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PubMed1988

Identification of T cell subsets and class I and class II antigen expression in islet grafts and pancreatic islets of diabetic BioBreeding/Worcester rats.

The BioBreeding/Worcester (BB/Wor) rat develops a spontaneous disorder that closely resembles human insulin-dependent (Type I) diabetes mellitus. The syndrome is preceded by lymphocytic insulitis that destroys pancreatic beta cells. The morphologic features of the spontaneous insulitis lesions are also observed within islets transplanted beneath the renal capsule of diabetes-prone and diabetic animals. This study reports the results of experiments in which immunohistochemical techniques were used to characterize the phenotype of the infiltrating mononuclear cells and detect the expression of class I and class II MHC antigens in native islets and islet transplants in diabetic and diabetes-prone BB/Wor rats. The infiltrates within native pancreatic islets and islet grafts were comprised predominantly of Ia+ cells (dendritic cells and macrophages) CD4+ cells (helper/inducer lymphocytes and macrophages), CD5+ (pan-T) cells and smaller numbers of CD8+ (cytotoxic/suppressor and NK) cells. Pancreatic and graft insulitis were accompanied by markedly enhanced class I antigen expression on islet and exocrine cells. Class II (Ia) antigens were not detected on normal islet cells, islets undergoing insulitis or on islet transplants subjected to immune attack. In islet grafts stained with polymorphic MAbs that distinguish Ia antigens of donor and host origin, Ia antigen expression was limited to infiltrating dendritic cells and macrophages of host origin. It is concluded that the phenotypes of infiltrating mononuclear cells that comprise the insulitis lesion in spontaneous BB/Wor diabetes, and the inflammatory attack on islets transplanted into diabetic BB/Wor rats are the same, that pancreatic islet and graft insulitis occur in the presence of enhanced class I antigen expression but in the absence of class II antigen expression, and that infiltrating Ia+ cells within islet grafts are exclusively of recipient (BB/Wor) origin and may explain the initiation of immune insulitis within grafts derived from donors of incompatible MHC.

Animals↗
PubMed1992

The microanatomy of canine islets of Langerhans: implications for intra-islet regulation.

In recent years models for the internal ("intra-islet") regulation of hormone secretion have been proposed to explain how different islet cells might regulate each other by means of their respective secretory peptides. Models that emphasize the importance of a directed intra-islet blood flow and sequence of perfusion of islet cells rely on a certain type of islet microanatomy and vascular supply. The experimental studies underlying these models have partly been performed in dogs. To extend the incomplete morphological knowledge of the canine endocrine pancreas both canine islets of Langerhans and extrainsular cells have been analysed in immunostained serial semithin (0.5 microns) sections. In addition to their occurrence within islets of Langerhans, all endocrine cell types are also found at extrainsular sites (about 9% of all endocrine cells) where they are distributed in different quantities among the epithelial lining of exocrine acini or excretory ducts and the connective tissue. There are continuous transitions from single extrainsular cells to small mono- and polycellular cell groups to islets. In a comprehensive analysis of whole islets, including computer-assisted three-dimensional reconstructions, the size, shape and vascularization of the islets as well as their cellular composition and the microtopology of islet cells have been studied. We have found marked intra- and inter-islet heterogeneities of the parameters investigated that are not compatible with concepts of a uniform and directed vascular perfusion of the various islet cell populations. Instead, their paracrine regulation may occur primarily via hormonal secretion into the intercellular spaces or vascular hormonal delivery to adjacent cells.

Animals↗
PubMed1990

Human pancreatic islet cell specific 38 kilodalton autoantigen identified by cytomegalovirus-induced monoclonal islet cell autoantibody.

Our previous finding that about 15% of newly diagnosed patients with Type 1 (insulin-dependent) diabetes mellitus had human cytomegalovirus genome in their lymphocytes and islet cell autoantibodies in their sera, suggests that autoimmune Type 1 diabetes is associated with persistent cytomegalovirus infection under certain circumstances. This investigation was initiated to see if cytomegalovirus can induce islet cell autoantibodies and if the autoantibodies react with any specific islet protein(s). Monoclonal antibodies were generated after immunizing Balb/c mice with human cytomegalovirus. When these monoclonal antibodies were tested for the presence of islet cell antibodies were tested for the presence of islet cell antibodies, one (MCMVA-51) of 13 monoclonal antibodies reacted strongly with the islets. The titer of islet cell antibodies was 1:2000. When this monoclonal antibody was reacted with the proteins from the solubilized fraction of human pancreatic islets using the western immunoblotting technique, a band with a molecular weight of 38 kilodalton was detected. The 38 kilodalton band was not observed when the monoclonal antibody was reacted with the proteins prepared from pancreatic islet tissues of rats and mice or from other human organs including stomach, liver, spleen and brain, indicating that the 38 kilodalton protein is human islet cell-specific. It is concluded that human cytomegalovirus can induce islet cell antibodies that react with a 38 kilodalton human islet cell protein and that this protein component may represent islet cell-specific target antigens associated with persistent cytomegalovirus infection.

