A role for exposed mannosylations in presentation of human therapeutic self-proteins to CD4+ T lymphocytes

Several therapeutic self-proteins elicit immune responses when administered to patients. Such adverse immune responses reduce drug efficacy. To induce an immune response, a protein must interact with different immune cells, including antigen-presenting cells, T cells, and B cells. Each cell type recognizes distinct immunogenic patterns on antigens. Mannose-terminating glycans have been identified as pathogen-associated molecular patterns that are essential for internalization of microbes by antigen-presenting cells, leading to presentation. Here, we have investigated the importance of exposed mannosylation on an immunogenic therapeutic self-protein, procoagulant human factor VIII (FVIII). Administration of therapeutic FVIII to hemophilia A patients induces inhibitory anti-FVIII antibodies in up to 30% of the cases. We demonstrate that entry of FVIII into human dendritic cells (DC) leading to T cell activation, is mediated by mannose-terminating glycans on FVIII. Further, we identified macrophage mannose receptor (CD206) as a candidate endocytic receptor for FVIII on DC. Saturation of mannose receptors on DC with mannan, and enzymatic removal of mannosylated glycans from FVIII lead to reduced T cell activation. The interaction between FVIII and CD206 was blocked by VWF, suggesting that, under physiological conditions, the intrinsic mannose-dependent immunogenicity of FVIII is quenched by endogenous immunochaperones. These data provide a link between the mannosylation of therapeutic self-proteins and their iatrogenic immunogenicity. Such a link would be of special relevance in the context of replacement therapy where mechanisms of central and peripheral tolerance have not been established during ontogeny because of the absence of the antigen.     

Chemotherapy as initial treatment of locally advanced unresectable pancreatic cancer: a valid option?

INTRODUCTION: Radio-chemotherapy is the standard treatment for locally advanced unresectable pancreatic cancer (LAPC). Chemotherapy has been shown to be effective in the treatment of metastatic disease and we therefore evaluated its use as a first-line treatment for LAPC. PATIENTS AND METHODS: We carried out a retrospective analysis of all consecutive patients treated for LAPC (N=33) between July 1997 and April 2005, analysing the results of first-line chemotherapy (CT group) and radio-chemotherapy (RCT group) in this setting. RESULTS: The first-line treatment was RCT in six patients (18.3%) and CT in 26 patients (78.8%). Secondary treatment was administered to nine patients of CT group with well-controlled disease: "closure" radio-chemotherapy for seven patients (26.9%) and secondary resection for three (12%). After a median follow-up of 27 months, 23 patients died (69.7%). Overall survival was 13.8 months [95% CI: 10.1-19.4] for the whole population, 9.5 months [95% CI: 4.6-] for the RCT and 18.0 months [95% CI: 12.4-25.5] for the CT. Overall survival for the CT patients undergoing secondary surgery or "consolidation" radio-chemotherapy was 28.8 months [95% CI: 13.8-]. CONCLUSION: First-line chemotherapy is a valid option for LAPC treatment, making it possible to identify the patients who may benefit from secondary resection or radio-chemotherapy.     

Hepatitis C awareness among adolescents in the Alpes-Maritimes area of France

OBJECTIVES: Certain practices with a potential risk of hepatitis C virus (HCV) transmission begin early, during adolescence. In 2004, primary prevention interventions targeting adolescents aged 13-17 years attending school in the Alpes-Maritimes region of France were conducted by the "Réseau Hépatite C Ville H?pital C?te d'Azur". The aim of this study was to assess the adolescents' knowledge about HCV and to evaluate the impact of such interventions.METHODS: A random sample of secondary state schools in the Alpes-Maritimes was invited to participate in the study. Before and after presenting a slide show about HCV in the selected classrooms, the investigators asked the students to complete an anonymous self-administered questionnaire designed to assess their knowledge about HCV infection.RESULTS: The intervention concerned a study population of 2,946 students, mean age 14.4 +/- 2.5 years. Before the interventions, 21% had good knowledge of HCV infection and 24% had good know-ledge of disease contagion. These percentages increased significantly after the interventions to 95% and 84% respectively. Knowledge improvement was more significant among high school students and among students whose parents had an employment.CONCLUSIONS: Adolescents are poorly informed about HCV infection. The present intervention enabled significant improvement in their knowledge about the infection and disease contagion, independently of gender, age and geographical area.     

International consensus in Paris, 2006, on the indications and use of the endoscopic videocapsule test. Report of the SFED Capsule Commission

Following the 4th International Conference on Capsule Endoscopy (ICCE, Miami 2005), the main indications for videocapsule endoscopy (VCE) were reviewed. The consensus guidelines were published in Endoscopy in 2005. These propositions for VCE were based on an analysis of evidence reported in the literature published through 2005. A small working group of experts examined each methodology and presented their report at the plenary session. The final conclusions were then published. At the ICCE 2006 held in Paris, this first version of the consensus guidelines was improved and completed.     

Ureteral obstruction and Crohn's disease

Noncalculous ureteral obstructions in Crohn's disease are often asymptomatic and unidentified. Occurring in about 3% of patients, they occur on the right side in more than 70% of cases, because of frequently associated ileocecal disease. If they are associated with inflammation or fibrosis of retroperitoneal periureteral fat nephrectomy may become necessary. Conservative treatment should be considered first, with urine drainage (ureteral stent, or percutaneous nephrostomy), diet, and corticotherapy. However bowel resection is often necessary during follow up. If this fails to cure the ureteral obstruction, ureterolysis should be performed. We report the case of a 32 year old woman with noncalculous ureteral obstruction revealing Crohn's disease.