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Spontaneous Inflammatory Demyelinating Disease In Proc. Natl. Acad. Sci. USA Vol. 92, pp. 11294-11298, November 1995 Neurobiology Spontaneous inflammatory demyelinating disease in transgenic mice showing central nervous system-specific expression of tumor necrosis factor a (autoimmunity/disease model/neuroimmunology/inflammatory/cytokine) LESLEY PROBERT*, KATERINA AKASSOGLOU*, MANOLIS PASPARAKIS*, GEORGE KONTOGEORGOSt, AND GEORGE KOLLIAS*t *Department of Molecular Genetics, Hellenic Pasteur Institute, 127, Vas. Sofias Avenue, 115 21 Athens, Greece; and tDepartment of Pathology, General Hospital of Athens, 154, Messogion Avenue, 115 27 Athens, Greece Communicated by Rita Levi-Montalcini, Consiglio Nazionale Ricerche, Rome, Italy, August 4, 1995 ABSTRACT Cytokines are now recognized to play impor- tribution of increased TNF-a production in the CNS to disease tant roles in the physiology of the central nervous system pathogenesis and its mechanism of action are at present (CNS) during health and disease. Tumor necrosis factor a ill-defined. However, there is strong evidence that in the CNS, (TNF-a) has been implicated in the pathogenesis of several TNF-a acts as a potent proinflammatory cytokine and a major human CNS disorders including multiple sclerosis, AIDS effector of immune-mediated demyelination (15, 16). dementia, and cerebral malaria. We have generated trans- In our studies we have been addressing the role of TNF-a in genic mice that constitutively express a murine TNF-ca trans- vivo using transgenic mice. In one line, which expresses a gene, under the control of its own promoter, specifically in modified 3'-untranslated region murine TNF-a transgene their CNS and that spontaneously develop a chronic inflam- under the control of its own promoter, we have obtained an matory demyelinating disease with 100% penetrance from expression pattern specific to the CNS. From between 3 and 8 around 3-8 weeks of age. High-level expression of the trans- weeks of age, mice spontaneously develop a chronic demyeli- gene was seen in neurons distributed throughout the brain. nating disease, which is manifested by progressive neurological Disease is manifested by ataxia, seizures, and paresis and disturbances and leads to premature death within -8 months. leads to early death. Histopathological analysis revealed in- Our data establish TNF-a as a major effector molecule in filtration of the meninges and CNS parenchyma by CD4+ and chronic inflammatory demyelination in the CNS. The trans- CD8+ T lymphocytes, widespread reactive astrocytosis and genic line described in this study represents an important microgliosis, and focal demyelination. The direct action of model for gaining further insight into the pathogenesis of TNF-a in the pathogenesis of this disease was confirmed by similar diseases in humans. peripheral administration of a neutralizing anti-murine TNF-a antibody. This treatment completely prevented the MATERIALS AND METHODS development ofneurological symptoms, T-cell infiltration into the CNS parenchyma, astrocytosis, and demyelination, and Preparation of the Murine TNF-a-Globin Gene Construct greatly reduced the severity of reactive microgliosis. These and Generation of Transgenic Mice. The murine TNF-a gene results demonstrate that overexpression ofTNF-a in the CNS was derived from a 129 SV mouse genomic library (Strat- can cause abnormalities in nervous system structure and agene) using an EcoRI-Nar I fragment from the 5' end of the function. The disease induced in TNF-a transgenic mice shows murine TNF-a gene (kindly provided by C. V. Jongeneel, clinical and histopathological features characteristic of in- Ludwig Institute for Cancer Research, Lausanne, Switzerland) flammatory demyelinating CNS disorders in humans, and as a probe. The murine TNF-a-globin gene construct (see Fig. these mice represent a relevant in vivo model for their further 1A) was prepared in the pBluescript vector (Stratagene) as study. follows: the 2.8-kb EcoRI fragment, which contains the pro- moter and entire coding region of the murine TNF-a gene, was The nervous system and the immune system show an intimate ligated to the 0.77-kb EcoRI-Pst I/Sal I fragment, which structural and functional relationship and exhibit extensive contains the 3'-untranslated region and polyadenylylation site bidirectional communication, which is facilitated by the use of of the human 13-globin gene (17). ABamHI-Sal I fragment was common regulatory factors and receptors (1, 2). Cytokines, microinjected into fertilized eggs of (CBA x C57BL/6)F1 classically associated with the modulation of immune function hybrid mice as described (18, 19). Colonies of mice were and inflammatory response, are now also emerging as impor- maintained in both conventional and specific-pathogen-free tant mediators