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L Bouwens

Publications and source records attributed to L Bouwens.

At least 19 recordsLinked to original sources
PubMed2003

Netrin-1 expression in fetal and regenerating rat pancreas and its effect on the migration of human pancreatic duct and porcine islet precursor cells.

AIMS/HYPOTHESIS: We investigated the expression and function of netrin-1, a diffusible laminin-like protein known to regulate neuronal-cell migration in the pancreas. We questioned whether this factor regulates migration of pancreatic epithelial cells and whether this could be involved in islet neogenesis. METHODS: We studied fetal and adult rat pancreas wherein duct ligation induced islet neogenesis. Netrin-1 expression was analysed by RT-PCR, western blot and immunohistochemistry. In vitro cell migration was measured with a human pancreatic duct cell line (CAPAN-2) and with fetal porcine islet cells. We also studied the expression of two netrin-receptors, neogenin and deleted in colorectal cancer. RESULTS: We found a transient expression of netrin-1 mRNA and protein in fetal pancreas from E15 to E18, and in adult pancreas after duct ligation. In normal adult pancreas there was very little netrin-1 expression. Netrin-1 expression was observed both in endocrine and exocrine cells. At the immunohistochemical level, it was expressed by islet cells during tissue regeneration. We could show that netrin-1 increases the migration of fetal islet cells and of a ductal cell line, mainly via a chemokinetic effect. From the two well-established netrin receptors, DCC and neogenin, we only found neogenin to be expressed in the pancreas. Neogenin expression coincided with the period of netrin-1 up-regulation. CONCLUSION/INTERPRETATION: Netrin-1 is involved in pancreatic morphogenesis and tissue remodelling and plays a role in the regulation of duct-cell and fetal-islet cell migration. This can be of importance in islet regeneration, where migration of islet precursors takes place.

Adenocarcinoma↗
PubMed2001

Mitogenic effect of gastrin and expression of gastrin receptors in duct-like cells of rat pancreas.

BACKGROUND & AIMS: Ductular metaplastic cells are observed during pancreas injury. Growth control by gastrin and expression of gastrin/cholecystokinin (CCK) B receptors were evaluated in these cells. METHODS: Acinoductal transdifferentiation was induced in vitro by culturing of acinar cells, and ductular metaplasia was obtained in vivo by ligation of the pancreatic ducts. Mitogenic effects of gastrin I on ductal complexes in vivo and of tetragastrin, pentagastrin, and gastrin I and II, with or without the CCK-B receptor antagonist L-365,260, on duct-like cells in vitro were analyzed by 5-bromo-2'-deoxyuridine labeling. Immunocytochemistry, Western blotting, and reverse-transcription polymerase chain reaction were applied for detection of the CCK-B receptor. RESULTS: Gastrin analogues induced a mitogenic stimulus in the duct-like cells in vitro and in ductal complexes in duct-ligated rat pancreas. Immunocytochemistry showed expression of CCK-B receptors in these models and in fetal but not normal adult exocrine pancreas. Additionally, up-regulation of CCK-B receptors during ductular metaplasia was shown by Western blotting and reverse-transcription polymerase chain reaction. CONCLUSIONS: Duct-like pancreatic epithelial cells in vitro and ductal complexes in vivo express gastrin/CCK-B receptors and proliferate in response to gastrin.

Animals↗
PubMed2001

Role of pancreatic beta-cells in the process of beta-cell death.

Studies on the pathogenesis of type 1 diabetes have mainly focused on the role of the immune system in the destruction of pancreatic beta-cells. Lack of data on the cellular and molecular events at the beta-cell level is caused by the inaccessibility of these cells during development of the disease. Indirect information has been collected from isolated rodent and human islet cell preparations that were exposed to cytotoxic conditions. This article reviews in vitro experiments that investigated the role of beta-cells in the process of beta-cell death. beta-Cells rapidly die in necrosis because of toxic levels of oxidizing radicals or of nitric oxide; they progressively become apoptotic after prolonged culture at low glucose or with proinflammatory cytokines. Their susceptibility to necrosis or apoptosis varies with their functional state and thus with the environmental conditions. A change in cellular phenotype can alter its recognition of potentially cytotoxic agents and its defense mechanisms against cell death. These observations support the view that beta-cells are not necessarily passive victims of a cytotoxic process but can actively participate in a process of beta-cell death. Their role will be influenced by neighboring non-beta-cells, which can make the islet internal milieu more protective or toxic for the beta-cells. We consider duct cells as potentially important contributors to this local process.

