Browsing by Author "Quesniaux, Valerie"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Open Access
    Membrane TNF confers protection to acute mycobacterial infection
    (BioMed Central Ltd, 2005) Fremond, Cecile; Allie, Nasiema; Dambuza, Ivy M; Grivennikov, Sergei; Yeremeev, Vladimir; Quesniaux, Valerie; Jacobs, Muazzam; Ryffel, Bernhard
    BACKGROUND:Tumour necrosis factor (TNF) is crucial for the control of mycobacterial infection as TNF deficient (KO) die rapidly of uncontrolled infection with necrotic pneumonia. Here we investigated the role of membrane TNF for host resistance in knock-in mice with a non-cleavable and regulated allele (mem-TNF). METHODS: C57BL/6, TNF KO and mem-TNF mice were infected with M. tuberculosis H37Rv (Mtb at 100 CFU by intranasal administration) and the survival, bacterial load, lung pathology and immunological parameters were investigated. Bone marrow and lymphocytes transfers were used to test the role of membrane TNF to confer resistance to TNF KO mice. RESULTS: While TNF-KO mice succumbed to infection within 4-5 weeks, mem-TNF mice recruited normally T cells and macrophages, developed mature granuloma in the lung and controlled acute Mtb infection. However, during the chronic phase of infection mem-TNF mice succumbed to disseminated infection with necrotic pneumonia at about 150 days. Reconstitution of irradiated TNF-KO mice with mem-TNF derived bone marrow cells, but not with lymphocytes, conferred host resistance to Mtb infection in TNF-KO mice. CONCLUSION: Membrane expressed TNF is sufficient to allow cell-cell signalling and control of acute Mtb infection. Bone marrow cells, but not lymphocytes from mem-TNF mice confer resistance to infection in TNF-KO mice. Long-term infection control with chronic inflammation likely disrupting TNF mediated cell-cell signalling, additionally requires soluble TNF.
  • Thumbnail Image
    Item
    Open Access
    The susceptibility of baboons to the novel immunosuppressant, FTY720
    (2000) Semple, P L; Quesniaux, Valerie
    Since there is a major scarcity of donor organs world-wide, the experimental search for human organs has focused on two alternatives; mechanical devices and cross-species transplants. The use of mechanical devices as substitute organs is understandably limited due to complications from trying to duplicate the function of complex organs such as the liver. This has resulted in a renewed interest in xenotransplantation. Organs from non-human primates would arguably be the organs of choice but ethical consideration prevents this. The transplantation of organs from pigs or sheep to humans i.e. xenotransplants, results in hyperacute rejection. The development of immunosuppressive agents such as Cyc1osporine A and Tacrolimus have significantly improved the survival of organ transplants. However, although there is a good 1-5 year survival, the recurrent problem of chronic rejection still remains, and unresponsiveness to allografts has never been induced by these immunosuppressive agents. More importantly, the presence of adverse side effects including immunological complications and drug toxicity e.g. nephrotoxicity, remains a serious problem. Since the drugs currently available for allotransplantation preferably target T -cells, and are therefore unlikely to be sufficient for xenotransplantation where there is a strong B-cell driven response, there is a need for new immunosuppressive agents. FTY720 (2 amino-2-(2-[ 4-octylphenyl] ethyl)-1,3-propanediol hydrochloride), a novel, immunosuppressive drug active in rodent and dog transplantation models, has shown no toxic side effects in pre-clinical studies although no long-term patient studies exist.
  • Thumbnail Image
    Item
    Open Access
    TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis
    (BioMed Central Ltd, 2015) Francisco, Ngiambudulu; Hsu, Nai-Jen; Keeton, Roanne; Randall, Philippa; Sebesho, Boipelo; Allie, Nasiema; Govender, Dhirendra; Quesniaux, Valerie; Ryffel, Bernhard; Kellaway, Lauriston; Jacobs, Muazzam
    BACKGROUND: Tuberculosis (TB) affects one third of the global population, and TB of the central nervous system (CNS-TB) is the most severe form of tuberculosis which often associates with high mortality. The pro-inflammatory cytokine tumour necrosis factor (TNF) plays a critical role in the initial and long-term host immune protection against Mycobacterium tuberculosis (M. tuberculosis) which involves the activation of innate immune cells and structure maintenance of granulomas. However, the contribution of TNF, in particular neuron-derived TNF, in the control of cerebral M. tuberculosis infection and its protective immune responses in the CNS were not clear. METHODS: We generated neuron-specific TNF-deficient (NsTNF / ) mice and compared outcomes of disease against TNF f/f control and global TNF / mice. Mycobacterial burden in brains, lungs and spleens were compared, and cerebral pathology and cellular contributions analysed by microscopy and flow cytometry after M. tuberculosis infection. Activation of innate immune cells was measured by flow cytometry and cell function assessed by cytokine and chemokine quantification using enzyme-linked immunosorbent assay (ELISA). RESULTS: Intracerebral M. tuberculosis infection of TNF / mice rendered animals highly susceptible, accompanied by uncontrolled bacilli replication and eventual mortality. In contrast, NsTNF / mice were resistant to infection and presented with a phenotype similar to that in TNF f/f control mice. Impaired immunity in TNF / mice was associated with altered cytokine and chemokine synthesis in the brain and characterised by a reduced number of activated innate immune cells. Brain pathology reflected enhanced inflammation dominated by neutrophil influx. CONCLUSION: Our data show that neuron-derived TNF has a limited role in immune responses, but overall TNF production is necessary for protective immunity against CNS-TB.