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Abnormal immunity and its related complications are the major causes of mortality and morbidity in diabetes patients. Macrophages, as one of the important innate cells, play pivotal roles in controlling immune homeostasis, immunity, and tolerance. The effects of hyperglycemia on the function of macrophages in hosts remain to be determined. Here we used mice with streptozotocin (STZ)-induced diabetes for long term to study the changes of macrophages. We found that F4/80+ peritoneal exudate macrophages (PEMs) from mice with diabetes for 4 months displayed significantly reduced CD86 and CD54 expression and tumor necrosis factor (TNF)-α and IL-6 production but enhanced nitric oxide (NO) secretion compared with control mice when treated with interferon (IFN)-γ and lipopolysaccharide (LPS), while the activity of arginase in PEMs from diabetic mice was significantly higher than control mice when stimulating with IL-4. These dysfunctions of macrophages could be efficiently reversed by insulin treatment. Importantly, in vitro bone marrow-derived macrophages showed similar functional changes, indicating the epigenetic alteration of macrophage precursors in these mice. In an in vitro culture system, high glucose and insulin significantly altered TNF-α, IL-6, and NO production and arginase activity of macrophages, which was reversed by the treatment with AKT and ERK inhibitors. Therefore, hyperglycemia and insulin deficiency can modify macrophage function through AKT-mTOR and ERK pathways and through epigenetic effects on macrophage precursors. To further identify different components of diabetes on the dysfunction of macrophages is important for efficient prevention of diabetic complications. J. Cell. Physiol. 227: 1670-1679, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objective and design: Leflunomide (LEF) is effective not only in different animal models of autoimmune diseases and the therapy of patients with rheumatoid arthritisbut also in graft rejection. The effect of LEF on CD4CD25T regulatory cells (Treg) was determined in a mouse model of allogeneic bone marrow transplantation. Material or subjects: BALB/c and C57BL/6 mice were used as donors and recipients, respectively. Treatment: C57BL/6 mice were given 2 Gy total-body irradiation, followed by an intravenous injection of 2 × 10 BALB/c bone marrow cells (BMCs). Mice were treated with LEF daily at a dose of 30 mg/kg/day for 2 weeks. Results: In naïve mice, LEF significantly decreased the percentage of CD4CD25 Treg cells in spleens ( P < 0.05), but not in lymph nodes, though LEF enhanced the percentages of CD4CD25 Treg cells in CD4 single positive cells in the thymocytes and blood ( P < 0.05). Furthermore, LEF significantly decreased the percentage of CD4CD25 Treg cells in the spleens of mice that received allogeneic BMCs. Conclusions: LEF decreases peripheral CD4CD25 Treg cells in un-immunizing and immunizing recipients, indicating that LEF might not be an ideal candidate for the treatment of autoimmune diseases or graft rejection with respect to induction of immune tolerance. [ABSTRACT FROM AUTHOR]

The immune regulatory function of macrophages (Møs) in mixed chimeras has not been determined. In the present study, with a multi-lineage B6-to-BALB/c mixed chimeric model, we examined the ability of donor-derived splenic Møs in the induction of regulatory T cells (Treg). B6 splenic Møs from mixed chimeras induced significantly less cell proliferation, more IL-10 and TGF-β, and less IL-2 and IFN-γ productions of CD4+ T cells from BALB/c mice than naive B6 Møs did, whereas they showed similar stimulatory activity to the third part C3H CD4+ T cells. Importantly, highly purified donor F4/80+CD11c− Møs efficiently induced recipient CD4+Foxp3+ Treg cells from CD4+CD25−Foxp3− T cells. Furthermore, donor Møs of mixed chimeras produced more IL-10 and less IFN-γ than those of naive mice when cultured with BALB/c but not the third party C3H CD4+ T cells. Induction of recipient CD4+ Treg cells by donor Møs was significantly blocked by anti-IL-10, but not by anti-TGF-β mAb. Therefore, donor Møs have the ability to induce recipient CD4+Foxp3+ Treg cells in a donor antigen-specific manner, at least partially, via an IL-10-dependent pathway. This study for the first time showed that, in mixed allogeneic chimeras, donor Møs could be specifically tolerant to recipients and gained the ability to induce recipient but not the third party Foxp3+ Treg cells. Whether this approach is involved in transplant immune tolerance needs to be determined. [ABSTRACT FROM AUTHOR]