Animals↗
PubMed2000

Modulation of rat pancreatic acinoductal transdifferentiation and expression of PDX-1 in vitro.

AIMS/HYPOTHESIS: In adult pancreatic regeneration models exocrine acini are found to transdifferentiate to duct-like complexes. This has also been associated with the formation of new endocrine islet cells. We aimed to establish an in vitro model in which this transdifferentiation process is characterised and can be modulated. METHODS: Purified rat pancreatic acini were cultured in suspension. Differentiation was analysed by immunocytochemistry, electron microscopy, western blotting and RT-PCR. RESULTS: During culture acinar cells directly transdifferentiated without dividing, the cells lost their acinar phenotype and started to express cytokeratins 20 and 7 and fetal liver kinase-1 (Flk-1) receptors for vascular endothelial growth factor. Expression of the acinar pancreatic exocrine transcription factor (PTF-1) remained and the pancreatic duodenal homeobox-containing transcription factor (PDX-1) was induced. When transdifferentiation was completed, the cells started to express protein gene product 9.5, a panneuroendocrine marker. By combining these features, the transdifferentiated cells show similar characteristics to precursor cells during active beta-cell neogenesis. We were able to modulate the differentiation state by addition of nicotinamide or sodium butyrate, agents which are known to stimulate endocrine differentiation in other models. CONCLUSION/INTERPRETATION: Here, we present an in vitro system in which the cellular differentiation of putative pancreatic endocrine precursor cells and their PDX-1 expression can be modulated, thereby providing a possible model for the study of beta-cell transdifferentiation.

Animals↗
PubMed2000

Endocytosis of low-density lipoprotein by human pancreatic beta cells and uptake in lipid-storing vesicles, which increase with age.

Studies with I(125)-labeled low-density lipoproteins (LDLs) have shown the presence of high-affinity LDL receptors on insulin-producing beta cells but not on neighboring alpha cells. By using gold-labeled lipoproteins, we demonstrate receptor-mediated endocytosis of LDLs and very low-density lipoproteins in rat and human beta cells. Specific for human beta cells is the fusion of LDL-containing endocytotic vesicles with lipid-storing vesicles (LSVs; diameter, 0.6-3.6 microm), which are absent in rodent beta cells. LSVs also occur in human pancreatic alpha and duct cells, but these sequester little gold-labeled LDL. In humans <25 years old, LSVs occupy 1% of the cytoplasmic surface area in beta, alpha, and duct cells. In humans >50 years old, LSV surface area in beta cells (11 +/- 2% of cytoplasmic surface area) is fourfold higher than in alpha and duct cells and 10-fold higher than in beta cells at younger ages (P < 0.001); the mean LSV diameter in these beta cells (1.8 +/- 0.04 microm) is larger than at younger ages (1.1 +/- 0.2 microm; P < 0.005). Oil red O staining on pancreatic sections confirms that neutral lipids accumulate in beta cells of older donors. We conclude that human beta cells can incorporate LDL and very low-density lipoprotein material in LSVs. The marked increase in the LSV area of aging human beta cells raises the question whether it is caused by prolonged exposure to high lipoprotein levels such as occurs in Western populations and whether it is causally related to the higher risk for type 2 diabetes with aging.

Adolescent↗
PubMed2000

Mechanisms of coxsackievirus-induced damage to human pancreatic beta-cells.

