Development of an Interleukin-1ß Vaccine in Patients with Type 2 Diabetes.

Interleukin-1ß (IL-1ß) is a key cytokine involved in inflammatory illnesses including rare hereditary diseases and common chronic inflammatory conditions as gout, rheumatoid arthritis, and type 2 diabetes mellitus, suggesting reduction of IL-1ß activity as new treatment strategy. The objective of our study was to assess safety, antibody response, and preliminary efficacy of a novel vaccine against IL-1ß. The vaccine hIL1bQb consisting of full-length, recombinant IL-1ß coupled to virus-like particles was tested in a preclinical and clinical, randomized, placebo-controlled, double-blind study in patients with type 2 diabetes. The preclinical simian study showed prompt induction of IL-1ß-specific antibodies upon vaccination, while neutralizing antibodies appeared with delay. In the clinical study with 48 type 2 diabetic patients, neutralizing IL-1ß-specific antibody responses were detectable after six injections with doses of 900 µg. The development of neutralizing antibodies was associated with higher number of study drug injections, lower baseline body mass index, improvement of glycemia, and C-reactive protein (CRP). The vaccine hIL1bQb was safe and well-tolerated with no differences regarding adverse events between patients receiving hIL1bQb compared to placebo. This is the first description of a vaccine against IL-1ß and represents a new treatment option for IL-1ß-dependent diseases such as type 2 diabetes mellitus (ClinicalTrials.gov NCT00924105).

Identification of a SIRT1 mutation in a family with type 1 diabetes.

Type 1 diabetes is caused by autoimmune-mediated ß cell destruction leading to insulin deficiency. The histone deacetylase SIRT1 plays an essential role in modulating several age-related diseases. Here we describe a family carrying a mutation in the SIRT1 gene, in which all five affected members developed an autoimmune disorder: four developed type 1 diabetes, and one developed ulcerative colitis. Initially, a 26-year-old man was diagnosed with the typical features of type 1 diabetes, including lean body mass, autoantibodies, T cell reactivity to ß cell antigens, and a rapid dependence on insulin. Direct and exome sequencing identified the presence of a T-to-C exchange in exon 1 of SIRT1, corresponding to a leucine-to-proline mutation at residue 107. Expression of SIRT1-L107P in insulin-producing cells resulted in overproduction of nitric oxide, cytokines, and chemokines. These observations identify a role for SIRT1 in human autoimmunity and unveil a monogenic form of type 1 diabetes.

Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes.

OBJECTIVE: Metabolic activation of the innate immune system governed by interleukin (IL)-1ß contributes to ß-cell failure in type 2 diabetes. Gevokizumab is a novel, human-engineered monoclonal anti-IL-1ß antibody. We evaluated the safety and biological activity of gevokizumab in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: In a placebo-controlled, dose-escalation study, a total of 98 patients were randomly assigned to placebo (17 subjects) or gevokizumab (81 subjects) at increasing doses and dosing schedules. The primary objective of the study was to evaluate the safety profile of gevokizumab in type 2 diabetes. The secondary objectives were to assess pharmacokinetics for different dose levels, routes of administration, and regimens and to assess biological activity. RESULTS: The study drug was well tolerated with no serious adverse events. There was one hypoglycemic event whereupon concomitant insulin treatment had to be reduced. Clearance of gevokizumab was consistent with that for a human IgG(2), with a half-life of 22 days. In the combined intermediate-dose group (single doses of 0.03 and 0.1 mg/kg), the mean placebo-corrected decrease in glycated hemoglobin was 0.11, 0.44, and 0.85% after 1, 2 (P = 0.017), and 3 (P = 0.049) months, respectively, along with enhanced C-peptide secretion, increased insulin sensitivity, and a reduction in C-reactive protein and spontaneous and inducible cytokines. CONCLUSIONS: This novel IL-1ß-neutralizing antibody improved glycemia, possibly via restored insulin production and action, and reduced inflammation in patients with type 2 diabetes. This therapeutic agent may be able to be used on a once-every-month or longer schedule.

[Homeparenteral nutrition or nutrition for life]. / Heimparenterale Ernährung oder Ernährung um zu leben.

We describe the management of HPN on the basis of a case report. Since TPN is associated with severe complications such as catheter-related sepsis, thrombosis of venous access, metabolic disorders and liver disease, education and peer support of HPN-patients is an important issue and is associated with reduced depression, reduced septic complications and improved QoL. Although SBTx has advanced in the last years, SBTx is only an option when TPN failed, as survival rates after SBTx are still low compared to treatment with TPN.

Podocyte bridges between the tuft and Bowman's capsule: an early event in experimental crescentic glomerulonephritis.

Although experimental crescentic glomerulonephritis starts with an endocapillary inflammation, the crescents themselves seem to originate from the proliferation of parietal epithelial cells (PEC). In this study, an attempt was made to disclose a link between the two processes by a morphologic analysis of early stages of the disease. Mice were immunized with rabbit IgG in complete Freund's adjuvant on day -6. At day 0, they received an intravenous injection of a rabbit antiglomerular basement membrane serum. On days 3, 6, and 10, the kidneys were fixed by vascular perfusion for examination by light and electron microscopy. On day 3, morphologic alterations affected mainly the endocapillary compartment; most podocytes appeared to be intact. On day 6, alterations of podocytes were widespread, including foot process effacement and prominent microvillous transformation, and some crescents were found. On day 10, crescents were found in 40% of glomeruli. The most surprising finding was podocytes that adhered to both the glomerular basement membrane and the parietal basement membrane, thus forming bridges between the tuft and Bowman's capsule. Those podocyte bridges were sparse on day 3 but were regularly encountered on days 6 and 10 in glomeruli without crescents and also as a component of crescents. They were interposed between PEC and later between the cells of a crescent without formation of junctional connection with these cells. It is proposed that the spreading of podocytes on the parietal basement membrane represents a lesion of the parietal epithelium and that this process initiates the proliferation of PEC to form a crescent.