Animals↗
PubMed1996

Microsphere distribution in the pancreas of anesthetized rats. Alloxan stimulates the blood flow to all islets whereas glucose only affects the blood perfusion of a subgroup of islets.

CONCLUSION: Islet blood flow stimulation induced by alloxan leads to an increased blood perfusion in all islets, whereas glucose induces a flow increase only in a subgroup of islets. BACKGROUND: The aim of the present study was to investigate if an increased islet blood flow was associated with an enhanced total number of perfused islets, or whether only a subgroup of the islets increased their blood flow. METHODS: For this purpose, the whole pancreatic and islet blood flow was measured with a microsphere technique (4.5 x 10(5) microspheres/kg body wt) in anesthetized Sprague-Dawley rats. Blood flow measurements were made 3 min after an i.v. injection of 1 mL of saline, alloxan (75 mg/kg body wt), or D-glucose (300 mg/mL). RESULTS: Alloxan reduced whole pancreatic blood flow by 50%, but almost doubled islet blood flow. Glucose did not affect whole pancreatic blood flow, but increased islet blood flow 100%. Approximately 10% of the islets in control and glucose-injected rats contained microspheres, compared with about 25% in alloxan-injected rats (P < 0.001). When the islets containing a certain number of microspheres were compared, alloxan induced a homogeneous shift of the curve to the right, i.e., increased the number of islets that contained all amounts of microspheres. Glucose preferentially increased only the fraction of islets containing > or = 3 microspheres.

Alloxan↗
PubMed1991

Species differences in human and rat islet sensitivity to human cytokines. Monoclonal anti-interleukin-1 (IL-1) influences on direct and indirect IL-1-mediated islet effects.

Species differences in sensitivity to human recombinant cytokines were observed when human or rat islets were co-cultured with human recombinant cytokines for 6 days. Suppression of both human and rat islet insulin secretion resulted from co-culture with recombinant interleukin-1 alpha (rIL-1 alpha) or interleukin-1 beta (rIL-1 beta); however, direct rIL-1 alpha and rIL-1 beta cytotoxicity was seen with rat islets but not with human islets. Human islet insulin secretion was also suppressed during co-culture with recombinant tumor necrosis factor (rTNF) or interferon (rIFN), but not with lymphotoxin (rLT) or rIL-6; rat islet insulin secretion was not suppressed by any of these cytokines. No direct cytotoxic effects resulted from co-culture of human islets with rLT, rTNF, rIFN, or rIL-6; rLT was slightly cytotoxic for rat islets. Human islet cytotoxic synergy occurred between rLT and rIL-1 alpha, rIL-1 beta, or rIFN; synergy in suppression of human islet insulin secretion occurred between rLT and rIL-1 beta, and between rIFN and rTNF. Pretreatment of rIL-1 with monoclonal antibody (mAb) specific for non-crossreactive epitopes on rIL-1 alpha (H43 and H12) or rIL-1 beta (H34 and H21) prevented islet cytotoxic synergy between rIL-1 alpha or rIL-1 beta, respectively, and rLT. Although all four mAb's neutralize the thymocyte and fibroblast stimulatory activities of rIL-1 alpha or rIL-1 beta, mAb H21 does not neutralize rIL-1 beta activity against rat islets. Implications for cytokine-mediated islet cytotoxicity and suppression of insulin secretion are discussed.

Animals↗
PubMed2003

Pancreas preservation by the 2-layer cold storage method before islet isolation protects isolated islets against apoptosis through the mitochondrial pathway.

