Recurrence of Type 1 Diabetes After Simultaneous Pancreas-Kidney Transplantation, Despite Immunosuppression, Is Associated With Autoantibodies and Pathogenic Autoreactive CD4 T-Cells

ObjectiveTo investigate if recurrent autoimmunity explained hyperglycemia and C-peptide loss in three immunosuppressed simultaneous pancreas-kidney (SPK) transplant recipients.Research design and methodsWe monitored autoantibodies and autoreactive T-cells (using tetramers) and performed biopsy. The function of autoreactive T-cells was studied with in vitro and in vivo assays.ResultsAutoantibodies were present pretransplant and persisted on follow-up in one patient. They appeared years after transplantation but before the development of hyperglycemia in the remaining patients. Pancreas transplant biopsies were taken within approximately 1 year from hyperglycemia recurrence and revealed beta-cell loss and insulitis. We studied autoreactive T-cells from the time of biopsy and repeatedly demonstrated their presence on further follow-up, together with autoantibodies. Treatment with T-cell-directed therapies (thymoglobulin and daclizumab, all patients), alone or with the addition of B-cell-directed therapy (rituximab, two patients), nonspecifically depleted T-cells and was associated with C-peptide secretion for >1 year. Autoreactive T-cells with the same autoantigen specificity and conserved T-cell receptor later reappeared with further C-peptide loss over the next 2 years. Purified autoreactive CD4 T-cells from two patients were cotransplanted with HLA-mismatched human islets into immunodeficient mice. Grafts showed beta-cell loss in mice receiving autoreactive T-cells but not control T-cells.ConclusionsWe demonstrate the cardinal features of recurrent autoimmunity in three such patients, including the reappearance of CD4 T-cells capable of mediating beta-cell destruction. Markers of autoimmunity can help diagnose this underappreciated cause of graft loss. Immune monitoring during therapy showed that autoimmunity was not resolved by the immunosuppressive agents used

Investigating the Role of T-Cell Avidity and Killing Efficacy in Relation to Type 1 Diabetes Prediction

During the progression of the clinical onset of Type 1 Diabetes (T1D), high-risk individuals exhibit multiple islet autoantibodies and high-avidity T cells which progressively destroy beta cells causing overt T1D. In particular, novel autoantibodies, such as those against IA-2 epitopes (aa1-577), had a predictive rate of 100% in a 10-year follow up (rapid progressors), unlike conventional autoantibodies that required 15 years of follow up for a 74% predictive rate (slow progressors). The discrepancy between these two groups is thought to be associated with T-cell avidity, including CD8 and/or CD4 T cells. For this purpose, we build a series of mathematical models incorporating first one clone then multiple clones of islet-specific and pathogenic CD8 and/or CD4 T cells, together with B lymphocytes, to investigate the interaction of T-cell avidity with autoantibodies in predicting disease onset. These models are instrumental in examining several experimental observations associated with T-cell avidity, including the phenomenon of avidity maturation (increased average T-cell avidity over time), based on intra- and cross-clonal competition between T cells in high-risk human subjects. The model shows that the level and persistence of autoantibodies depends not only on the avidity of T cells, but also on the killing efficacy of these cells. Quantification and modeling of autoreactive T-cell avidities can thus determine the level of risk associated with each type of autoantibodies and the timing of T1D disease onset in individuals that have been tested positive for these autoantibodies. Such studies may lead to early diagnosis of the disease in high-risk individuals and thus potentially serve as a means of staging patients for clinical trials of preventive or interventional therapies far before disease onset

The Effect of Opioid Receptor Blockade on the Neural Processing of Thermal Stimuli

The endogenous opioid system represents one of the principal systems in the modulation of pain. This has been demonstrated in studies of placebo analgesia and stress-induced analgesia, where anti-nociceptive activity triggered by pain itself or by cognitive states is blocked by opioid antagonists. The aim of this study was to characterize the effect of opioid receptor blockade on the physiological processing of painful thermal stimulation in the absence of cognitive manipulation. We therefore measured BOLD (blood oxygen level dependent) signal responses and intensity ratings to non-painful and painful thermal stimuli in a double-blind, cross-over design using the opioid receptor antagonist naloxone. On the behavioral level, we observed an increase in intensity ratings under naloxone due mainly to a difference in the non-painful stimuli. On the neural level, painful thermal stimulation was associated with a negative BOLD signal within the pregenual anterior cingulate cortex, and this deactivation was abolished by naloxone

ConectCat : aplicación web : fiestas locales y otros servicios y puntos de interés en Cataluña

Aplicación web basada en mapas interactivos y timeline. Permite visualizar las fiestas locales así como otros servicios y puntos de interés de Cataluña

Microalgae as a promising and sustainable nutrition source for managed honey bees

Managed honey bee colony losses are attributed to a number of interacting stressors, but many lines of evidence point to malnutrition as a primary factor. Commercial beekeepers have become increasingly reliant on artificial pollen substitute diets to nourish colonies during periods of forage scarcity and to bolster colony size before pollination services. These artificial diets may be deficient in essential macronutrients (proteins, lipids, prebiotic fibers), micronutrients (vitamins, minerals), and antioxidants. Therefore, improving the efficacy of pollen substitutes can be considered vital to modern beekeeping. Microalgae are prolific sources of plant‐based nutrition with many species exhibiting biochemical profiles that are comparable to natural pollen. This emerging feed source has been employed in a variety of organisms, including limited applications in honey bees. Herein, I introduce the nutritional value and functional properties of microalgae, extrapolating to central aspects of honey bee physiology and health. To conclude, I discuss the potential of microalgae‐based feeds to sustainably provision managed colonies on an agricultural scale

Honey Bee Nutrition

This item is part of the Arizona Land and People (formerly Progressive Agriculture in Arizona) archive. It was digitized from a physical copy provided by the College of Agriculture and Life Sciences at The University of Arizona. For more information about this periodical, please email CALS Publications at [email protected]

Carbohydrates in Honey Bee Hemolymph

1. The hemolymph sugars of honey bees (Apis mellifera) were determined by spectrophotometric and gas-liquid chromatographic methods. 2. A new phenol-acetate reagent was developed that enabled quantification of trehalose in the presence of sucrose. 3. The results of these analyses provide insight into the means by which honey ees utilize hemolyph sugars for energy for flight

Pesticides and honey bees /

no.56

AMINO ACIDS AND PROTEIN ADEQUACY FOR HONEY BEES OF POLLENS FROM DESERT PLANTS AND OTHER FLORAL SOURCES

International audienc