islet leukocyte infiltration

The relationship between sex steroids, mega-islet formation, and leukocyte infiltration can be explained in different ways. We provide the first comprehensive analysis of the extracellular matrix (ECM) composition of peri-islet capsules, composed of the peri-islet basement membrane (BM) and subjacent interstitial matrix (IM), in development of type 1 diabetes in NOD mice and in human type 1 diabetes. D: Stereological analyses of pancreatic sections from 5- and 14-week-old normoglycemic and 21-week-old diabetic NOD mice (n = 3/each group) were used to quantify the number of islets with intact peri-islet BMs (healthy islets and islets in peri-insulitis stage) vs. invaded islets showing loss of peri-islet BM staining. Penetration of the peri-islet BM is a critical step in disease progression in NOD mice. Taken together, in vivo silencing of AIF1 suppresses insulitis, as shown by reduced infiltration of leukocytes into the pancreas and lower proinflammatory cytokine profiles. CMV-infected recipients demonstrated accelerated islet graft failure compared to noninfected controls. Leukocytes utilize both alpha4 and alpha5 integrins for intraislet infiltration in non-obese diabetic mice. Adaptive Immunity and Pathogenesis of Diabetes: Insights Provided by the α4-Integrin Deficient NOD Mouse. W, weeks. Leukocytes infiltrate the pancreatic islets of nonobese diabetic mice, causing beta-cell destruction and autoimmune Type I diabetes. As in NOD samples, the healthy human pancreatic islet was surrounded by a capsule composed of a peri-islet BM and subjacent IM (Fig. Quantitative analyses revealed significantly reduced mean fluorescence intensity of the peri-islet BM pan-laminin staining at sites of leukocyte invasion of islets and loss of insulin+ cells and that this correlates with disease progression, with a higher incidence of insulitis when more islets showed penetration of the peri-islet BM. Islet leukocyte infiltration and cytokine mRNA expression MLD-STZ induced an infiltrate of F4/80+ macrophages, CD4+ T cells, and CD8+ T cells in the islets of WT mice ( Fig. Our data demonstrate global loss of peri-islet BM and IM components only at sites of leukocyte infiltration into the islet. CMV-infected recipients demonstrated accelerated islet graft failure compared to noninfected controls. 2 ). (A–C, nPOD case 6024, healthy pancreas) D: Schematic representation of the areas analyzed. Comment on: Korpos et al. Diabetologia. Diabetes 2013;62:531–542 Our data demonstrate global loss of peri-islet BM and IM components only at sites of leukocyte infiltration into the islet. Epub 2004 Oct 19. In marked contrast, a marginal-to-modest islet destruction and leukocyte infiltration were found in the pancreatic islets of NOD mice treated with catenarin at 4 mg/kg and over (Figure 2 (b)). 1999 May;12(3):167-76. doi: 10.1006/jaut.1998.0268. Immunofluorescence staining of cryosections was performed as described previously (26). At 14weeks, 40% of the small islets, but more than 80% of large islets, showed leukocyte infiltration. Data reveal upregulation of caspase 7 and 8 in infiltrated islets, which are members of the aspartic-specific cysteine protease family associated with apoptotic events (30). It also suggests the involvement of several proteases or of proteases with broad specificity. The existing data, which are extremely limited, suggest that the biochemical nature of the ECM may determine the mechanism used by the immune cells for its penetration, with protease-independent migration dominating (15–17). Protease- and protease inhibitor–specific microarray analyses (CLIP-CHIP) of laser-dissected leukocyte infiltrated and noninfiltrated pancreatic islets and confirmatory quantitative real time PCR and protein analyses identified cathepsin S, W, and C activity at sites of leukocyte penetration of the peri-islet BM in association with a macrophage subpopulation in NOD mice and human type 1 diabetic samples and, hence, potentially a novel therapeutic target specifically acting at the islet penetration stage. 