BACKGROUND: Apoptosis in isolated islets has been implicated in primary nonfunction or early graft failure after islet transplantation. Recently, pancreas preservation by the 2-layer method (TLM) before islet isolation has been proved to improve the islet yield, quality, and transplant results not only in experimental models, but also in clinical settings. We examined the influence of TLM on apoptosis of isolated islets. METHOD: Rat islets freshly isolated and after pancreas preservation by TLM or conventional cold storage in University of Wisconsin solution (UW) were examined and compared. Islet apoptosis was assessed by TUNEL and annexin V assays. The apoptosis pathways involved were investigated by measurement of caspase 3, 8, and 9 activities and by immunoblotting for total and phosphorylated c-Jun NH2-terminal kinase (JNK) and p38. RESULTS: Islet apoptosis in the UW group was significantly increased compared with the fresh and TLM groups. Both caspase 3 and 9 activities in the UW group were higher than in the fresh and TLM groups with an approximate increase of 2- to 3-fold. On the other hand, there was no significant difference in caspase 8 activity among these 3 groups. JNKs were strongly activated both in the TLM and UW groups; although they were not activated in the fresh group, p38 was activated to almost the same levels in these 3 groups. CONCLUSIONS: Pancreas preservation by TLM before islet isolation protects isolated islets against apoptosis mainly through the mitochondrial pathway. Pancreas storage before islet isolation even with TLM triggers activation of JNKs in isolated islets.

Animals↗
PubMed1994

Intra- and extracellular amyloid fibrils are formed in cultured pancreatic islets of transgenic mice expressing human islet amyloid polypeptide.

Islet amyloid polypeptide (IAPP) is the constituent peptide of amyloid deposits found in the islets of non-insulin-dependent diabetic patients. Formation of islet amyloid is associated with a progressive destruction of insulin-producing beta cells. Factors responsible for the conversion of IAPP into insoluble amyloid fibrils are unknown. Both the amino acid sequence of human IAPP (hIAPP) and hypersecretion of hIAPP have been implicated as factors for amyloid fibril formation in man. We have generated transgenic mice using rat insulin promoter-hIAPP or rat IAPP (rIAPP) gene constructs. No fibrillar islet amyloid was detectable in vivo in these normoglycemic mice, although small amorphous perivascular accumulations of IAPP were observed in hIAPP mice only. To determine the effects of glucose on IAPP secretion and fibrillogenesis, pancreatic islets from transgenic and control mice were examined in vitro. Islet IAPP secretion and content were increased in transgenic islets compared with control islets. IAPP-immunoreactive fibrils were formed at both intra- and extracellular sites in isolated hIAPP islets cultured with glucose at 11.1 and 28 mM for only 7 days. At 28 mM glucose, fibrils were present in deep invaginations of beta cells as observed in non-insulin-dependent diabetic patients. No fibrils were present at low glucose concentrations in hIAPP islets or at any glucose concentration in rIAPP or control islets. Thus, glucose-induced expression and secretion of hIAPP in transgenic mouse islets can lead to formation of amyloid fibrils similar to that found in non-insulin-dependent diabetes mellitus.

Amyloid↗
PubMed2004

Caspase-3 inhibitor prevents apoptosis of human islets immediately after isolation and improves islet graft function.

OBJECTIVES: Apoptosis appears in islets after isolation, and it has a detrimental effect on the islet function. To improve the outcome of clinical islet transplantation, it is crucial to protect islets from apoptosis. The aim of this study was to determine whether a caspase-3 inhibitor (Z-DEVD-FMK) added to culture media protects islets from apoptosis and to compare the effects of fetal bovine serum (FBS) with human serum albumin (HSA) as a protein supplement in culture. METHODS: Isolated human islets were cultured under 4 different conditions: 0.5% HSA (control), 0.5% HSA + 25 micromol/L Z-DEVD-FMK, 0.5% HSA + 100 micromol/L Z-DEVD-FMK and 10% FBS for 2 days. Next, 1000 IEQ islets precultured with 0.5% HSA and with or without 100 micromol/L Z-DEVD-FMK were transplanted to diabetic nude mice. RESULTS: The islet yields were higher in Z-DEVD-FMK-treated groups, and the inhibitor prevented apoptosis dose dependently. The yield and insulin release were higher in FBS-treated group than in the control group, but FBS did not affect apoptosis. All 6 mice transplanted with islets pretreated with Z-DEVD-FMK, and 3 of 8 mice with control islets became normoglycemic posttransplantation. CONCLUSION: Z-DEVD-FMK prevented apoptosis of isolated human islets and improved its function. FBS (10%) improved the islet yield and insulin secretion more than 0.5% HSA.

Adult↗
PubMed1999

Neonatal pig islets induce a lower T-cell response than adult pig islets in IDDM patients.

