55 research outputs found

    Apoptosis of Inflammatory Cells in Immune Control of the Nervous System: Role of Glia

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    Normal individuals have T lymphocytes capable of reacting to central nervous system (CNS) antigens such as myelin basic protein (MBP) (Martin et al., [1990]). In view of recent evidence indicating that T cells are much more cross-reactive than previously thought (Mason, [1998]), it is likely that these autoreactive T cells are often primed by exposure to cross-reacting environmental antigens. Indeed it has been shown that viral and bacterial peptides can activate myelin-reactive human T cells (Wucherpfennig and Strominger, [1995]; Hemmer et al., [1997]). Furthermore, normal healthy subjects experience surges of increased frequencies of circulating myelin-reactive T cells that might be driven by cross-reactive environmental antigens (Pender et al., [2000]). Such activated myelin-reactive T cells would be expected to enter the CNS in healthy individuals, because activated T cells of any specificity, including autoreactive T cells, enter the normal CNS parenchyma (Wekerle et al., [1986]; Hickey et al., [1991]). If CNS-reactive T cells survive in the CNS, they have the potential to attack the CNS, either directly or through the recruitment of other inflammatory cells, and thus lead to CNS damage such as demyelination. Therefore, the physiological control of autoreactive T cells in the CNS is likely to have an important role in preventing the development of autoimmune CNS disorders such as multiple sclerosis (MS) (Pender, [1998]). T-cell apoptosis in the CNS has been proposed to be an important mechanism for controlling autoimmune attacks on the CNS (Pender et al., [1992]; Schmied et al., [1993]). Although other mechanisms, such as immune deviation (Wenkel et al., [2000]), may possibly also contribute to the control of the immune response in the CNS, this review will focus on T-cell apoptosis in the CNS and the role of glia in this process

    TNFR1 inhibition with a nanobody protects against EAE development in mice

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    TNF has as detrimental role in multiple sclerosis (MS), however, anti-TNF medication is not working. Selective TNF/TNFR1 inhibition whilst sparing TNFR2 signaling reduces the pro-inflammatory effects of TNF but preserves the important neuroprotective signals via TNFR2. We previously reported the generation of a Nanobody-based selective inhibitor of human TNFR1, TROS that will be tested in experimental autoimmune encephalomyelitis (EAE). We specifically antagonized TNF/TNFR1 signaling using TROS in a murine model of MS, namely MOG(35-55)-induced EAE. Because TROS does not cross-react with mouse TNFR1, we generated mice expressing human TNFR1 in a mouse TNFR1-knockout background (hTNFR1 Tg), and we determined biodistribution of Tc-99m-TROS and effectiveness of TROS in EAE in those mice. Biodistribution analysis demonstrated that intraperitoneally injected TROS is retained more in organs of hTNFR1 Tg mice compared to wild type mice. TROS was also detected in the cerebrospinal fluid (CSF) of hTNFR1 Tg mice. Prophylactic TROS administration significantly delayed disease onset and ameliorated its symptoms. Moreover, treatment initiated early after disease onset prevented further disease development. TROS reduced spinal cord inflammation and neuroinflammation, and preserved myelin and neurons. Collectively, our data illustrate that TNFR1 is a promising therapeutic target in MS

    Cultured Murine Thyroid Epithelial Cells Expressing Transgenic Fas-Associated Death Domain-Like Interleukin-1β Converting Enzyme Inhibitory Protein Are Protected from Fas-Mediated Apoptosis

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    The antiapoptotic molecule Fas-associated death domain-like IL-1β-converting enzyme inhibitory protein (FLIP) inhibits Fas-mediated apoptosis by blocking activation of caspase-8. We previously showed that expression of transgenic FLIP on thyroid epithelial cells (TECs) of DBA/1 and CBA/J mice promoted earlier resolution of granulomatous experimental autoimmune thyroiditis in vivo. This study was undertaken to directly determine whether transgenic FLIP expressed on cultured TECs can protect TECs from Fas-mediated apoptosis in vitro. The results indicate that cultured TECs from DBA/1 and CBA/J mice can be sensitized in vitro by interferon-γ and TNF-α to undergo Fas-mediated apoptosis. Transgenic overexpression of FLIP protected cultured TECs of FLIP transgene (Tg)+ DBA/1 and CBA/J mice from Fas-mediated apoptosis, and FLIP small interfering RNA transfection of cultured TECs of FLIP Tg+ DBA/1 and CBA/J mice abolished the protective effect. These in vitro results are consistent with our previous in vivo studies using DBA/1 and CBA/J FLIP Tg+ mice and provide direct support for the hypothesis that transgenic expression of FLIP promotes resolution of granulomatous experimental autoimmune thyroiditis by protecting TECs from apoptosis

    Lack of TNFR2 expression by CD4(+) T cells exacerbates experimental colitis

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    TNF plays fundamental roles in the induction and perpetuation of inflammation. The effects of TNF are mediated through TNF receptor (TNFR) 1 or 2. As these two receptors mediate different functions, selective targeting of one receptor may represent a more specific treatment for inflammatory disorders than the complete blocking of TNF. TNFR2 expression is up-regulated in inflammatory bowel disease. Hence, we directly assessed the role of TNFR2 signaling in the CD4(+) T-cell transfer model of colitis using TNFR2(-/-) or WT mice as donors of colitogenic CD4(+)CD45RB(hi) T cells for transfer into syngeneic RAG2(-/-) or RAG2(-/-)TNFR2(-/-) recipient mice. Although the absence of TNFR2 expression by non-lymphoid cells of the recipient mice does not influence the course of colitis, transfer of TNFR2(-/-) CD4(+) T cells leads to an accelerated onset of disease and to more severe signs of inflammation. The enhanced colitogenic potential of TNFR2(-/-) CD4(+) T cells is associated with reduced activation-induced cell death, resulting in an increased accumulation of TNFR2(-/-) CD4(+) T cells. Hence, TNFR2 signaling is crucial for the TNF-dependent contraction of the disease-inducing T cells. Therefore, a selective blocking of TNFR2 may lead to exacerbation rather than attenuation of T-cell-mediated inflammatory disorders
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