiology of viral infections. In this study, we investigated the mechanisms of poly I:CeCinduced diabetes using BL/6 mice that express the B7.1 costimulatory molecule in the pancreatic islets. This study confirms our previous report that the sensitivity to induce diabetes using poly I:C is lost when the B7.1 transgene on a C57BL/6 background is backcrossed onto BALB/c mice (20).
To investigate the pathway that may be responsible for the diabetes phenotype related to poly I:C sensitivity, IFN- response was studied. It was interesting to note that the presence of B7.1 in the islet -cells is critical for a robust IFN- response to poly I:C. Lymphoid cells from the spleen can be a source of IFN- induction in our diabetes induction model with poly I:C. IFN- produced primarily by plasmacytoid dendritic cells is a potent component of the antiviral innate immune response and modulates adaptive immunity (22). Primary control of IFN- production occurs at a cellular level and is highly dependent upon regulatory factors and their products. One potential explanation for a higher IFN- response seen in mice with the islet RIP B7.1 transgene compared with mice without the B7.1 transgene is that B7.1 acts as an enhancer of immune activation within islets or nonislet tissues (23). It is known that B7.1 can transform nonprofessional antigen-presenting cells (APCs), such as islets, into competent APCs that trigger autoimmunity when additional factors such as local inflammation (24), upregulated major histocompatibility complex Ag expression (25), or high numbers of potentially autoreactive T-cells (26) are present. Therefore, disease induction by IFN- may require both immune system activation and target organ inflammation, such as -cell major histocompatibility complex class I upregulation, as suggested by a recent report by Zinkernagel et al. (27). The expression of IFN- appears to reflect an important biological activity in these mice. A higher peak IFN- is observed in diabetic compared with nondiabetic mice. Furthermore, the level of poly I:CeCinduced IFN- predicts diabetes in both the frequency and time to onset of diabetes. Earlier onset of diabetes is correlated to a higher peak IFN- level. While it is possible that induced IFN- is only a reflection of islet inflammation in pre-diabetic mice, our data incriminate IFN- in playing a role in disease pathogenesis.
The data provide evidence that the pathway of poly I:CeCinduced diabetes in this model is IFN- dependent. The neutralization of IFN- with a monoclonal antibody suppressed the incidence of poly I:CeCinduced diabetes in the BL/6 B7.1 mice. Also, the administration of IFN- alone, similar to poly I:C alone, is capable of inducing diabetes in this model. Furthermore, we have shown that the islet cells of the B7.1-positive mice were not the main cells responsible for IFN- production. It is clear from our study that IFN- could not be detected after only 1 day of poly I:C administration, but once the mouse was primed with poly I:C for 5 days, IFN- levels could be detected.
IFN- is used in the treatment of persistent hepatitis B and C infections and various malignancies (28). IFN- has antiviral, cytostatic, and prominent immunomodulatory effects, all of which are of great importance during viral infections. However, prolonged exposure of the immune system to type 1 IFN in the treatment of such diseases can break tolerance and initiate an autoimmune reaction, eventually leading to autoimmune disease. Autoimmune diseases implicated with IFN- therapy include thyroiditis, autoimmune gastritis, psoriasis, systemic lupus erythematosis, and rheumatoid arthritis (29eC31). In addition, there have been numerous case reports of type 1A diabetes or islet autoantibody expression with IFN- therapy (7). Our current data suggest that IFN- serves as a link between the innate response to poly I:C and the adaptive immune response that eventually leads to the induction of autoimmune diabetes.
In tissue culture, IFN- can decrease insulin synthesis and secretion (32,33). Furthermore, human -cells show a marked induction of oligoadenylate synthase (marker of apoptosis induction) with IFN- (34). IFN- can also have a direct cytolytic effect on -cells or an indirect effect by activating the innate immune system (7). In one particular study, investigators evaluated the expression of messenger RNA for a series of cytokines in the pancreas and islets of patients with and without type 1A diabetes. They found that only IFN- was significantly overexpressed in diabetic patients (9). Elevated IFN- levels have also been documented in the serum of adult diabetic patients (35,36). In almost all cases of new-onset type 1A diabetes, pancreatic -cells contained IFN-, which correlated with overexpression of the IFN- gene (37).
