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

Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
Nature Immunology (Impact Factor: 24.97). 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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    • "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.
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    Diabetes 06/2012; · 8.47 Impact Factor
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    ABSTRACT: Macrophages are multifunctional immune cells that may either drive or modulate disease pathogenesis depending on their activation phenotype. Autoimmune type 1 diabetes (T1D) is a chronic proinflammatory condition characterized by unresolved destruction of pancreatic islets. Adoptive cell transfer of macrophages with immunosuppressive properties represents a novel immunotherapy for treatment of such chronic autoimmune diseases. We used a panel of cytokines and other stimuli to discern the most effective regimen for in vitro induction of immunosuppressive macrophages (M2r) and determined interleukin (IL)-4/IL-10/transforming growth factor-β (TGF-β) to be optimal. M2r cells expressed programmed cell death 1 ligand-2, fragment crystallizable region γ receptor IIb, IL-10, and TGF-β, had a potent deactivating effect on proinflammatory lipopolysaccharide/interferon-γ-stimulated macrophages, and significantly suppressed T-cell proliferation. Clinical therapeutic efficacy was assessed after adoptive transfer in NOD T1D mice, and after a single transfer of M2r macrophages, >80% of treated NOD mice were protected against T1D for at least 3 months, even when transfer was conducted just prior to clinical onset. Fluorescent imaging analyses revealed that adoptively transferred M2r macrophages specifically homed to the inflamed pancreas, promoting β-cell survival. We suggest that M2r macrophage therapy represents a novel intervention that stops ongoing autoimmune T1D and may have relevance in a clinical setting.
    Diabetes 06/2012; 61(11):2881-92. DOI:10.2337/db11-1635 · 8.47 Impact Factor
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