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Brain Advance Access published online on June 16, 2004
Brain, doi:10.1093/brain/awh205
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Received January 23, 2004
Revised March 24, 2004
Accepted March 29, 2004

Article

Modelling paraneoplastic CNS disease: T-cells specific for the onconeuronal antigen PNMA1 mediate autoimmune encephalomyelitis in the rat

Hannah Pellkofer 1, Anna S. Schubart 1, Romana Höftberger 2, Nadine Schutze 3, Maria Pagany 1, Martina Schüller 1, Hans Lassmann 4, Reinhard Hohlfeld 5, Raymond Voltz 5*, Christopher Linington 6

1 Department of Neuroimmunology, Max Planck Institute for Neurobiology, Martinsried, Germany
2 Department of Neuroimmunology, Brain Research Institute, Wien, Austria; Institute of Neurology, University of Vienna Medical School-Vienna General Hospital (AKH), Austria
3 Institute of Clinical Neuroimmunology, Klinikum der Universität, Grosshadern, Ludwig-Maximilians Universität München, München, Germany
4 Department of Neuroimmunology, Brain Research Institute, Wien, Austria
5 Department of Neuroimmunology, Max Planck Institute for Neurobiology, Martinsried, Germany; Institute of Clinical Neuroimmunology, Klinikum der Universität, Grosshadern, Ludwig-Maximilians Universität München, München, Germany
6 Department of Neuroimmunology, Max Planck Institute for Neurobiology, Martinsried, Germany; Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, Aberdeen, UK

* To whom correspondence should be addressed. E-mail: rvoltz{at}nro.med.uni-muenchen.de.


  Abstract

Summary Antibodies directed against onconeuronal antigens provide a specific diagnostic marker for paraneoplastic neurological syndromes (PNS) and suggest that these autoantigens are targeted during disease pathogenesis. However, so far attempts to generate autoimmune models of PNS have been unsuccessful. Here we show that the adoptive transfer of T-cells specific for the autologous onconeuronal antigen Pnma1 cause encephalomyelitis in the Dark Agouti (DA) rat. The sequence of rat Ma1 (rPnma1) was determined by RT-PCR using primers for human PNMA1, followed by 5' and 3' genome walking. Rat Pnma1 is 93.8% identical to human PNMA1 at the amino acid level. Rat Pnma1 was cloned into the expression vector pQE60, and recombinant protein purified by metal chelate chromatography. Female DA rats were immunized with recombinant rPnma1 and rPnma1-specific CD4+ T-helper 1 (Th1) T-cell lines generated from the draining lymph nodes 10 days post-immunization. Freshly activated T-cell blasts were transferred into naive female DA rats, which were killed up to 9 days later. Proliferation assays demonstrated that the CD4+ Th1 T-cells were highly specific for rPnma1. After T-cell transfer the recipients developed a perivascular inflammatory response involving CNS regions affected in human disease. Anti-Pnma1 antibodies were induced by protein immunization, but this was associated with minimal CNS pathology. The induction of an inflammatory response in the CNS following the adoptive transfer of rat Pnma1-specific T-cells demonstrates for the first time that a paraneoplastic autoantigen can initiate a pathogenic effector T-cell response. This animal model strongly supports the hypothesis that the pathogenesis of paraneoplastic CNS neurological syndromes in man involves an autoimmune T-cell component.

Keywords: animal model; experimental autoimmune encephalomyelitis; onconeuronal; paraneoplastic; PNMA1
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