We have demonstrated a quantitative correlation of IFN- levels and progression to diabetes in the poly I:C RIP-B7.1eCinduced diabetes model. We speculate that viral infections through the generation of double-stranded RNA may induce IFN- that in turn, in a genetically susceptible individual (e.g., DR3/4-DQ2/DQ8), will trigger anti-islet autoimmunity. Therefore, the response to IFN- may be an important component of type 1A diabetes risk, and pharmacologic regulation of the pathway may be important for disease prevention.
ACKNOWLEDGMENTS
This research was supported by grants from the National Institutes of Health (NIH) (DK 055969, DK 062718, and AI 055466), the Autoimmunity Prevention Center U19 (AI 050864), the Diabetes Endocrine Research Center (P30 DK57516), the American Diabetes Association, the Juvenile Diabetes Foundation, and the Children’s Diabetes Foundation. D.D. is supported by an Eli Lilly fellowship award, and E.L. is supported by an NIH grant (DK 06405).
FOOTNOTES
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
IFN, interferon; poly I:C, polyinosinic:polycytidylic acid; RIP, rat insulin promoter
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ABSTRACT
A number of studies and clinical case reports have implicated interferon (IFN)- as a potential mediator of type 1 diabetes pathogenesis. Administration of polyinosinic:polycytidylic acid (poly I:C), a mimic of viral double-stranded RNA, induces diabetes in C57BL/6 mice expressing the B7.1 costimulatory molecule in islets. We investigated the potential role of IFN- in this disease model. The quantitative correlation between IFN- levels and time to diabetes, diabetes prevention with antieCIFN- antibody, and ability of IFN- itself to induce diabetes are consistent with the hypothesis that poly I:C in this model acts by induction of IFN- in a genetically susceptible host. Numerous recent studies highlight the importance of the innate immune system and toll receptors in determining adaptive immune responses, and we speculate that for type 1 diabetes, viral and other environmental factors may act through induction of IFNs.
Type 1A diabetes results from T-celleCmediated destruction of -cells in the pancreas with evidence of islet-specific autoimmunity (1eC3). Both genetic and environmental factors appear to play an important role in the pathogenesis of type 1A diabetes. Since the concordance for type 1A diabetes is only 40eC50% for monozygotic twins, environmental factors such as toxins, viruses, and certain diets may be involved in the initiation of this disease (4). With the recent increase in the incidence of type 1A diabetes worldwide, many investigators have been searching for environmental factors that could potentially play a role in the pathogenesis of the disease (5).
Viruses have been implicated as an important factor triggering type 1A diabetes in genetically susceptible humans and in many animal models (6). The mechanism of viral infection leading to -cell destruction may be due to its direct or indirect effect on the -cells of the pancreas or directly on lymphoid cells. Furthermore, islet -cells produce a wide range of antiviral responses for host protection that may stimulate an immune-mediated islet destruction (7). There is accumulating evidence implicating the viral induction of the cytokine interferon (IFN)- in the disease process (8eC11). There have been numerous case reports describing IFN- therapy and the appearance of islet autoantibodies, i.e., type 1A diabetes (12). In addition, IFN- can accelerate and induce autoimmune diabetes when expressed as a transgene in islets of mice (13).
Double-stranded RNA is produced during the process of viral replication of both DNA and RNA viruses (14). The viral mimic poly I:C (polyinosinic:polycytidilic acid) is a synthetic double-stranded RNA that stimulates an immune response similar to those observed in viral infections and is specifically recognized by toll-like receptor 3 (7). Furthermore, poly I:C is a potent IFN- inducer that stimulates a variety of cells of the innate immune system, namely dendritic cells, macrophages, T-cells, and NK cells (7). Poly I:C induces diabetes in the BB rat (15,16) and in streptozotocin-treated mice (13). Paradoxically, low-dose poly I:C has been shown to prevent diabetes in NOD mice (17). In "normal" wild-type BALB/c mice, insulin autoantibodies and insulitis were induced following immunization with insulin peptide B:9eC23 and poly I:C (18). Poly I:C has also been shown to induce diabetes in transgenic mice in which -cells express the human costimulatory molecule B7.1 under the control of the rat insulin promoter (RIP) (19).
We have recently shown that diabetes induction with poly I:C in mice expressing the B7.1 molecule in islet -cells is related to genetic background. C57BL/6 mice treated with poly I:C develop diabetes, whereas BALB/c mice are resistant (20). In this current study, we provide evidence that the induction of IFN- by poly I:C is essential for the development of autoimmune diabetes in RIP-B7.1 mice, and this disease induction can be blocked by systemic administration of antibodies to IFN-.
