Granulocyte macrophage-colony stimulating factor (GM-CSF) is one of the most widely used growth factors for enhancing immune responses and is known to recruit and activate antigen-presenting cells (APCs). This study hypothesized that overexpression of this cytokine within the pancreatic beta-cells would recruit, expand, and activate APCs. The question was whether this would lead to tolerance or autoimmunity to pancreatic antigens. This possibility was tested by preparing transgenic mice (ins-GM-CSF) whose islets expressed murine GM-CSF. By 6-8 weeks of age, these mice developed a profound mononuclear cell infiltration that often overwhelmed the exocrine pancreas, although no changes in enzyme or hormone function were apparent. The majority of the mononuclear infiltrate within the pancreas was identified as F4/80+ macrophages. Transgenic ins-GM-CSF mice had splenomegaly due to a massive increase in the macrophage population. Additionally, mononuclear cells were found within the livers of transgenic mice, with F4/80+ cells also identified within the infiltrate, indicating that GM-CSF-activated mononuclear cells circulated to organs other than the pancreas. To assess the disease potential, this study tested whether macrophage recruitment to the pancreas might accelerate or protect the islets from diabetes. It was found that the induction of diabetes by low-dose streptozotocin (STZ) was delayed and reduced within ins-GM-CSF transgenic mice, in comparison with negative littermates. Together, these data highlight the role of GM-CSF in recruiting APCs such as macrophages. Advanced cellular infiltration does not overtly harm, and may even protect, pancreatic function, as seen with the delay in chemically induced diabetes.

In the presence of interferon-gamma (IFN-gamma), pancreatic ductal epithelial cells grow continuously, and islets undergo neogenesis. To determine whether these new islets are derived from conventional precursors, we tested whether IFN-gamma can complement the loss of transcription factors known to regulate pancreatic development. We analyzed the effect of a transgene on lethality in mice lacking the transcription factors Pax4, Pax6, or Pdx-1, by intercrossing such mice with transgenic mice whose pancreatic cells make IFN-gamma (ins-IFN-gamma mice). However, IFN-gamma expression did not rescue these mice from the lethal mutations, because no homozygous knockout mice carrying the IFN-gamma transgene survived, despite the survival of all other hemizygous gene combinations. This outcome demonstrates that the pathway for IFN-gamma regeneration requires the participation of Pax4, Pax6, and Pdx-1. We conclude that the striking islet regeneration observed in the ins-IFN-gamma NOD strain is regulated by the same transcription factors that control initial pancreatic development.

The aims of this study were (1) to evaluate the prognostic value of negative wall motion (WM) and myocardial perfusion during contrast-dobutamine stress echocardiography (DSE), (2) to determine whether WM-myocardial contrast echocardiography (MCE) had incremental prognostic value over just WM during DSE in patients with chest pain in the emergency room(ER), and (3) to compare the prognostic value of negative DSE-WM, and DSE-WM-MCE to nuclear-myocardial perfusion imaging (N-MPI) in a similar patient population over the same time period. We retrospectively studied 569 patients with real time contrast DSE, and 147 patients underwent N-MPI for evaluation of chest pain. Follow-up for cardiac events was obtained between 12 and 25 months. The cumulative cardiac event-free survival was 94.5% in negative DSE-WM, 97.1% in negative DSE-WM-MCE and 96.7% in negative N-MPI group. Cardiac event-free survival of the negative DSE-WM-MCE group was significantly higher than the DSE-WM group (log rank P < 0.01), and similar in the DSE-WM-MCE group compared to the N-MPI group. Combined WM and perfusion during DSE was the strongest independent predictor for cardiac events. The negative predictive power of DSE-WM-MCE is superior to that of just negative DSE-WM and is comparable to that of N-MPI. Myocardial perfusion and WM analysis during DSE provide independent information for predicting cardiac events in patients with chest pain syndrome in the ER.

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