Enteroviruses may be involved in the pathogenesis of insulin-dependent diabetes mellitus, either through direct beta-cell infection or as triggers of autoimmunity. In the present study we investigated the patterns of infection in adult human islet cell preparations (consisting of 56+/-14% beta-cells) by several coxsackieviruses. The cells were infected with prototype strains of coxsackievirus B (CBV) 3, 4, and 5 as well as coxsackievirus A9 (CAV-9). The previously characterized diabetogenic strain of coxsackievirus B4 (CBV-4-E2) was used as a reference. All viruses replicated well in beta-cells, but only CBVs caused cell death. One week after infection, the insulin response of the beta-cells to glucose or glucose plus theophylline was most severely impaired by CBV-3 and CBV-5 infections. CBV-4 also caused significant functional impairment, whereas CAV-9-infected cells responded like uninfected controls. After 2 days of infection, about 40% of CBV-5-infected cells had undergone morphological changes characteristic of pyknosis, i.e. highly distorted nuclei with condensed but intact chromatin. Both mitochondria and plasma membrane were intact in these cells. DNA fragmentation was found in 5.9+/-1.1% of CBV-5-infected beta-cell nuclei (2.1+/-0.3% in controls; P<0.01). CAV-9 infection did not induce DNA fragmentation. One week after infection the majority of infected cells showed characteristics of secondary necrosis. Medium nitrite and inducible nitric oxide synthase messenger ribonucleic acid levels were not significantly up-regulated by CBV infection. These results suggest that several enteroviruses may infect human beta-cells. The infection may result in functional impairment or death of the beta-cell or may have no apparent immediate adverse effects, as shown here for CAV-9. Coxsackie B viruses cause functional impairment and beta-cell death characterized by nuclear pyknosis. Apoptosis appears to play a minor role during a productive CBV infection in beta-cells.

Adult↗
PubMed2000

Adult human pancreatic duct and islet cells exhibit similarities in expression and differences in phosphorylation and complex formation of the homeodomain protein Ipf-1.

The homeodomain transcription factor encoded by the pancreatic and duodenal homeobox gene-1 (Ipf-1) is essential for pancreatic ontogenesis. Whether Ipf-1 is also involved in the neogenesis of beta-cells in the adult pancreas is unknown. We examined whether Ipf-1 is expressed in adult human pancreatic ducts, which are thought to generate new beta-cells. In tissue sections, virtually all duct cells were immunopositive for Ipf-1, as were the islet beta-cells but not the acinar cells. After isolation and culture, both duct and islet cell preparations contained the Ipf-1 immunoreactive proteins p42 and p45 (42 and 45 kDa, respectively) in similar proportions, but the expression levels were twofold lower in duct cells. After 4 h of labeling, the endocrine cells exhibited a sevenfold higher phosphorylation of p42 than the duct cells, whereas p45 was phosphorylated only in endocrine cells. Homeobox binding transcription factor complexes with Ipf-1 in duct cells differed from those in endocrine cells in terms of gel mobility, sequence specificity, and affinity. The observed similarities in Ipf-1 expression by adult human pancreatic duct cells and endocrine cells may reflect their common ontogenic origin, whereas the differences in Ipf-1 phosphorylation and complex formation may correlate with their divergent differentiation.

Adolescent↗
PubMed2000

PACS and multimodality in medical imaging.

A PACS (Picture Archiving and Communication System) is a system that is able to store, exchange, display and manipulate images and associated diagnoses from any modality within a hospital in a timely and cost-effective way. Several developments, such as the DICOM standard, fast and convenient networking, and new storage solutions for large amounts of data, make the setup of such a PACS system possible. As the information acquired with various imaging modalities is then available and often complementary, it is desirable for the clinician to have a point-by-point spatial co-registration of images from different modalities in order to enable a synergistic use of the multimodality imaging of a patient for increased diagnostic accuracy. Various types of algorithms are available for the matching of medical images from the same or from different modalities. Co-registration algorithms based on voxel properties consist of a similarity or dissimilarity measure and an iterative or non-iterative method minimizing the dissimilarity or maximizing the similarity between the two images by a transformation of one image relative to the other.

Belgium↗
PubMed2000

Nonuniform transmission in brain SPECT using 201Tl, 153Gd, and 99mTc static line sources: anthropomorphic dosimetry studies and influence on brain quantification.