2 ). The peri-islet BM is marked here by perlecan staining. Laminin α5 expression was stronger in the arterioles where smooth muscle cells express this chain in addition to endothelial cells (Fig. Immunofluorescence staining revealed some colocalization of F4/80+ macrophages with cathepsin C staining (Fig. R.K. and C.M.O. CLIP-CHIP microarray analyses support the latter possibility, with the identification of upregulation of several members of the cathepsin protease family and protease inhibitors in leukocyte-infiltrated islets. Reconstitution of the peri-islet capsule after resolution of inflammation in NOD pancreata. Islet leukocyte infiltration and cytokine mRNA expressionMLD-STZ induced an infiltrate of F4/80+ macrophages, CD4+ T cells, and CD8+ T cells in the islets of WT mice (Fig. Nevertheless, anti-alpha4 subunit mAb monotherapy alone was very effective, reducing insulitis to levels similar to those obtained with combinational antibody treatment, suggesting that alpha4 integrins are major receptors contributing to leukocyte infiltration. 2004 Oct;47(10):1657-60. doi: 10.1007/s00125-004-1518-0. In contrast, the group with IL‐33 treatment showed well‐preserved islet morphology with reduced/minimal leukocyte infiltration (Fig 1F). Only IL-10 expression was retained, which could aid immunosuppression. The mean fluorescence intensity per micrometer of BM length was measured at sites showing continuous pan-laminin staining (Supplementary Fig. To investigate whether leukocyte infiltration into the human pancreatic islets is also associated with loss of peri-islet ECM components, human type 1 diabetic samples were analyzed (Supplementary Tables 2 and 3). For confocal microscopy of whole mounts, pancreata were fixed in 4% paraformaldehyde and blocked in 1% BSA/0.3% TritonX-100. In this context, the role of the pancreatic endothelium as a barrier for autoimmunity- and inflammation-related Rijksuniversiteit Groningen founded in 1614 - top 100 university. Although it is a T-cell (CD4 and CD8)–mediated disease, macrophages, dendritic cells (DCs), and natural killer cells are also essential for disease progression (1). 1A and B; Supplementary Video 1). Please enable it to take advantage of the complete set of features! 2). Nevertheless, the data suggest that cellular interaction with the peri-islet BM is required for its integrity and barrier function. NOD mice are one of the best-studied animal models of type 1 diabetes (2) due to similarities with the pathogenesis and genetics of human type 1 diabetes. 1F). Although MMPs, in particular MMP-2 and MMP-14, were also upregulated at the transcriptional level, in situ zymography demonstrated the absence of correlation between gelatinase activity and sites of leukocyte infiltration. The peri-islet basement membrane, a barrier to infiltrating leukocytes in type 1 diabetes in mouse and human. of Langerhans. 5H), which has been shown to be a ligand for β-cells, interaction with which enhances insulin production (28). Precisely how the cathepsins function in leukocyte penetration of the peri-islet BM is not clear. Leukocyte infiltration toward the islet graft was evidenced by CD11b immunostaining (Figure 3G). Immunofluorescence staining of NOD 21-week-old pancreas sections for cathepsin C (A), cathepsin S (B), and cathepsin W (C) shows localization at sites where peri-islet BM staining is lost (arrows), as shown here by laminin (LM) γ1 staining. Unable to load your collection due to an error, Unable to load your delegates due to an error. In contrast, the group with IL-33 treatment showed well-preserved islet morphology with reduced/minimal leukocyte infiltration (Fig 1F). (G) PCNA + islet cells. Autoimmune diabetes: ongoing development of immunological intervention strategies targeted directly against autoreactive T cells. 6A–C). Calcinaro F, Dionisi S, Marinaro M, Candeloro P, Bonato V, Marzotti S, Corneli RB, Ferretti E, Gulino A, Grasso F, De Simone C, Di Mario U, Falorni A, Boirivant M, Dotta F. Diabetologia. Immunofluorescence staining of a whole mount (A) and thin sections (B; boxed areas show higher magnification) of leukocyte-invaded islets for pan-laminin (PLM) as a marker of the peri-islet BM, and the pan-leukocyte marker CD45 illustrates the correlation between the loss of the peri-islet BM and leukocyte infiltration into the pancreatic islet. This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. D.H. and S.C. were involved in project development and contributed significantly to compilation of the manuscript. Hence, reconstitution of the peri-islet BM may have important ramifications to islet transplantation studies. Protease- and protease inhibitor–specific