Article

Early window of diabetes determinism in NOD mice, dependent on the complement receptor CRIg, identified by noninvasive imaging. Nat Immunol

Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
Nature Immunology (Impact Factor: 20). 02/2012; 13(4):361-8. DOI: 10.1038/ni.2233
Source: PubMed

ABSTRACT

All juvenile mice of the nonobese diabetic (NOD) strain develop insulitis, but there is considerable variation in their progression to diabetes. Here we used a strategy based on magnetic resonance imaging (MRI) of magnetic nanoparticles to noninvasively visualize local effects of pancreatic-islet inflammation to predict the onset of diabetes in NOD mice. MRI signals acquired during a narrow early time window allowed us to sort mice into groups that would progress to clinical disease or not and to estimate the time to diabetes development. We exploited this approach to identify previously unknown molecular and cellular elements correlated with disease protection, including the complement receptor of the immunoglobulin superfamily (CRIg), which marked a subset of macrophages associated with diabetes resistance. Administration of a fusion of CRIg and the Fc portion of immunoglobulin resulted in lower MRI signals and diabetes incidence. In addition to identifying regulators of disease progression, we show here that diabetes is set at an early age in NOD mice.

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Available from: Gregory Robert Wojtkiewicz, Sep 28, 2015
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    • "The initial stages of diabetes pathogenesis are triggered by the islet infiltration of innate immune cells, including macrophages and DCs[6,7], which precede the priming and recruitment of b cell– specific lymphocytes into the islets. Initially, b cell– reactive lymphocytes are kept in check by immune regulatory mechanisms, but when regulation fails, a destructive insulitis phase ensues that is characterized by massive islet infiltration of activated b cell–specific T cells to mediate b cell destruction8910. In NOD mice, initial T cell priming begins as early as 10 d of age, insulitis starts at 3–4 wk of age, and the onset of destructive insulitis and hyperglycemia is observed beginning at 12–16 wk of age. "
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    ABSTRACT: Type 1 diabetes is an autoimmune disease that results from the defective induction or maintenance of T cell tolerance against islet b cell self-antigens. Under steady-state conditions, dendritic cells with tolerogenic properties are critical for peripheral immune tolerance. Tolerogenic dendritic cells can induce T cell anergy and deletion and, in some contexts, induce or expand regulatory T cells. Dendritic cells contribute to both immunomodulatory effects and triggering of pathogenesis in type 1 diabetes. This immune equilibrium is affected by both genetic and environmental factors that contribute to the development of type 1 diabetes. Genome-wide association studies and disease association studies have identified .50 polymorphic loci that lend susceptibility or resistance to insulin-dependent diabetes mellitus. In parallel, diabetes susceptibility regions known as insulin-dependent diabetes loci have been identified in the nonobese diabetic mouse, a model for human type 1 diabetes, providing a better understanding of potential immunomodulatory factors in type 1 diabetes risk. Most genetic candidates have annotated immune cell functions, but the focus has been on changes to T and B cells. However, it is likely that some of the genomic susceptibility in type 1 diabetes directly interrupts the tolerogenic potential of dendritic cells in the pathogenic context of ongoing autoimmunity. Here, we will review how gene polymorphisms associated with autoimmune diabetes may influence dendritic cell development and maturation processes that could lead to alterations in the tolerogenic function of dendritic cells. These insights into potential tolerogenic and pathogenic roles for dendritic cells have practical implications for the clinical manipulation of dendritic cells toward tolerance to prevent and treat type 1 diabetes.
    Full-text · Article · Jan 2016 · Journal of Leukocyte Biology
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    • "CRIg expression is promoted by the regulatory molecule IL-10 and inhibited by the inflammatory molecule IFN-γ as well as other inflammatory molecules such as arachidonic acid [13]. Importantly, the expression of CRIg by pancreatic macrophages is negatively correlated with the progression to T1D [12]. Both IL-10 and IFN-γ are cytokines: diffusing, extracellular molecules used for communication between cells, typically of the immune system. "
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    ABSTRACT: Type 1 diabetes (T1D) is an autoimmune disease of the beta cells of the pancreas. The nonobese diabetic (NOD) mouse is a commonly used animal model, with roughly an 80% incidence rate of T1D among females. In 100% of NOD mice, macrophages and T-cells invade the islets in a process called insulitis. It can be several weeks between insulitis and T1D, and some mice do not progress at all. It is thought that this delay is mediated by regulatory T-cells (Tregs) and that a gradual loss of effectiveness in this population leads to T1D. However, this does not explain why some mice progress and others do not. We propose a simple mathematical model of the interaction between beta cells and the immune populations, including regulatory T-cells. We find that individual mice may enter one of two stable steady states: a `mild' insulitis state that does not progress to T1D and a `severe' insulitis state that does. We then run a sensitivity analysis to identify which parameters affect incidence of T1D versus those that affect age of onset. We also test the model by simulating several experimental manipulations found in the literature that modify insulitis severity and/or Treg activity. Notably, we are able to match a reproduce a large number of phenomena using a relatively small number of equations. We finish by proposing experiments that could help validate or refine the model.
    Preview · Article · Dec 2014
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    • "Indeed, by immunohistology analysis these highly proliferative CD11b+ cells were found interspersed around the islets and surrounding blood vessels (Fig. 3A). Further phenotypic analysis indicated that two subpopulations among CD11b+ cells increased during IL-2 treatment: CD11b+ Ly6C+ F4/80+ cells, likely representing tissue macrophages; and CD11b+ Ly6G+ cells, likely representing neutrophils (18) (Fig. 3B). "
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    ABSTRACT: Administration of low-dose IL-2 alone or combined with rapamycin (RAPA) prevents hyperglycemia in NOD mice. Also, low-dose IL-2 cures recent onset type 1 diabetes (T1D) in NOD mice, partially by boosting pancreatic regulatory T cells (Treg cells). These approaches are currently being evaluated in humans. Our objective was to study the effect of higher IL-2 doses (250,000-500,000 IU, daily) as well as low-dose IL-2 (25,000 IU, daily) and RAPA (1mg/kg, daily) (RAPA/IL-2) combination. We show that despite further boosting Treg cells, high doses of IL-2 rapidly precipitated T1D in pre-diabetic female and male mice and increased myeloid cells in the pancreas. Also, we observed that RAPA counteracted IL-2 effects on Treg cells, failed to control IL-2-boosted NK cells and broke IL-2-induced tolerance in a reversible way. Notably, RAPA/IL-2 combination failure to cure T1D was associated to an unexpected deleterious effect on glucose homeostasis at multiple levels, including β-cell division, glucose tolerance and liver glucose metabolism. Our data help understand the therapeutic limitations of IL-2 alone or RAPA/IL-2 combination and could lead to the design of improved therapies for T1D.
    Full-text · Article · May 2013 · Diabetes
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