BACKGROUND: Pancreatic pig islets may provide a substitute in the future for difficult to obtain human islets for transplantation in insulin-dependent diabetes millitus (IDDM) patients. However, the immune response to xenografts may significantly hamper this approach. Because neonatal tissue is believed to be less immunogenic, we examined whether the T-cell response to neonatal pig islets differs from the response to adult islets. METHODS: The T-cell proliferative response to different concentrations of sonicated neonatal and adult pig islets, as well as to insulin and mitogens, was tested in 21 recent onset IDDM patients and 21 healthy controls. We determined the presence of various circulating islet autoantibodies and their association with the T-cell response in IDDM patients. RESULTS: In the IDDM patients, sonicated adult pig islets (at 1 microg protein/ml) induced a significantly higher frequency (12 of 21 vs. 1 of 21, p<0.001) and magnitude (2.58+/-0.44 vs. 1.38+/-0.13, p<0.02) of positive T-cell responses than neonatal islets at the same concentration. Similar results were obtained with a 10-fold higher concentration of islet sonicate. There was no significant association between the individual T-cell responses and the presence of circulating autoantibodies in IDDM patients. CONCLUSION: These results indicate that neonatal pig islets induce a lower T-cell reactivity than adult islets, suggesting that the neonatal tissue may be immunologically more suitable for future islet xenotransplantation.

Adolescent↗
PubMed2005

Cell permeable peptide of JNK inhibitor prevents islet apoptosis immediately after isolation and improves islet graft function.

Although application of the Edmonton protocol has markedly improved outcomes for pancreatic islet transplantation, the insulin independence rate after islet transplantation from one donor pancreas has proven to remain low. During the isolation process and subsequent clinical transplantation, islets are subjected to severe adverse conditions that impair survival and ultimately contribute to graft failure. Pancreas preservation with the two-layer method (TLM) has proven to improve transplant results by protecting isolated islets against apoptosis through the mitochondrial pathway. However, pancreas storage with TLM cannot protect against activation of c-Jun NH2-terminal kinase (JNK) in isolated islets. This study investigated whether delivery of a JNK inhibitory peptide (JNKI) via the protein transduction system can prevent apoptosis of islet cells immediately after isolation. For efficient delivery of the (JNKI into isolated islets, we synthesized JNKI as a C-terminal fusion peptide with the 11-arginine protein transduction domain (11R-JNKI). 11R efficiently delivered the JNKI into isolated islets and 11R-JNKI prevented islet apoptosis immediately after isolation and improved islet graft function. These findings suggest that peptide drugs could be useful for the prevention of the impairment of islet cells and lead to improvement in the outcomes for pancreatic islet transplantation.

Amino Acid Sequence↗
PubMed2006

Minimization of immunosuppressive therapy after islet transplantation: combined action of heme oxygenase-1 and PEGylation to islet.

We previously established a type of PEGylated islets to attenuate cellular immune reactions by immobilizing polyethylene glycol (PEG) molecules on islet surfaces, thereby synergistically reducing the dose of immunosuppressant cyclosporine A (CsA; 3 mg/kg/day) to protect transplanted islets. However, higher doses of immunosuppressants should be administered after islet transplantation due to nonspecific inflammation. This study documents that PEGylated islets can be cooperatively protected by the systemic overexpression of heme oxygenase-1 (HO-1), which has a potent cytoprotective function in preventing nonspecific inflammation during an early stage following islet transplantation. Under this scheme, the viability of PEGylated islets was improved; that is, PEG molecules could block cellular immunity and HO-1 could exert its cytoprotective property against inflammation. Interestingly, when employed with a low dose of CsA (1 mg/kg/day), a cooperative action of PEG molecules and HO-1 in immune reactions could result in the complete survival of transplanted islets for 100 days without islet function impairment. However, unmodified islets (control) were completely rejected within 2 weeks despite cotreatment with HO-1 expression and CsA. These results demonstrated that the combinatorial protocol of initial induction of HO-1 expression, followed by the daily administration of a low dose CsA after transplantation of PEGylated islets can be employed as a successful cell therapy in clinical islet transplantation.

Animals↗
PubMedDate not supplied

Islet cell transplantation: in vivo and in vitro functional assessment of nonhuman primate pancreatic islets.

Transplantation of pancreatic islets of Langerhans as a therapeutic approach for treatment of type I diabetes offers an alternative to subcutaneous insulin injections. Normalization of blood glucose levels by transplanted islets may prevent the development of diabetes-related complications. Problems related to rejection, recurrence of autoimmunity, and local inflammation upon transplantation of islets into the liver need to be solved before the implementation of islet cell transplantation can be viewed as a justifiable procedure in a large cohort of patients. Islet cell isolation has been quite successful in small animals, but the translation of this approach to nonhuman primates has been less rewarding. One of the main problems encountered in nonhuman primate models is the difficulty of isolating an adequate number of functional islets for transplantation. The aim of the present study was to develop a method for isolating a sufficient number of viable islets from nonhuman primates to allow for reversal of diabetes. By implementing minor modifications in the automated method for human islet isolation we were able to obtain viable, functional islets that responded normally to glucose stimulation in vitro. These islets were also able to reverse diabetes in immunocompromised nude mice, rendered diabetic by streptozotocin. This method of islet cell isolation has enabled us to proceed with protocols of allogeneic islet cell transplantation in preclinical, nonhuman primate models.

