Résumé des résultats (Abstract)
(Anglais)
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The goal of the project was to study the functional role of the blood brain barrier in infections and autoimmune diseases of the central nervous system (CNS). One of the roads travelled investigated the role of vascular endothelial cells in the CNS to play a pivotal role in the initiation of experimental autoimmune encephalomyelitis (EAE). Interestingly, mice harboring an inactivation of the interleukin 6 (IL-6) gene were found to be resistant to EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG) (1). Resistance seems to be determined by low level expression of the adhesion molecule VCAM-1. Indeed, the bacterial superantigen staphylococcus enterotoxin B (SEB) increases VCAM-1 and overcomes resistance to EAE in IL-6 knockout mice. This effect is dependent on TNFa and TNF receptor 1 because double knockout mice with deletions of both IL-6 and TNFa or IL-6 and TNF receptor 1 do neither develop EAE when immunized with MOG and treated with SEB nor do they show upregulation of VCAM-1 (2). Thus the interaction of T-cell and monocyte derived factors including TNFa with the endothelium is impaired in IL-6 knockout mice. When T cells overcome the endothelial barrier they induce expression of MHC class II antigens on macrophages and resident microglia cells. However, besides of blood derived monocytes also dendritic cells invade the CNS (3). Expression of MHC class II molecules involves induction of MHC class II transactivator (CIITA) which is highly upregulated in the CNS of mice with EAE (3). Regulation of the CIITA gene is mainly transcriptional and involves different promoters. Analysis of mice with an inactivation of CIITA type IV still express MHC class II molecules on dendritic cells and upon injection with interferon gamma (IFNg) on macrophages and microglia cells. However, non-macrophage lineage cells such as astrocytes are refractory to the effect of IFNg to induce MHC class II (4). Of note is that mice with EAE express both CIITA form I and IV, but not form III which is B-cell specific.
The endothelial barrier was also used in a therapeutic approach in experimental glioma. Since the proapoptotic cytokine Fas Ligand (FasL) induces wide spread apoptosis including liver cell death, the therapeutic use of FasL to treat Fas positive tumors is limited. Since the CNS shows only a limited extent of Fas expression and the blood brain barrier hinders access of FasL into the blood when FasL is injected into the CNS, local expression of FasL can be used to treat Fas positive brain tumors (gliomas). Indeed, intratumoral injection of adenovirus expressing FasL prolongs the survival of rats with gliomas by 50 % (5). This effect was not associated with systemic toxicity. Furthermore, improvement of the amount of FasL expressed in the tumors is likely to yield better therapeutic effects than those seen with the adenovirus approach.
In another approach experiments were designed to protect endothelial cells from being disrupted by leukocytes in bacterial or viral meningitis. This approach included infection of an antibody to the junctional adhesion molecule (JAM) which has been described to limit the extent of transfer of leukocytes into the CNS. However, our experiments did not allow to come to this conclusion (6).
REFERENCES
(1) Eugster H.-P., Frei K., Kopf M., Lassmann H., Fontana A.: IL-6 deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. Eur. J. Immunol. 28: 2178-2187 (1998)
(2) Eugster H.-P., Frei K., Winkler F., Koedel U., Pfister W., Lassman H., Fontana A.: Superantigen overcomes resistance of IL-6-deficient mice towards MOG-induced EAE by a TNFR1 controlled pathway. Eur. J. Immunol. 31, 2302-2312, 2001
(3) Suter T., Malipiero U., Otten L, Ludewig B., Muhlethaler-Mottet A., Mach B., Reith W., Fontana A.: Dendritic cells and usage of the MHC class II transactivator (CIITA) promoter I in the central nervous system in experimental autoimmune encephalomyelitis. Eur. J. Immunol. 30: 794-802 (2000)
(4) Waldburger J.-M., Suter T., Fontana A., Acha-Orbea H., Reith W.: Selective abrogation of MHC class II expression on extrahematopoietic cells in mice lacking promoter IV of the CIITA gene. J. Exp. Med., 194: 392-406, 2001
(5) Ambar B.B., Frei K., Malipiero U., Morelli A.E., Castro M.G., Lowenstein P.R., Fontana A.: Treatment of experimental glioma by administration of adenoviral vectors expressing Fas Ligand. Human Gene Therapy 10:1641 - 1648 (1999)
(6) Lechner F., Sahrbacher U., Suter T., Frei K., Brockhaus M., Koedel U., Fontana A.: Antibodies to the junctional adhesion molecule cause disruption of endothelial cells and do not prevent leukocyte influx into the meninges after viral or bacterial infection. J. Infect. Dis. 182: 978-982 (2000)
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