RESEARCH DESIGN AND METHODS
C57BL/6.RIP-B7.1 and BALB/c.RIP-B7.1 (backcross 10) transgenic mice were kindly given by L. Wen (Yale University). These mice are designated BL/6 B7.1 and BALB/c B7.1, respectively. Backcross (BC) mice were created by crossing (C57BL/6-RIP-B7.1 x BALB/c) F1 to BALB/c. The RIP-B7.1 transgene expression was detected by PCR amplification of the B7.1 gene using genomic DNA isolated from tail biopsies. C57BL/6 mice and BALB/c were purchased from The Jackson Laboratory. The mice were housed in a pathogen-free animal colony at the Barbara Davis Center for Childhood Diabetes with approved protocols from the University of Colorado Health Sciences Center Animal Care and Use Committee.
Reagents.
Poly I:C salt was purchased from Sigma-Aldrich. Mouse IFN- was purchased from Research Diagnostics (Flanders, NJ), and rat IgG1 anti-mouse IFN- antibody (clone F18, 6.25 x 104 neutralizing units/mg antibody) was purchased from Cell Sciences (Canton, MA). Insulin peptide B:9eC23 (SHLVEALYLVCGERG) and tetanus toxin (TT) peptide 830eC843 (QYIKANSKFIGIFE) were purchased from SynPep (Dublin, CA). The peptide was >90% high-performance liquid chromatography purified, dissolved in lipopolysaccharide-free sterile saline, and adjusted to a neutral pH.
Disease induction protocol.
Poly I:C was given intraperitoneally on days 1eC5 and 8eC14 (starting at 4 weeks of age) at a concentration of 7.5 e/g body wt. In the group of mice given recombinant mouse IFN-, 10,000 units i.p. were given as per the poly I:C protocol. In the group of mice given anti-mouse IFN- monoclonal antibody and poly I:C, 60,000 units i.p. of anti-mouse IFN- monoclonal antibody was given three times a week during weeks 3 and 4 and subsequently given 80,000 units i.p. three times a week during weeks 5 and 6. This regimen was based on a similar work described by Stewart et al. (21). Poly I:C was given intraperitoneally as per protocol described above. Blood glucose was measured weekly with the Freestyle blood glucose monitoring system (Therasense, Alameda, CA), and the mice were considered diabetic after two consecutive blood glucose values >250 mg/dl.
IFN- measurement.
Mouse IFN- in serum was detected using the enzyme-linked immunosorbent assay kit purchased from PBL Biomedical Laboratories (Piscataway, NJ). The standard provided by the kit is based on the international standard for mouse IFN- provided by the National Institute of Health. The detection range of the assay was 12.5eC500 pg/ml. This kit does not cross-react with mouse IFN- or -.
IFN- response to poly I:C in vitro.
To determine which cell(s) was responsible for the induction of circulating IFN- levels in response to poly I:C in vitro, the following experiment was conducted. BC1 B7.1 and BC1 (without B7.1 transgene) mice (four in each group) were killed 4 h posteCday 6 of poly I:C injections (to mimic the similar peak response seen in serum IFN-, see RESULTS). A separate group of mice without any in vivo exposure to poly I:C was studied as well. Splenocytes and lymphocytes from pancreatic lymph nodes were cultured (1 x 108 cells/ml) in a final volume of 200 e蘬 in a 96-well flat-bottom microtiter plate in RPMI-1640 with 0.5% (heat-inactivated) mouse serum, 1 mmol/l sodium pyruvate, penicillin-streptomycin, and 1% HEPES. Cells were cultured with no stimulus or with poly I:C at a 100-e/ml final concentration. At the end of a 24-h culture period, samples of supernatant were obtained for IFN- analysis. Pancreatic islets were isolated from the BC1 B7.1 mice by collagenase digestion. Pancreatic islets were dispersed in calcium-free HEPES-buffered Earle’s medium containing 1 mmol/l EDTA and 25 e/ml trypsin. Isolated cells were diluted in the calcium-free Earle’s medium buffer and filtered through a 63-e nylon screen to remove cell clumps and undigested material. Islet cells were seeded at a concentration of 2 x 104 cells/200 e蘬 in a 96-well flat-bottom plate with RPMI-1640 medium (Invitrogen) supplemented with 10% heat-activated fetal bovine serum, 1 mmol/l HEPES, 1 mmol/l sodium pyruvate, penicillin-streptomycin, 2 mmol/l L-glutamine, and nonessential amino acids. After an overnight incubation (37°C, 5% CO2), the islet cells were either activated with or without poly I:C at a 100-e/ml final concentration. Supernatant from each well was removed 24 h later for IFN- analysis.
