Soluble factors, including TNF alpha, secreted by human T cells are both cytotoxic and cytostatic for medulloblastoma cells.

We studied the effect of the treatment of a medulloblastoma cell line by human T cells derived soluble factors. Medulloblastoma is one of the more common aggressive solid neoplasms in children for which there is no adequate therapy. Cell lines established from such tumours may be helpful to test the effect of various molecules on cell proliferation. Previous studies have suggested that T cell-derived factors may be toxic for the medulloblastoma cell line Dev. Cytokines were thought to mediate this effect. In this paper, we described changes in morphology, survival and cell cycle induced in Dev cells cocultured with human T cell lines chronically infected with a retrovirus (HTLV-I) and known to secrete high level of cytokines TNF alpha, IL1alpha and IL6. Such cocultures resulted in the death of a part of Dev cells and in decreased proliferation of surviving cells, associated with morphological changes and increase in vimentin expression. Treatment with conditioned medium from infected Dev cells, containing virus induced cytokines, triggered the same effect. Reduction of these effects by TNF alpha deprivation of conditioned medium suggested that this cytokine may be implicated. Direct treatment of Dev cells with recombinant cytokines indicated that TNF alpha, but not IL1 or IL6, is associated with Dev cell alterations. TNF alpha was shown to induce the death of Dev cells by an apoptotic pathway. Furthermore, TNF alpha had a bimodal effect on the cell cycle of surviving Dev cells. These differential effects of such cytokines on medulloblastoma cells could be therefore of interest for immunotherapy of these tumours.

Effect of parenteral medium- and long-chain triglycerides on lymphocytes subpopulations and functions in patients with acquired immunodeficiency syndrome: a prospective study.

BACKGROUND: Total parenteral nutrition (TPN) may offer significant clinical benefit in malnourished patients with acquired immunodeficiency syndrome (AIDS). However, the immunologic effect of parenteral lipids remains unknown in these severely immunodepressed patients. METHODS: We undertook a prospective randomized double-blind multicenter study comparing the effects of two i.v. lipid emulsions used during TPN: long-chain triglycerides (LCT) or balanced emulsion of long-and medium-chain triglycerides (LCT/MCT). Thirty-three AIDS patients requiring TPN for wasting and reduced oral intake were allocated randomly to receive a ternary TPN mixture consisting of 1.5 g/kg/d proteins, 18 kcal/kg/d lipids, and 12 Kcal/kg/d carbohydrates for 6 days. The following tests were performed at days 0 and 7: immunoglobulins, complement fractions, lymphocyte subpopulations count, and lymphocyte proliferation with mitogens. RESULTS: Patients were all severely malnourished (weight loss: -14.0 +/- 1.3 kg). No clinical or biological differences were observed between the groups at baseline. At day 7, both groups reported a significant increase in weight. Patients in the LCT group exhibited a significant decrease in phytohemagglutinin A response (p = .04) compared with baseline. Patients in the LCT/MCT group exhibited a lower level of IgM (p = .03) and significant increase in C3 fraction (p = .03) compared with baseline. They also showed a tendency to have a higher CD4/CD8 lymphocyte ratio (p = .07), whereas other immunological parameters remained unchanged CONCLUSIONS: Parenteral ternary mixture containing LCT or LCT/MCT are clinically well tolerated in AIDS patients over 6 days. With 2 g/kg/d of lipids, LCT seems to induce significant abnormalities in lymphocyte function. Such abnormalities are not observed with LCT/MCT.

Aerosol administration of a recombinant adenovirus expressing CFTR to cystic fibrosis patients: a phase I clinical trial.

Ad CFTR, a replication-deficient adenovirus expressing the human cystic fibrosis transmembrane conductance regulator (CFTR), was administered by aerosolization in a single escalating dose to three pairs (cohorts) of cystic fibrosis (CF) patients. Buffer only was administered to the nose and lungs 9-14 days before nasal instillation of virus followed the day after by aerosolization of Ad CFTR to the lung. Nasal doses (defined in terms of viral plaque forming units, pfu) were 10(5), 10(7), and 4 x 10(8), whereas aerosolized doses were 10(7), 10(8), 5.4 x 10(8) for each cohort, respectively. No acute toxic effects were observed in the first 4 weeks after virus treatment. Shedding of infectious Ad CFTR was never detected, whereas detection of vector DNA sequences and CFTR expression demonstrated DNA transfer to the nose and airways of patients. No significant deviations in immunological and inflammatory parameters were observed in serum and in bronchoalveolar lavage (BAL). Importantly, for all patients, the serum anti-adenovirus antibody levels did not change significantly from baseline and no antibodies against adenovirus were found in BAL.

Cholera toxin beta subunit induces the differentiation of human medulloblastoma cell line DEV in a neuronal pathway.

Medulloblastomas are primitive neuroectodermal tumours that are thought to arise from multipotent precursor cells in the cerebellum. Medulloblastoma cells may be undifferentiated or exhibit glial, neuronal or ependymal characteristics, suggesting that they may conserve their ability to differentiate in appropriate circumstances. Medulloblastoma cell lines may thus provide models to study the commitment and differentiation of multipotent CNS progenitor cells. A human medulloblastoma cell line, DEV, has previously been shown to differentiate in an astrocytic pathway after infection by the retrovirus HTLV-1. In this study immunofluorescence flow cytometry shows that cholera toxin beta subunit (CT beta), which binds to the ganglioside GM1, induces a twofold increase in the number of DEV cells differentiating towards a neuronal pathway, as shown by the increased proportion and labelling intensity of cells stained by an anti-neurofilament antibody. Immunocytochemistry shows that after 3 days in culture with CT beta, DEV cells develop processes which stain positive for neurofilaments and MAP-1. This suggests that CT beta induces DEV cells to express a more neuronal phenotype.