microarray analyses (CLIP-CHIP) of laser-capture microdissection (LCM) material revealed upregulation of cathepsin S, W, and C in leukocyte-infiltrated islets compared with noninvaded pancreatic islets. Therefore, the infiltration of the islets in. This indicates that leukocyte penetration of the peri-islet BM is a critical step in disease progression and potentially represents a new therapeutic target. Our data demonstrate global loss of peri-islet BM and IM components only at sites of leukocyte infiltration into the islet. (A high-quality digital representation of this figure is available in the online issue.). Johnson GG, Mikulowska A, Butcher EC, McEvoy LM, Michie SA. In opposition to this proposal. 2C; Supplementary Fig. cells of the pancreatic islets of Langerhans. Curr Pharm Des. Diabetes 2013;62:531–542 - July 01, 2013, http://clinicaltrials.gov/ct2/show/NCT01319331, http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0432/-/DC1, http://creativecommons.org/licenses/by-nc-nd/3.0/. Prevention and treatment information (HHS). C: A 3-dimensional projection of a whole-mount staining shows that glucagon+ cell clusters are individually ensheathed by a peri-islet BM, shown by perlecan staining. performed all experiments and was involved in writing the manuscript. (A high-quality digital representation of this figure is available in the online issue.). The islet surface has been coated with heparin complex by exploiting biotin-avidin chemistry to inhibit coagulation [52]. Our data demonstrate global loss of peri-islet BM and IM components only at sites of leukocyte infiltration into the islet. For investigation of correlations between peri-islet BM integrity and disease progression, frozen pancreata from 5-, 14- (normoglycemic) and 21-week-old (diabetic) NOD mice were sectioned completely, and every 10th section was immunofluorescently stained with pan-laminin antibody to label BMs, CD45, a pan-leukocyte marker, and insulin. Our data demonstrate global loss of peri-islet BM and IM components only at sites of leukocyte infiltration into the islet. We therefore used diabetic NOD mice (aged >21 weeks) supplemented with subcutaneous insulin pellets to investigate whether reconstitution of the peri-islet BM indeed occurs after inflammation has subsided and what is the potential cellular source or sources of these BM proteins. Recent studies have reported the existence of laminins, collagen type IV, and perlecan surrounding the pancreatic islets and the absence of staining for these antigens in pancreata of NOD mice, however, without correlation to disease progression in mice or with type 1 diabetes in humans (23,24). Consistent with the results of the PAS staining, MLD-STZ Jnk1−/− mice also showed a macrophage and T cell infiltrate, the composition of which was not different to that seen in WT mice ( Fig. Animal experiments were conducted according to the Swedish and German animal welfare guidelines. The reduced neutrophil infiltration by thalidomide provides additional protection to the islet graft. Loss of intra-islet heparan sulfate is a highly sensitive marker of type 1 diabetes progression in humans The Peri-islet Basement Membrane, a Barrier to Infiltrating Leukocytes in Type 1 … 2B and D). 4C and D), suggesting that a macrophage subpopulation may be one of the cellular sources that secrete these proteases at the site of leukocyte penetration of the peri-islet BM. IFN-I is also a potent inducer of human leukocyte antigen I (HLA-I) molecules, a hallmark of T1D . C: The peri-islet BM is further surrounded by a dense network of IM, represented here by collagen type III. Treatment with anti-alpha4 integrin antibody retained some therapeutic benefit when administered from days 7, 40, or 70 of age. Endothelial cells have also been used to coat the islets; transplantation of these coated islets has reduced coagulation, complement activation, and leukocyte infiltration [53, 54]. Epub 2004 May 10. This leukocyte infiltration is chiefly composed of T-cells (CD8+ and CD4+), but not macrophages (Bogdani et al. Treatment of islet/leukocyte cocultures with SCH58261 (25 nM final concentration) ... Infiltration of neutrophils and monocytes contributes to tissue injury by disrupting islet morphology and triggering islet cell death by direct cytotoxicity or apoptotic induction.

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