Immunohistology.
A portion of the pancreata obtained from the mice was fixed in 10% formalin, paraffin embedded, and stained with hematoxylin and eosin. Pancreatic sections were microscopically examined for the presence of insulitis. Paraffin-embedded pancreatic sections were stained with polyclonal guinea pig anti-insulin and anti-glucagon antibodies (Linco Research Immunoassay, St. Charles, MO), followed by a peroxidase-labeled antieCguinea pig IgG secondary antibody (Kirkegaard & Perry Laboratories, Gaithersburg, MD). Subsequently, the sections were counterstained with hematoxylin and coverslipped. Pancreatic frozen sections were stained by monoclonal antibodies to mouse CD4 and CD8 (Becton Dickinson, San Diego, CA). A universal peroxidase-conjugated secondary antibody (Dako, Glostrop, Denmark) was used as the detection system
RESULTS
Poly I:C triggers diabetes in BL/6 B7.1 but not in BALB/c B7.1 mice.
We have recently reported that poly I:C, a mimic of viral double-stranded RNA, can induce diabetes in the BL/6 B7.1 model (with islet-induced expression of the costimulatory molecule B7.1), but diabetes induction is decreased when backcrossing the B7.1 transgene onto the BALB/c strain (20). Consistent with prior observations, 78% of the BL/6 B7.1 mice developed diabetes by 20 weeks of age with poly I:C administration (Fig. 1) and 66% of the BC1 B7.1 mice developed diabetes with poly I:C. Only 10% of the BALB/c B7.1 (backcross 10) became diabetic with poly I:C.
C57BL/6 (0/10), BC1 (0/8), and BALB/c (0/8) mice that did not express the B7.1 transgene remained diabetes free with poly I:C when followed up to 40 weeks of age (data not shown).
Peak IFN- after poly I:C stimulation is higher in BL/6 B7.1 mice.
To investigate the differential effects of poly I:C on the induction of diabetes in the various models, we studied the pattern of IFN- expression in the serum of these mice after poly I:C administration at 4 weeks of age. We measured IFN- over time following the 6th day of poly I:C administration. Of note, the IFN- response after the first injection (day 1) of poly I:C in the BC1 B7.1 mice, did not demonstrate any detectable IFN- levels when it was measured at similar times (data not shown). On the 6th day of treatment, serum was taken before the injection of poly I:C (the basal level) and at 1, 2, 4, 6, and 12 h postadministration. IFN- levels appeared to peak earlier in BL/6 B7.1 mice (2 h postinjection) than in BC1 B7.1 and BALB/c B7.1 mice (4eC6 h postinjection). The backcross 1 (BC1), BALB/c, and C57BL/6 mice without the B7.1 transgene (five mice in each group) have a much lower peak IFN- response compared with the similar group of mice with the B7.1 transgene (P < 0.01) (Fig. 2A). The mean peak IFN- levels in the BL/6 B7.1 mice was significantly higher than in the BC1 B7.1 and BALB/c B7.1 (P < 0.01) mice. However, despite a difference in susceptibility to diabetes between BC1 B7.1 and BALB/c B7.1 mice, there was no significant difference in peak IFN- levels, suggesting inherent factors other than IFN- susceptibility that might predispose to diabetes (Fig. 2B).
Lymphoid cells (from spleen) induce higher IFN- than islets in BC1 B7.1 mice.
The mean IFN- production from four BC1 B7.1 mouse splenocytes stimulated in vivo with poly I:C and subsequently in vitro was 68.6 pmol/l. This was higher (P < 0.05) when compared with the mean production from lymphocytes (pancreatic lymph nodes) or islets (44.3 and 19.4 pg/ml, respectively) (Table 1). In contrast, cells that were not stimulated in vivo had a much lower mean IFN- induction with in vitro poly I:C stimulation alone (spleen 28.6, lymphocytes 19.9, and islets <12.5 pg/ml). In BC1 B7.1 mice that were given poly I:C in vivo but not in vitro, splenocytes, lymphocytes, and islet induction of IFN- were (mean) 17.8, <12.5, and <12.5 pg/ml, respectively. In BC1 mice without the B7.1 transgene, only splenocytes stimulated in vivo and in vitro induced any detectable IFN- (14.4 pg/ml). Of note, all four mice in each group had detectable IFN-, except the B7.1-negative group of splenocytes given poly I:C in vivo and in vitro (mean 14.4 pg/ml), in which two of the four mice had detectable levels.