of central nervous function facilities at the Hellenic Pasteur Institute. system (CNS) (3). RNA Preparation and Analysis. Total RNA was extracted Tumor necrosis factor a (TNF-a) is a powerful proinflamma- from tory cytokine (for review, see ref. 4), which is produced by freshly dissected mouse tissues and cell isolates using the neurons in the normal murine brain (5) and exerts neuro- lithium chloride/urea method (20). Peritoneal macrophages modulatory effects (6). The expression of TNF-a is upregu- were prepared as described (21). Splenocytes were incubated lated in a wide of CNS disorders in RPMI containing 5% (vol/vol) fetal calf serum with or range including multiple without the addition of concanavalin A (Sigma) at 1 ,ug/ml and sclerosis (MS) (7, 8), AIDS dementia complex (9), bacterial phorbol 12-myristate 13-acetate (Sigma) at 10 ,.Lg/ml for 8 hr meningitis (10), Parkinson disease (11), and human and mu- at 37°C in 5% C02/95% air. Astrocyte cultures were prepared rine cerebral malaria (12). This increased expression might as described elsewhere (22). Si nuclease protection derive from activated infiltrating T cells or macrophages (4), analysis activated astrocytes (13), and microglial cells (14). The con- Abbreviations: CNS, central nervous system; TNF-a, tumor necrosis factor a; GFAP, glial fibrillary acidic protein; EAE, experimental The publication costs of this article were defrayed in part by page charge autoimmune encephalomyelitis; MS, multiple sclerosis; P, postnatal payment. This article must therefore be hereby marked "advertisement" in day. accordance with 18 U.S.C. §1734 solely to indicate this fact. 4To whom reprint requests should be addressed. 11294 Downloaded by guest on September 27, 2021 Neurobiology: Probert et al. Proc. Natl. Acad. Sci. USA 92 (1995) 11295 using 5' murine TNF-a, 3' f3-globin, and human f3-actin DNA A probes was carried out using standard procedures (21, 23). BamHI EcoRI NorI EcoRi SaIl In situ hybridization was performed essentially according to Wilkinson et al. (24) using single-stranded 35S-labeled murine 3' ,-globin TNF-a and f3-globin RNA probes on parasagittal sections 790 nt (input) - * : - 770nt(input) taken from 4% (wt/vol) paraformaldehyde-fixed, Paraplast 130 nt(protected) -* &- 210 nt(protected) (BDH)-embedded brains of Tg6O74 mice and normal control littermates. B Histology and Immunocytochemistry. Histological analysis Tg 6074 Normal was carried out using standard hematoxylin/eosin, oil red/ hematoxylin, and luxol fast blue/cresyl violet staining proce- c dures. Immunocytochemistry was carried out using the Vec- u tastain ABC alkaline phosphatase method (Vector Labora- J]y4 X'a3a8 8 tories) as described (21). Antibodies to the following markers were used: glial fibrillary acidic protein (GFAP; astrocyte 220 ...... 3 13 globin marker; Dakopatts, Glostrup, Denmark), F4/80 (microglial and macrophage marker; Serotec), CD18 (microglia and leu- 22 ; kocytes; provided by Leslie Moloney, Tanabe Research Lab- 154 oratories, San Diego), CD4 and CD8 (mature T lymphocytes; 5'murineTNF YTS191.1.2 and YTS169.4.2, respectively; provided by Steve Cobbold, University of Oxford, United Kingdom). 0 actin TNF-a Monoclonal Antibody Injections. Transgenic mice ...:.. '.:.D l ,..,/. qi,~I.'" .3'1C1 ..: ...: (n = 9) received, from birth, once-weekly intraperitoneal .. ......~~ ~Y injections of a chimeric hamster/mouse monoclonal antibody 220 to murine TNF-a bearing the variable regions of the hamster c TN3.19.12 antibody (20 ,g/g of body weight in saline) (pro- Tg Fl vided by Roly Foulkes, Celltech, Berkshire, U.K.), whereas Fl Tg6074 4 transgenic (n = 5) and normal (n = 15) littermates remained untreated or received an equivalent concentration of control hamster IgG (Pierce) (n = 5 transgenic mice). Animal weights 3 globin and clinical signs were recorded weekly for 11 consecutive weeks. Measurement of Serum Murine TNF-a. Serum levels of murine TNF-a protein were measured by ELISA (Endogen, 154- Cambridge, MA) according to the manufacturer's specifica- 5'n TNF tions. nurine REStJLTS aI ctin Murine TNF-a Transgenic Mice. Earlier transgenic studies in our laboratory showed that replacement of the 3'- untranslated region and 3'-flanking DNA sequences of a FIG. 1. (A) Structure of the murine TNF-a-globin construct that human TNF-a transgene with similar sequences from the was microinjected into mouse zygotes. The 5' murine TNF-a and 3' human f-globin gene resulted in its constitutive overexpres- f-globin DNA probes used for Si nuclease protection analysis are also represented. (B) S1 nuclease protection analysis of total RNA from sion in several mouse tissues (25). Microinjection of a similar normal F1 and Tg6074 tissues. (C) Si nuclease protection analysis of murine TNF-a-human 3-globin hybrid gene construct
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