UNLABELLED: Nonuniform attenuation correction in brain SPECT can be done routinely by means of additional gamma transmission CT (TCT) measurements, using different commercially available line-source isotopes, 201Tl, 153Gd, and 99mTc are among the most commonly used isotopes, depending on practical and cost-effectiveness issues. We have measured additional radiation burden from static uncollimated brain SPECT transmission sources for these isotopes. The influence of the transmission isotope on brain quantification was also measured and compared with uniform attenuation correction for phantom and human data. Full iterative transmission and emission reconstruction were compared with filtered backprojection techniques. METHODS: Rod sources with 201Tl, 153Gd, and 99mTc were used on a triple-head gamma camera. Dosimetry was performed using LiF TLD-100 pellets and an anthropomorphic RANDO phantom. Effective dose equivalents were calculated on the basis of measured and extrapolated absorbed doses. For brain activity measurements, a Hoffman phantom was used. Images were corrected for scatter (triple-energy window) and were reconstructed by Chang attenuation correction and filtered backprojection as well as full iterative reconstruction (ordered-subsets expectation maximization [OSEM]). To study the effect of inhomogeneous bone attenuation, realistic measurements were performed on 10 young, healthy volunteers with 153Gd TCT. After stereotactic image realignment, a volume-of-interest analysis normalized to total counts was performed. RESULTS: Brain SPECT-TCT using 201Tl, 153Gd, and 99mTc produced total effective dose-rate equivalents of 50.3 +/- 11.2, 32.0 +/- 2.7, and 71.1 +/- 7.1 microSv/GBq x h, respectively, representing dose equivalents of 18.6, 11.9, and 26.3 microSv for a typical 20-min brain SPECT scan at maximal used source strength. Standardized quantification resulted in insignificant differences between the isotopes and methods (Chang versus OSEM) used for nonuniform correction. Iterative reconstruction enhanced image contrast and provided more accurate gray-to-white matter ratios. Between nonuniform and uniform attenuation with an optimized attenuation coefficient, slight central discrepancies were found for volunteer studies. Significantly lower intersubject variation was found for nonuniform corrected values in infratentorial and posterior brain regions. CONCLUSION: Brain transmission scanning using 201Tl, 153Gd, or 99mTc results in limited effective radiation dose equivalents compared with the typical radiation burden. Relative brain perfusion quantification is not significantly different for the various nonuniform TCT isotopes. Iterative reconstruction improves gray-to-white contrasts but has no significant influence on brain perfusion semiquantification. Nonuniform attenuation correction decreases intersubject variability in the posterior brain regions that were compared, which may lead to improved sensitivity toward clinical applications.

Adult↗
PubMed1999

Contribution of ductal cells to cytokine responses by human pancreatic islets.

In type 1 diabetes, autoimmune destruction of pancreatic beta-cells has been attributed to cytokines released from infiltrating immunocytes. Exposure of isolated islets to cytokines leads to nitric oxide (NO) production, which can damage beta-cells. Because ductal cells are closely associated with human beta-cells, we examined whether they can contribute to this process. Isolated human ductal cells were cultured for 48 h with various cytokines. The combination of interleukin-1beta (IL-1beta) plus interferon-gamma (IFN-gamma) increased nitric oxide production 12-fold while stimulating mRNA expression of inducible nitric oxide synthase (iNOS). In this condition, 10-20% of cells positive for the cytokeratin-19 duct marker also stained positive for iNOS protein, whereas no positive cells were found in control preparations. Comparison of the magnitude of iNOS mRNA expression and nitric oxide production in these cells with that in isolated human islets suggests that >50% of total islet nitric oxide production might originate from associated ductal cells. It is concluded that ductal cells are a potential source of nitric oxide production in human islets infiltrated by cytokine-releasing immunocytes.

Adolescent↗
PubMed1998

Transdifferentiation versus stem cell hypothesis for the regeneration of islet beta-cells in the pancreas.

The pancreas is composed of at least three types of differentiated tissue: the hormone-containing cells in islets (4 different cell types), the exocrine zymogen-containing acini, and the centroacinar cells, ductules and ducts (ductal tree). All of these cells appear to have a common origin during embryogenesis in the form of duct-like protodifferentiated cells. Later in life, the acinar and ductal cells retain a significant proliferative capacity that can ensure cell renewal and growth, whereas the islet cells become mitotically inactive. Interestingly, new islet cells, including the insulin-producing beta-cells, can regenerate after tissue injury by a process called neogenesis. The neogenetic process involves differentiation of duct-like (exocrine) epithelial cells to hormone-expressing cells. In this paper, we review the question whether islet beta-cell regeneration or neogenesis in the pancreas depends on "embryonic-like" stem cells or on transdifferentiation of "fully differentiated" cells. This issue is important to find the right model for in vitro research aiming at controlling the process of beta-cell neogenesis. The latter could lead to applications in the treatment of diabetes where functional beta-cells are deficient. We conclude from the available evidence that there is as yet no evidence for the existence of "dormant" stem cells in the adult pancreas. There is some evidence, however, that differentiated exocrine acinar and/or duct cells retain the capacity to transdifferentiate into insulin-expressing beta-cells.