Peak IFN- after poly I:C stimulation is higher in diabetic mice and correlates to age of onset of diabetes.
A total of 50 BC1 B7.1 mice were divided according to phenotype as diabetes or no diabetes by 40 weeks of age, and the peak IFN- levels were compared for these two groups (Fig. 3). The mean peak IFN- levels were significantly (P < 0.001) higher in the group that progressed to diabetes compared with the nondiabetic group. BC1 B7.1 mice were divided into "high" IFN- responders (rise in IFN- 25 pg/ml from the basal level) and "low" IFN- responders (rise of <25 pg/ml from basal level), and diabetes incidence was compared (Fig. 4). By life-table analysis, an IFN- response of >25 pg/ml is highly predictive of diabetes development (positive predictive value 82%). Finally, the peak IFN- levels were compared with the time to onset (age) of diabetes in the poly I:CeCtreated BC1 B7.1 mice. There was a significant inverse correlation (r = eC0.58, P < 0.01) between the age of onset of diabetes with the peak IFN- levels (Fig. 5). These data taken together suggest that the mechanism of diabetes induction with poly I:C in the B7.1 model may involve IFN-.
Neutralizing IFN- after poly I:C induction prevents diabetes in BL/6 B7.1 and BC1 B7.1 mice.
Administration of a monoclonal antibody to IFN- prevented diabetes in all BL/6 B7.1 mice treated with poly I:C (Fig. 6). A similar effect was observed in the BC1 B7.1 mice, whereby only 1 of 12 mice developed diabetes when the monoclonal antibody was coadministered with poly I:C.
Recombinant mouse IFN- induces diabetes in BC1 B7.1 mice.
To further support the role of IFN- in the induction of diabetes in this B7.1 model, recombinant mouse IFN- was administered to BC1 B7.1 mice. Of the 10 BC1 B7.1 mice, 4 developed diabetes in a similar time period when compared with the survival curve using poly I:C alone (P = 0.12 for the IFN- group compared with the poly I:C group) (Fig. 7).
CD4- and CD8-positive staining in islets of poly I:CeCinduced diabetic mice.
Lymphocytic infiltration of the islets (insulitis) is a hallmark of autoimmune type 1A diabetes. Poly I:CeCtreated mice displayed the characteristic CD4 and CD8 T-cell infiltrate in the islets of the pancreas at the time of diabetes onset (Fig. 8A and B). The pancreas in mice that developed diabetes after the administration of recombinant mouse IFN- also showed a similar pattern of insulitis (Fig. 8C and D). In contrast, mice that were given monoclonal antibody to IFN- to block poly I:C disease induction showed no evidence of CD4 and CD8 infiltration when killed at the age of 30 weeks (Fig. 8E and F). Interestingly, mice that did not develop diabetes with poly I:C administration when studied at 40 weeks of age did not show any evidence of insulitis (Fig. 8G and H), suggesting an "all or none" phenomenon in this model of poly I:CeCinduced diabetes.
DISCUSSION
Viruses are considered important environmental agents that may initiate -cell destruction in genetically susceptible individuals (6). The double-stranded RNA viral mimic poly I:C has been extensively used in various experimental models to mimic part of the pathophysiology of viral infections. In this study, we investigated the mechanisms of poly I:CeCinduced diabetes using BL/6 mice that express the B7.1 costimulatory molecule in the pancreatic islets. This study confirms our previous report that the sensitivity to induce diabetes using poly I:C is lost when the B7.1 transgene on a C57BL/6 background is backcrossed onto BALB/c mice (20).
