Laboratory of Translational Immunology

The use of probiotics as a food supplement has gained tremendous interest in the last few years as beneficial effects were reported in gut homeostasis and nutrient absorption but also in immunocompromised patients, supporting protection from colonization or infection with pathogenic bacteria or fungi. As a treatment approach for inflammatory bowel diseases, a suitable probiotic strain would ideally be one with a low immunogenic potential.

Current multimodal treatments for patients with neuroblastoma (NBL), including anti-disialoganglioside (GD2) monoclonal antibody (mAb) based immunotherapy, result in a favorable outcome in around only half of the patients with advanced disease. To improve this, novel immunocombinational strategies need to be developed and tested in autologous preclinical NBL models. A genetically well-explored autologous mouse model for NBL is the TH-MYCN model. However, the immunobiology of the TH-MYCN model remains largely unexplored. We developed a mouse model using a transplantable TH-MYCN cell line in syngeneic C57Bl/6 mice and characterized the immunobiology of this model. In this report, we show the relevance and opportunities of this model to study immunotherapy for human NBL. Similar to human NBL cells, syngeneic TH-MYCN-derived 9464D cells endogenously express the tumor antigen GD2 and low levels of MHC Class I. The presence of the adaptive immune system had little or no influence on tumor growth, showing the low immunogenicity of the NBL cells. In contrast, depletion of NK1.11 cells resulted in enhanced tumor outgrowth in both wild-type and Rag1 2/2 mice, showing an important role for NK cells in the natural anti-NBL immune response. Analysis of the tumor infiltrating leukocytes ex vivo revealed the presence of both tumor associated myeloid cells and T regulatory cells, thus mimicking human NBL tumors. Finally, anti-GD2 mAb mediated NBL therapy resulted in ADCC in vitro and delayed tumor outgrowth in vivo. We conclude that the transplantable TH-MYCN model represents a relevant model for the development of novel immunocombinatorial approaches for NBL patients.

The superoxide-forming NADPH oxidase of human phagocytes is composed of membrane-bound and cytosolic proteins which, upon cell activation, assemble on the plasma membrane to form the active enzyme. Patients suffering from chronic granulomatous disease (CGD) are defective in one ofthe following components: p47-phox and p67-phox, residing in the cytosol of resting phagocytes, and gp9l-phox and p22-phox, constituting the membrane-bound cytochrome b55s. In an X-linked CGD patient we identified a novel missense mutation predicting an Asp --Gly substitution at residue 500 of gp9l-phox, associated with normal amounts of nonfunctional cytochrome b559 in the patient's neutrophils. In PMA-stimulated neutrophils and in a cell-free translocation assay with neutrophil membranes and cytosol, the association of the cytosolic proteins p47-phox and p67-phox with the membrane fraction of the patient was strongly disturbed. Furthermore, a synthetic peptide mimicking domain 491-504 of gp9l-phox inhibited NADPH oxidase activity in the cell-free assay (IC5o about 10 ,uM), and the translocation of p47-phox and p67-phox in the cell-free translocation assay. We conclude that residue 500 of gp9l-phox resides in a region critical for stable binding of p47phox and p67-phox. (J. Clin. Invest. 1994.95:2120-2126 cell activation, p47-phox and p67-phox translocate to the plasma membrane, to form the membrane-bound oxidase

oxidase: consequences for oxidase assembly of human NADPH phox Four novel mutations in the gene encoding gp91http://bloodjournal.hematologylibrary.org/content/95/2/666.full.html Updated information and services can be found at: (973 articles) Phagocytes Articles on similar topics can be found in the following Blood collections http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub_requests

Guillain-Barré syndrome (GBS) is an immune-mediated neuropathy, in which leukocytes and humoral components of the immune system proposedly initiate localized inflammation. An important pathogenic role for anti-GM1 ganglioside antibodies has been suggested. Therefore, we evaluated anti-GM1 IgG antibody-induced leukocyte effector functions such as degranulation and phagocytosis using serum of 24 GBS patients. Serum without anti-GM1 antibodies of 9 GBS patients as well as pooled serum from healthy individuals served as controls. Ten out of 15 (67%) of anti-GM1 IgG positive sera were capable of inducing leukocyte degranulation, and 8 out of 15 (53%) of anti-GM1 IgG positive sera were capable of inducing phagocytosis of GM1-coated beads. In all of these sera anti-GM1 antibody titers were >1:800.