Animals↗
PubMed1998

Cytokeratins and cell differentiation in the pancreas.

Keratins, or cytokeratins, represent a family of more than 20 different polypeptides which are important markers of epithelial cell differentiation. This review deals with the use of keratin immunohistochemistry in the study of pancreatic cell differentiation. Exocrine acinar cells and endocrine islet cells are well-differentiated cells which express the keratin combination 8 and 18, whereas the less-differentiated cells of the ductal tree are characterized by the additional expression of keratin 7, keratin 19, and, in the rat, keratin 20. Keratin expression is stable and can be used for cell identification after isolation and culture, and in clinical or experimental injury. The intercalated ductal cells and centroacinar cells are inconspicuous unless specific immunohistochemical markers, such as keratins, are used. In conditions where there is morphogenetic differentiation such as in fetal life, or where transdifferentiation is occurring, keratins have been used to trace the origin and fate of pancreatic cells.

Biomarkers↗
PubMed1998

Implantation of standardized beta-cell grafts in a liver segment of IDDM patients: graft and recipients characteristics in two cases of insulin-independence under maintenance immunosuppression for prior kidney graft.

Islet allografts in insulin-dependent diabetic (IDDM) patients exhibit variable survival lengths and low rates of insulin-independence despite treatment with anti-T-cell antibodies and maintenance immunosuppression. Use of poorly characterized freshly isolated preparations makes it difficult to determine whether failures are caused by variations in donor tissue. This study assesses survival of standardized beta-cell allografts in C-peptide negative IDDM patients on maintenance immunosuppression following kidney transplantation and without receiving anti-T-cell antibodies or additional immunosuppression. Human islets were isolated from pancreatic segments after maximal 20 h cold-preservation. During culture, preparations were selected according to quality control tests and combined with grafts with standardized cell composition (> or = 50% beta cells), viability (> or = 90%), total beta-cell number (1 to 2 x 10(6)/kg body weight) and insulin-producing capacity (2 to 4 nmol x graft(-1) x h(-1)). Grafts were injected in a liver segment through the repermeabilized umbilical vein. After 2 weeks C-peptide positivity, four out of seven recipients became C-peptide negative; two of them were initially GAD65-antibody positive and exhibited a rise in titre during graft destruction. The other three patients remained C-peptide positive for more than 1 year, two of them becoming insulin-independent with near-normal fasting glycaemia and HbA1c; they remained GAD65- and islet cell antibody negative. The three patients with surviving grafts presented a history of anti-thymocyte globulin therapy at kidney transplantation. Long-term surviving grafts increased C-peptide release following intravenous glucagon or oral glucose but not following intravenous glucose. Thus, cultured human beta-cells can survive for more than 1 year in IDDM patients on maintenance anti-rejection therapy for a prior kidney graft and without the need for an increased immunosuppression at the time of implantation. The use of functionally standardized beta-cell grafts helps to identify recipient and graft factors which influence their survival and metabolic effects. Insulin-independence can be achieved by injection of 1.5 million beta-cells per kg body weight in a liver segment. These beta-cell implants respond well to adenylcyclase activators but poorly to glucose.

Adolescent↗
PubMed1998

Extra-insular beta cells associated with ductules are frequent in adult human pancreas.

Routine immunohistochemical analysis of human donor pancreata indicated the frequent occurrence of single insulin-immunoreactive cells. In a quantitative analysis of nine organs consecutively recruited from adult donors, 15 percent of all beta cells were found in units with a diameter less than < 20 microm and without associated glucagon-, somatostatin-, or pancreatic polypeptide cells. These single beta-cell units are located in or along ductules, from which they appear to bud as previously noticed in fetal and neonatal organs. They contain significantly smaller beta cells than endocrine aggregates with a larger diameter. The use of ductal cell markers such as cytokeratin 19, carbonic anhydrase-II and carbohydrate antigen 19.9 identified a close topographical association between ductal cells and budding beta cells; it also indicated that pancreatic lobules are composed of nearly one third ductal cells. The presence of Ki67 proliferation marker-immunoreactive ductal cells (0.05 %) and absence of Ki67-immunoreactive budding beta cells is compatible with the view that beta cell neogenesis depends on ductal cell proliferation and differentiation. The high proportion of budding beta cells in the adult human pancreas suggests the presence of numerous loci with a potential for beta cell neogenesis.

