Essential contribution of macrophages to islet cell destruction in vivo and in vitro

Kolb, Hubert; Burkart, Volker; Appels, Britta; Hanenberg, Helmut; Kantwerk-Funke, Gudrun; Kiesel, U; Funda, J; Schraermeyer, Ulrich; Kolb‐Bachofen, V.

doi:10.1016/s0896-8411(09)90020-8

Cited by 52 publications

(29 citation statements)

References 11 publications

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“…Diabetogenesis after MLD-STZ treatment is mediated by an early influx of macrophages into the pancreatic islets, [18,19], efficient presentation of released diabetogenic antigens and recruitment of T cells. By day 23 after diabetes induction, IL-23 stimulated this process, leading to peri-insulitis and insulitis (Fig.…”

Section: Il-23 Greatly Enhances Influx Of Mononuclear Cellsmentioning

confidence: 99%

“…This family of cytokines is produced by antigen-presenting cells such as macrophages, dendritic cells (reviewed in [15]) and microglia in the central nervous system (CNS) [16]. While both macrophages and a small number of dendritic cells are present in intact adult pancreatic islets [17], blood-borne macrophages are the first cells to infiltrate the islets after MLD-STZ diabetes induction [18,19]. Dendritic cells are also known to either enhance [20] or prevent [21] autoimmunity leading to diabetes, depending on their activation status.…”

Section: Introductionmentioning

confidence: 99%

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IL‐23 leads to diabetes induction after subdiabetogenic treatment with multiple low doses of streptozotocin

et al. 2005

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IL-23, a proximal regulator of IL-17, may be a major driving force in the induction of autoimmune inflammation. We have used a model of subdiabetogenic treatment with multiple low doses of streptozotocin (MLD-STZ; 4 Â 40 mg/kg body weight) in male C57BL/6 mice to study the effect of IL-23 on immune-mediated b cell damage and the development of diabetes, as evaluated by blood glucose, quantitative histology, immunohistochemistry and expression of relevant cytokines in the islets. Ten daily injections of 400 ng IL-23, starting on the first day of MLD-STZ administration led to significant and sustained hyperglycemia along with weight loss compared with controls (no IL-23), and a significant increase in the number of infiltrating cells, a lower insulin content, enhanced apoptosis, expression of IFN-c and IL-17 (not seen in the controls) and a significant increase in the expression of TNF-a and IL-18 in the pancreatic islets. IL-23 treatment started 5 days prior to MLD-STZ administration had no effect on diabetogenesis or cytokines expression in the pancreatic islets. We provide the first evidence in an animal model that IL-23 is involved in the development of type-1 diabetes, by inducing IL-17 and possibly IFN-c production in the target tissue.

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Section: Il-23 Greatly Enhances Influx Of Mononuclear Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IL‐23 leads to diabetes induction after subdiabetogenic treatment with multiple low doses of streptozotocin

et al. 2005

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“…Importantly, this compound sustains islets in culture (Korsgren et al, 1993), increasing the resistance of β-cells to toxic chemicals, activated macrophages (Kolb et al, 1990), and inflammatory cytokines (Pipeleers and Van de Winkel 1986;Buscema et al, 1992;Kallmann et al, 1992). Based on these observations, nicotinamide has been tested for therapeutic effects in insulin-dependent diabetes of recent onset, in animal models and clinical trials (Elliott and Chase, 1991;Chase et al, 1992;Ueki et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Effect of nicotinamide on early graft failure following intraportal islet transplantation

et al. 2009

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Intraportal islet transplantation (IPIT) may potentially cure Type 1 diabetes mellitus; however, graft failure in the early post-transplantation period presents a major obstacle. In this study, we tested the ability of nicotinamide to prevent early islet destruction in a syngeneic mouse model. Mice (C57BL/6) with chemically-induced diabetes received intraportal transplants of syngeneic islet tissue in various doses. Islets were cultured for 24 h in medium with or without 10 mM nicotinamide supplementation. Following IPIT, islet function was confirmed by an intraperitoneal glucose tolerance test (IPGTT) and hepatectomy. The effects of nicotinamide were evaluated by blood glucose concentration, serum monocyte chemoattractant protein-1 (MCP-1) concentration, and immunohistology at 3 h and 24 h after IPIT. Among the various islet doses, an infusion of 300 syngeneic islets treated with nicotinamide exhibited the greatest differences in glucose tolerance between recipients of treated and untreated (i.e., control) islets. One day after 300 islet equivalent (IEQ) transplantation, islets treated with nicotinamide were better granulated than the untreated islets (P = 0.01), and the recipients displayed a slight decrease in serum MCP-1 concentration, as compared to controls. After 15 days, recipients of nicotinamide-pretreated islets showed higher levels of graft function (as measured by IPGTT) than controls. The pretreatment also prolonged graft survival (＞ 100 days) and function; these were confirmed by partial hepatectomy, which led to the recurrence of diabetes. Pretreatment of islet grafts with nicotinamide may prevent their deterioration on the early period following IPIT in a syngeneic mouse model.

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“…(ii) contributing to collagen production for wound recovery (44), (iii) mediating parasite expulsion (22), and (iv) upregulation of arginase, thereby reducing arginine availability for inducible nitric oxide synthase-mediated generation of NO. As classically activated macrophages have been implicated in ␤-cell destruction during T1D development in NOD mice (2,16,21), it is possible that their alternative activation reduces macrophage-mediated pathogenesis. Helminth parasites have potent immunoregulatory functions, as they induce IL-10, TGF-␤, and Tregs in the host and are able to manipulate the ability of the host immune system to respond to unrelated antigens (26,48).…”

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confidence: 99%

Helminth Infection Can Reduce Insulitis and Type 1 Diabetes through CD25- and IL-10-Independent Mechanisms

et al. 2009

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Parasitic helminth infection has been shown to modulate pathological inflammatory responses in allergy and autoimmune disease. The aim of this study was to examine the effects of infection with a helminth parasite, Heligmosomoides polygyrus, on type 1 diabetes (T1D) in nonobese diabetic (NOD) mice and to elucidate the mechanisms involved in this protection. H. polygyrus inoculation at 5 weeks of age protected NOD mice from T1D until 40 weeks of age and also inhibited the more aggressive cyclophosphamide-induced T1D. Moreover, H. polygyrus inoculation as late as 12 weeks of age reduced the onset of T1D in NOD mice. Following H. polygyrus inoculation of NOD mice, pancreatic insulitis was markedly inhibited. Interleukin-4 (IL-4), IL-10, and IL-13 expression and the frequency of CD4 ؉ CD25 ؉ FoxP3 ؉ regulatory T cells were elevated in mesenteric and pancreatic lymph nodes. Depletion of CD4 ؉ CD25 ؉ T cells in vivo did not abrogate H. polygyrus-induced T1D protection, nor did anti-IL-10 receptor blocking antibody. These findings suggest that infection with H. polygyrus significantly inhibits T1D in NOD mice through CD25-and IL-10-independent mechanisms and also reduces the severity of T1D when administered late after the onset of insulitis.

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Essential contribution of macrophages to islet cell destruction in vivo and in vitro

Cited by 52 publications

References 11 publications

IL‐23 leads to diabetes induction after subdiabetogenic treatment with multiple low doses of streptozotocin

IL‐23 leads to diabetes induction after subdiabetogenic treatment with multiple low doses of streptozotocin

Effect of nicotinamide on early graft failure following intraportal islet transplantation

Helminth Infection Can Reduce Insulitis and Type 1 Diabetes through CD25- and IL-10-Independent Mechanisms

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