To investigate the pathway that may be responsible for the diabetes phenotype related to poly I:C sensitivity, IFN- response was studied. It was interesting to note that the presence of B7.1 in the islet -cells is critical for a robust IFN- response to poly I:C. Lymphoid cells from the spleen can be a source of IFN- induction in our diabetes induction model with poly I:C. IFN- produced primarily by plasmacytoid dendritic cells is a potent component of the antiviral innate immune response and modulates adaptive immunity (22). Primary control of IFN- production occurs at a cellular level and is highly dependent upon regulatory factors and their products. One potential explanation for a higher IFN- response seen in mice with the islet RIP B7.1 transgene compared with mice without the B7.1 transgene is that B7.1 acts as an enhancer of immune activation within islets or nonislet tissues (23). It is known that B7.1 can transform nonprofessional antigen-presenting cells (APCs), such as islets, into competent APCs that trigger autoimmunity when additional factors such as local inflammation (24), upregulated major histocompatibility complex Ag expression (25), or high numbers of potentially autoreactive T-cells (26) are present. Therefore, disease induction by IFN- may require both immune system activation and target organ inflammation, such as -cell major histocompatibility complex class I upregulation, as suggested by a recent report by Zinkernagel et al. (27). The expression of IFN- appears to reflect an important biological activity in these mice. A higher peak IFN- is observed in diabetic compared with nondiabetic mice. Furthermore, the level of poly I:CeCinduced IFN- predicts diabetes in both the frequency and time to onset of diabetes. Earlier onset of diabetes is correlated to a higher peak IFN- level. While it is possible that induced IFN- is only a reflection of islet inflammation in pre-diabetic mice, our data incriminate IFN- in playing a role in disease pathogenesis.
The data provide evidence that the pathway of poly I:CeCinduced diabetes in this model is IFN- dependent. The neutralization of IFN- with a monoclonal antibody suppressed the incidence of poly I:CeCinduced diabetes in the BL/6 B7.1 mice. Also, the administration of IFN- alone, similar to poly I:C alone, is capable of inducing diabetes in this model. Furthermore, we have shown that the islet cells of the B7.1-positive mice were not the main cells responsible for IFN- production. It is clear from our study that IFN- could not be detected after only 1 day of poly I:C administration, but once the mouse was primed with poly I:C for 5 days, IFN- levels could be detected.
IFN- is used in the treatment of persistent hepatitis B and C infections and various malignancies (28). IFN- has antiviral, cytostatic, and prominent immunomodulatory effects, all of which are of great importance during viral infections. However, prolonged exposure of the immune system to type 1 IFN in the treatment of such diseases can break tolerance and initiate an autoimmune reaction, eventually leading to autoimmune disease. Autoimmune diseases implicated with IFN- therapy include thyroiditis, autoimmune gastritis, psoriasis, systemic lupus erythematosis, and rheumatoid arthritis (29eC31). In addition, there have been numerous case reports of type 1A diabetes or islet autoantibody expression with IFN- therapy (7). Our current data suggest that IFN- serves as a link between the innate response to poly I:C and the adaptive immune response that eventually leads to the induction of autoimmune diabetes.
In tissue culture, IFN- can decrease insulin synthesis and secretion (32,33). Furthermore, human -cells show a marked induction of oligoadenylate synthase (marker of apoptosis induction) with IFN- (34). IFN- can also have a direct cytolytic effect on -cells or an indirect effect by activating the innate immune system (7). In one particular study, investigators evaluated the expression of messenger RNA for a series of cytokines in the pancreas and islets of patients with and without type 1A diabetes. They found that only IFN- was significantly overexpressed in diabetic patients (9). Elevated IFN- levels have also been documented in the serum of adult diabetic patients (35,36). In almost all cases of new-onset type 1A diabetes, pancreatic -cells contained IFN-, which correlated with overexpression of the IFN- gene (37).
We have demonstrated a quantitative correlation of IFN- levels and progression to diabetes in the poly I:C RIP-B7.1eCinduced diabetes model. We speculate that viral infections through the generation of double-stranded RNA may induce IFN- that in turn, in a genetically susceptible individual (e.g., DR3/4-DQ2/DQ8), will trigger anti-islet autoimmunity. Therefore, the response to IFN- may be an important component of type 1A diabetes risk, and pharmacologic regulation of the pathway may be important for disease prevention.
ACKNOWLEDGMENTS
This research was supported by grants from the National Institutes of Health (NIH) (DK 055969, DK 062718, and AI 055466), the Autoimmunity Prevention Center U19 (AI 050864), the Diabetes Endocrine Research Center (P30 DK57516), the American Diabetes Association, the Juvenile Diabetes Foundation, and the Children’s Diabetes Foundation. D.D. is supported by an Eli Lilly fellowship award, and E.L. is supported by an NIH grant (DK 06405).
FOOTNOTES
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
IFN, interferon; poly I:C, polyinosinic:polycytidylic acid; RIP, rat insulin promoter
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