Adolescent↗
PubMed1998

Culture of adult human islet preparations with hepatocyte growth factor and 804G matrix is mitogenic for duct cells but not for beta-cells.

It has recently been reported that human adult beta-cells proliferate during culture on an extracellular matrix prepared from rat 804G cells and in the presence of hepatocyte growth factor (HGF). The present study compares the mitogenic effect of this condition on human beta-cells and on neighboring non-endocrine duct cells. Islet cell-enriched fractions were prepared from adult human organ donors and cultured in suspension or on 804G matrix, with or without HGF. The combination of 804G matrix and HGF increased the number of 5-bromo-2'-deoxyuridine-positive (BrdU+) cells within 48 h reaching a maximum after 4 days. In sections, virtually all BrdU+ cells were negative for insulin or glucagon and for preproinsulin mRNA but expressed the ductal cell markers cytokeratin 19 and 7, carbonic anhydrase-II, and carbohydrate antigen 19-9. After 4 days of culture, the cytokeratin 19+ ductal cells exhibited a BrdU-labeling index of 30% (P < 0.01 vs. 2% without HGF and matrix), whereas <0.1% of insulin-positive and <1% of glucagon-positive cells were labeled. Formation of bilayers with ductal cells covering the endocrine cells may cause erroneous interpretation on double positivity in unsectioned tissue. It is concluded that culture of human islet cell preparations with HGF and 804G matrix stimulates the proliferation of the duct cells but not of the underlying beta-cells.

Adult↗
PubMed1997

Proliferation and differentiation in the human fetal endocrine pancreas.

The morphogenesis and growth of the endocrine pancreas has not been well investigated in man although it represents an important issue in diabetology. We examined human fetal pancreas from 12 to 41 weeks of gestation immunocytochemically to evaluate proliferative activity with the Ki-67 marker, and cytodifferentiation with cytokeratin 19 (ductal cells), synaptophysin (all endocrine cells), and insulin, glucagon, somatostatin and pancreatic polypeptide (islet cell types). Ki-67 labelling was found in all these cell types but was much higher in ductal cells than in islet cells. An intermediate population expressed synaptophysin but lacked islet hormones. With increasing gestational age the Ki-67 labelling index decreased from 17 to 4% in ductal cells, from 9 to 1% in synaptophysin-positive cells, and from 3 to 0.1% in insulin- or glucagon-positive cells. From 12 to 16 weeks, all epithelial cells including the endocrine islet cells expressed cytokeratin 19. Thereafter cytokeratin 19 expression decreased and eventually disappeared from most islet cells, whereas strong expression remained in the ductal cells. We show that differentiated human islet cells have only very limited proliferative capacity, and we demonstrate the existence of transitional differentiation stages between ductal and islet cells.

Biomarkers↗
PubMed1997

Effect of interferon-gamma and glucose on major histocompatibility complex class I and class II expression by pancreatic beta- and non-beta-cells.

Surface major histocompatibility complex (MHC) class I and class II expression by pancreatic islet cells is considered a local initiator or regulator of immune processes that can lead to diabetes. Locally released cytokines, in particular interferon-gamma, are known to stimulate MHC antigen expression by islet cells. The present study quantifies MHC expression in cultured pancreatic beta- and non-beta-cells from both rat and human organs. Interferon-gamma increased MHC class I expression in endocrine beta- and non-beta-cells as well as in pancreatic ductal cells. The cytokine induced a 6-fold increase in the MHC class I messenger ribonucleic acid levels in pancreatic beta-cells; this effect was 2-fold amplified in the presence of elevated glucose levels (20 mmol/L instead of 6 mmol/L). No MHC class II expression was observed in endocrine beta- or non-beta-cells; human, but not rat, ductal cells exhibited MHC class II expression that increased in the presence of interferon-gamma. These data indicate that the increase in beta-cell MHC class I expression described in the pancreata of diabetic patients may result from stimulated transcription after exposure to locally released interferon-gamma and/or to a hyperglycemic state. The association of human islets with ductal cells in which MHC class II expression is stimulated by interferon-gamma makes these cells potential participants in the autoimmune process in diabetes.

Adolescent↗