Animals↗
PubMed2003

The effect of FasL gene transfer to islet cells on pancreatic islet allografts.

OBJECTIVE: To investigate the effect of FasL gene transfer to islet cells on pancreatic islet allografts. METHODS: A recombinant and replication-deficient type-5 adenovirus encoding murine FasL (AdV- FasL) was constructed by the method of calcium phosphate precipitation. Pancreatic islets were infected with the recombinant adenovirus AdV-FasL, and transplanted into diabetic recipients. FasL expression was detected by RT-PCR and immunohistochemistry. The survival of allografts and the apoptosis of gene transferred islet allografts were analyzed. RESULTS: All animals receiving islet allograft alone returned to a diabetic state by several days (mean survival time 6.3+/-0.6 days). Compared with the control group, no delayed rejection and prolonged survival of allografts were observed in the group of FasL gene transfer. The rejection was accelerated and the allograft survival was shortened to 3.4+/-0.2 days (P<0.05). Pancreatic islets infected with AdV- FasL demonstrated positive staining of FasL at 24 h, with an increased intensity at 48 h, but not in AdV-5 infected or uninfected islets. TUNEL labeling of pancreatic islet allografts at 24, 48 h revealed apoptosis that was not in AdV-5 infected allografts. CONCLUSIONS: Though co-transplantation of FasL-expressing testicular cells can induce privilege of islet allografts and prolong allograft survival, direct expression of FasL on islet allografts infected with AdV-FasL may accelerate islets rejection by islet apoptosis and granulocyte infiltration.

Adenoviridae↗
PubMed2004

[Improvement of massive human islet isolation techniques and the evaluation of isolated human islets].

OBJECTIVE: To obtain massive human pancreatic islets with modified techniques and evaluation of the islets for the clinical allo-transplantation to treat type I and II diabetes. METHODS: 28 consecutive adult human pancreata were isolated with modified automated techniques. Islets were purified using continuous density gradient. The islet yield was counted with international standard known as islet equivalent (IEQ). The function of the isolated islets was evaluated by measuring DNA/insulin ratio, static glucose stimulating test in vitro and transplanting the islets into diabetic nude mice in vivo followed by abdominal glucose tolerance test and C peptide measurement. RESULTS: The yield of 28 consecutive human pancreata isolations ranged from 5 000 to 1 030 000 IEQs/pancreas with the average of 291 635 IEQs/pancreas. The first 13 isolations yielded 49 123 IEQs/pancreas, 846 IEQs/g and, purity 87% in average. The remained 15 isolations after the modifications yielded 501 813 IEQs/pancreas, 7 003 IEQs/g and purity 89% in average. The results of in vitro SGS showed good response to the different glucose concentration. 34 diabetic nude mice were transplanted under the renal capsule with the freshly isolated islets. 29 out of 34 diabetic mice obtained normoglycemia within 12 hours and the glucose tolerance tests were near normal. Serum C peptide level of transplanted mice is close to that of the control group. CONCLUSIONS: Massive human islets can be isolated with the modified techniques. Quality assessment of these islets both in vitro and in vivo has indicated that these high quality human islets could be used for the clinical allogeneic islet transplantation.

Adult↗
PubMed1984

[Allotransplantation of isolated pancreatic islets in diabetic rats. Effect of culture on islet rejection].

Reduction of the immunogenicity of the tissue by tissue culture has been a controversial concept in transplantation immunology. In the present study, isolated islets were cultured prior to allotransplantation. The obtained results were compared in comparison with the results of the non-cultured islet allotransplantation group. Two kinds of rats differing from each other in histocompatibility antigen were used. WKA rats ( RT1k ) were donors, and LEJ rats ( RT1j ) recipients. No immunosuppressive agents were given. About 500 isolated islets of the donors were transplanted to the spleen of the recipients with streptozotocin induced diabetes mellitus. Although the mean survival time of non-cultured islet was 12.2 +/- 4.3 days, that of 7-day cultured islet increased significantly to 26.4 +/- 4.8 days. The response of the lymphocytes to the islets was also examined by mixed lymphocyte-islet culture. Response of lymphocytes to non-cultured islet was compared with that of lymphocytes to 7-day cultured islets. The response of lymphocytes to the 7-day cultured islets was significantly decreased. These results suggested that the cultured islet prolongs survival time and islet culture diminish the concentration or availability of stimulatory antigens on the cell surface membranes.

Animals↗