There is a growing body of evidence to suggest that the autoimmunity observed in type 1 diabetes mellitus (T1DM) is the result of an imbalance between autoaggressive and regulatory cell subsets. Therapeutics that supplement or enhance the existing regulatory subset are therefore a much sought after goal in this indication. Here, we report the results of a double blind, placebo controlled, phase I clinical trial of a novel antigen-specific therapeutic in 12 subjects with recently diagnosed T1DM. Our primary objective was to test its safety. The study drug, human insulin Bchain in incomplete Freund's adjuvant (IFA) was administered as a single intramuscular injection, with subjects followed for 2 years. All subjects completed therapy and all follow-up visits. The therapy was generally safe and well-tolerated. Mixed meal stimulated C-peptide responses, measured every 6 months, showed no statistical differences between arms. All patients vaccinated with the autoantigen, but none who received placebo, developed robust insulin-specific humoral and T cell responses. Up to two years following the single injection, in peripheral blood from subjects in the experimental arm, but not the control arm, insulin B-chain-specific CD4+ T cells could be isolated and cloned that showed phenotypic and functional characteristics of regulatory T cells. The induction of a lasting, robust immune response generating autoantigen-specific regulatory T cells provides strong justification for further testing of this therapy in type 1 diabetes. (clinicaltrials.gov identifier NCT00057499).
Invariant NKT (iNKT) cells are considered to be important in some autoimmune diseases including Type 1 diabetes mellitus (T1DM). So far, the published data are contradictory in regard to the role of iNKT cells in T1DM. We aimed to study iNKT cell frequency and the function of different iNKT cell subgroups in T1DM. We compared the results of four subject groups: healthy (H), long-term T2DM (ltT2DM; more than 1 year), newly diagnosed T1DM (ndT1DM; less than 3 months), and ltT1DM (more than 1 year) individuals. We measured the iNKT cell frequencies by costaining for the invariant TCR alpha-chain with 6B11-FITC and Valpha24-PE. After sorting the Valpha24+6B11+ cells, the generated iNKT clones were characterized. We tested CD4, CD8, and CD161 expression and IL-4 and IFN-gamma production on TCR stimulation. The CD4+ population among the iNKT cells was decreased significantly in ltT1DM versus ndT1DM, ltT2DM, or H individuals. The T1DM iNKT cell cytokine profile markedly shifted to the Th1 direction. There was no difference in the frequency of iNKT cells in PBMC among the different patient groups. The decrease in the CD4+ population among the iNKT cells and their Th1 shift indicates dysfunction of these potentially important regulatory cells in T1DM.
Steadfast progress has been made from biopsy to surgery with interventional MRI (iMRI). Such image-guided interventions require specialized instrumentation due to the unusual elements of the MR environment. Suppliers/manufacturers of MR-compatible instrumentation were few in 1994, but now there are more than 50. We present fundamental issues of MR compatibility and a list of known suppliers/manufacturers.
We report the first endoscopic surgeries performed with patients under general anesthesia using intraoperative guidance with MRI. The procedures were experimental and intended to test (1) the unusual working environment of a unique new "open-configuration" MRI unit for head and neck surgery, and (2) real-time image guidance. Twelve patients underwent endoscopic sinus surgery while under general anesthesia in a new open MRI unit that provides the surgeon with access to the patient while imaging is performed. Eleven patients had chronic sinusitis (eight of them had bilateral disease), and one had a right nasoethmoid and antral tumor. All 12 surgeries were performed without complications. Both the endoscopic view and the MRI scans were available at the surgical field. The image plane was surgeon controlled, and the MRI updated images in as little as 14 seconds. MRI provided adequate visualization of both the disease and the related anatomy and allowed the surgeon to navigate during the procedure. The intraoperative data reflect the tissue changes during surgery and provide optimum feedback for surgical guidance. Although the operating environment poses some limitations, it has become apparent that intraoperative MRI has a role in the treatment of head and neck disorders and warrants further study.
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