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


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.


Available from: Gregory Wojtkiewicz, Sep 28, 2015
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Diabetes 05/2013; 62(9). DOI:10.2337/db13-0214 · 8.10 Impact Factor
  • Source
    • "Thus, the events leading to diabetes were temporally compressed or only a subset of the response was analyzed. Despite these limitations, important candidate markers for diabetes were identified, including genes that distinguish progressive versus non-progressive disease [30]. We have greatly expanded on our available datasets and present the first complete analysis of the entire natural diabetic program. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Our ability to successfully intervene in disease processes is dependent on definitive diagnosis. In the case of autoimmune disease, this is particularly challenging because progression of disease is lengthy and multifactorial. Here we show the first chronological compendium of transcriptional and cellular signatures of diabetes in the non-obese diabetic mouse. Our data relates the immunological environment of the islets of Langerhans with the transcriptional profile at discrete times. Based on these data, we have parsed diabetes into several discrete phases. First, there is a type I interferon signature that precedes T cell activation. Second, there is synchronous infiltration of all immunological cellular subsets and a period of control. Finally, there is the killing phase of the diabetogenic process that is correlated with an NF-kB signature. Our data provides a framework for future examination of autoimmune diabetes and its disease progression markers.
    PLoS ONE 03/2013; 8(3):e59701. DOI:10.1371/journal.pone.0059701 · 3.23 Impact Factor
Show more