Combination Therapy Reverses Hyperglycemia in NOD Mice With Established Type 1 Diabetes

An increasing number of therapies have proven effective at reversing hyperglycemia in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D), yet situations of successful translation to human T1D are limited. This may be partly due to evaluating the effect of treating immediately at diagnosis in mice, which may not be reflective of the advanced disease state in humans at disease onset. In this study, we treated NOD mice with new-onset as well as established disease using various combinations of four drugs: antithymocyte globulin (ATG), granulocyte-colony stimulating factor (G-CSF), a dipeptidyl peptidase IV inhibitor (DPP-4i), and a proton pump inhibitor (PPI). Therapy with all four drugs induced remission in 83% of new-onset mice and, remarkably, in 50% of NOD mice with established disease. Also noteworthy, disease remission occurred irrespective of initial blood glucose values and mechanistically was characterized by enhanced immunoregulation involving alterations in CD4⁺ T cells, CD8⁺ T cells, and natural killer cells. This combination therapy also allowed for effective treatment at reduced drug doses (compared with effective monotherapy), thereby minimizing potential adverse effects while retaining efficacy. This combination of approved drugs demonstrates a novel ability to reverse T1D, thereby warranting translational consideration.     

Long-term unpredictable foraging conditions and physiological stress response in mountain chickadees (Poecile gambeli)

Birds respond to short-term deterioration in foraging conditions by increasing their plasma level of corticosterone but the physiological effects of long-term deterioration in food supplies are not well known. In resident passerine birds that winter in temperate climates, such as the mountain chickadee (Poecile gambeli), the food supply may be limited and unpredictable over long periods of time. Whether the long-term limited and unpredictable food supply has an effect on (a) baseline levels of corticosterone and (b) the adrenocortical stress response to a standardized acute stress of handling and restraint in mountain chickadees was assessed. For a period of 94 days, one group of chickadees was maintained on limited and unpredictable food (food-restricted) and the other group was maintained on an ad libitum food supply. The food-restricted birds had significantly higher baseline levels of corticosterone than those maintained on ad libitum food. All birds responded to the acute stressor by an increasing secretion of corticosterone but there were no differences between the treatment groups in their stress response. There was a significant effect of sex on the stress response, with females reaching higher levels of corticosterone and responding at a faster rate than males. These results suggest that permanent resident birds wintering in harsh environments may have elevated levels of corticosterone on a long-term basis. Whereas other factors, such as day length and ambient temperature, may contribute to energetic hardship during the winter, the results showed that limited and unpredictable food alone can trigger significant changes in baseline levels of plasma corticosterone. The potential costs and benefits of long-term increased corticosterone levels in resident food-caching birds are discussed.     

Cell wall lipids from Mycobacterium bovis BCG are inflammatory when inoculated within a gel matrix: characterization of a new model of the granulomatous response to mycobacterial components

The chronic inflammatory response to Mycobacterium generates complex granulomatous lesions that balance containment with destruction of infected tissues. To study the contributing factors from host and pathogen, we developed a model wherein defined mycobacterial components and leukocytes are delivered in a gel, eliciting a localized response that can be retrieved and analysed. We validated the model by comparing responses to the cell wall lipids from Mycobacterium bovis bacillus Calmette-Guerin (BCG) to reported activities in other models. BCG lipid-coated beads and bone marrow-derived macrophages (input macrophages) were injected intraperitoneally into BALB/c mice. Input macrophages and recruited peritoneal exudate cells took up fluorescently tagged BCG lipids, and matrix-associated macrophages and neutrophils produced tumor necrosis factor, interleukin-1alpha, and interleukin-6. Leukocyte numbers and cytokine levels were greater in BCG lipid-bearing matrices than matrices containing non-coated or phosphatidylglycerol-coated beads. Leukocytes arrived in successive waves of neutrophils, macrophages and eosinophils, followed by NK and T cells (CD4(+), CD8(+), or gammadelta) at 7 days and B cells within 12 days. BCG lipids also predisposed matrices for adherence and vascularization, enhancing cellular recruitment. We submit that the matrix model presents pertinent features of the murine granulomatous response that will prove to be an adaptable method for study of this complex response.