Evidence for Initial Involvement of Macrophage in Development of Insulitis in NOD Mice

Abstract

Macrophages have been shown to be the major population of infiltrated immunocytes at the early stage of insulitis in diabetes-prone BB rats. This study was undertaken to investigate the role of macrophages in the development of insulitis in nonobese diabetic (NOD) mice. Administration of cyclophosphamide to NOD mice resulted in a significant increase in the incidence of overt diabetes and severity of insulitis compared with that in untreated NOD mice. Intraperitoneal injections of silica completely prevented the development of diabetes and insulitis in both cyclophosphamide-treated and untreated animals. Because silica is selectively toxic to macrophages, the results suggest that macrophages play an important role in the initiation of insulitis in NOD mice. Diabetes 37:989-91, 1988 E vidence indicates that many patients with insulindependent diabetes mellitus (IDDM) may result from an autoimmune process directed against pancreatic p-cells (1). Animal models for IDDM, such as BB rats and nonobese diabetic (NOD) mice, support the autoimmune hypothesis. However, the mechanism underlying the autoimmunity remains unknown (1). Various effector systems, e.g., T-lymphocytes, natural killer (NK) cells, macrophages, and/or humoral mediators, have been implicated as the possible effectors of immune responses.Recent studies from our laboratory and others revealed that most infiltrated immunocytes at the early stage of insulitis in BB rats are macrophages (2,3). These findings suggested that macrophages may be involved in the initiation of insulitis. We investigated whether macrophages have an initial permissive role in the immune response against pancreatic pcells in NOD mice. MATERIALS AND METHODSOur NOD mouse colony was produced from a breeding stock obtained from Clea Japan (Tokyo). These animals were maintained on regular rat chow and tap water ad libitum at the University of Calgary. Beginning at ~8 wk of age, their urinary glucose and ketone levels were determined twice weekly with Diastix and Ketostix reagent slips (Miles, Ontario, Canada). Individual mice were classified as diabetic on the basis of positive glycosuria. The overall cumulative incidence of diabetes among the colony was -1 5 % in males and 50% in females at 24 wk of age.A total of 32 male animals from 10 litters, divided into four groups (n = 8/group), were used for this study. We injected silica (Steinkohlen-Bergbau-Verein, Essen, FRG), at a dose of 200 mg • kg~1 body wt • wk~1 i.p., into one group of animals from 4 to 10 wk of age. The second group of animals received silica, as described above, and subsequently cyclophosphamide (Homer, Montreal, Canada), at a dose of 150 mg/kg body wt twice per 3-day interval, at age 10 wk. The third group received only cyclophosphamide, administered at a dose identical to the second group. The fourth group of animals received no chemicals and were used as controls.Two weeks after the second injection of cyclophosphamide, the mice were killed by suffocation with carbon dioxide, and their pancreases were fixed in 6% ...

Cellular distribution and contribution of cyclooxygenase (COX)-2 to diabetogenesis in NOD mouse

“…COX-2 was not detected in the zone of islet-infiltrating lymphocytes or inside the peri-islet area, which is consistent with independent regulation of the trafficking of antigen-presenting cell (APC): macrophages and dendritic cells and T cells that participate in the development of islet inflammation (Lee et al 1988;Fox and Danska 1998). The role of the macrophages in the inflamed islets is probably not restricted to secretion of cytotoxic and inflammation-inducing mediators only, because they also produce substances that participate in tissue reorganization including enzymes such as hyaluronidase, elastase, and collagenase, anti-proteases, regulatory growth factors and others.…”

The specific p38 mitogen-activated protein kinase pathway inhibitor FR167653 keeps insulitis benign in nonobese diabetic mice

“…These cytokines have been shown to be cytotoxic to pancreatic islets in vitro (Rabinovitch, 2000), and TNF-a has been reported to contribute to the development of both diabetes and insulitis (Hunger et al, 1997;Yang et al, 1994). In addition, macrophages are thought to be important in the initiation of insulitis in cyclophosphamide-treated NOD mice (Charlton et al, 1997;Lee et al, 1988). Using another model of type 1 diabetes, in which mice are treated with multiple low-doses of streptozotocin, we have shown that a thiazolidinedione compound, pioglitazone, prevents these animals from developing insulitis and diabetes, at least partly by inhibiting macrophage activation (Takamura et al, 1999).…”

Increased In Vitro Interleukin-12 Production by Peripheral Blood in High-Risk IDDM First Degree Relatives

“…Macrophages are the first cells, which appear in islets in animal models of diabetes (11). It is suggested that cytokiries released by these cells: interleukin-113 (lL-113), interleukin-i2 (IL-12) and tumor necrosis factor-ct (TNF-c) could have an initial role in 13-cell damage (1,11).…”