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*Unité Mixte de Recherche S 938, INSERM, and Université Pierre et Marie Curie, Paris 6, Hôpital Saint Antoine, Paris, France;
Department of Histology, Faculty of Medicine, University of Liege, Liege, Belgium;
Unité Mixte de Recherche S 702, INSERM, and Université Paris 6, Hôpital Tenon, Paris, France;
Unité Mixte de Recherche 7087, Hôpital Pitié-Salpêtrière, Paris, France; and
¶Veterinary Services, Hôpital Saint Antoine, Paris, France
There is to date no effective way of preventing or curing neurodegenerative diseases such as Alzheimer disease or transmissible spongiform encephalopathies. The idea of treating those conditions by immunological approaches has progressively emerged over the last ten years. Encouraging results have been reported in Alzheimer disease and in peripheral forms of mouse prion diseases following passive injection of Abs or active immunization against the peptides or proteins presumably at the origin of those disorders. Still, major difficulties persist due to some characteristics of those conditions such as slow evolution, brain location, uncertainties regarding precise pathogenic pathways, and, above all, the fact that the target Ag is self, meaning that it is poorly immunogenic and potentially harmful if tolerance was transgressed. To analyze some of those difficulties, we are developing adoptive cell transfer approaches. In this study, lymphocytes sensitized against the prion protein in nontolerant Prnp–/– mice were transferred into histocompatible wild-type recipients which were partly or totally devoid of their own lymphocytes. Under such conditions, we found that the engrafted T lymphocytes resisted peripheral tolerance, remained reactive for several months against epitopes of the prion protein, and significantly attenuated the progression of prions in secondary lymphoid organs with subsequent delay in the evolution of the neurological disease. Interestingly, those protective T lymphocytes secreted lymphokines and migrated more readily into the host CNS but did not appear to be engaged in cooperation with host B cells for Ab production.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Groupement d’Intérêt Scientifique "Maladies à Prions," European Union Project No. FOOD-CT-2006-023144, and INSERM and Université Pierre et Marie Curie Paris 6. P.G. is the recipient of a doctoral fellowship from the Ministry of Education and Research, S.G. was supported by the Fondation pour la Recherche Médicale, V.B. was supported by a postdoctoral fellowship from INSERM.
2 P.G. and S.G. contributed equally to this work.
3 Current address: Unité Mixte de Recherche 7087, Hôpital Pitié-Salpêtrière, Paris, F-75013 France.
4 Current address: Peter Gorer Department of Immunobiology, New Guy’s House, Guy’s Hospital, London SE1 9RT, U.K.
5 Address correspondence and reprint requests to Dr. Claude Carnaud, Unité Mixte de Recherche S 938, Hôpital Saint Antoine, 184 Rue du Faubourg St-Antoine Paris, F-75012 France. E-mail address: claude.carnaud{at}inserm.fr
6 Abbreviations used in this paper: TSE, transmissible spongiform encephalopathy; dpi, days postinfection; EAE, experimental autoimmune encephalomyelitis; FDC, follicular dendritic cell; GC, germinal center; i.c., intracerebral(ly); LN, lymph node; MFI, mean fluorescence intensity; PK, proteinase K; PrPc, cellular prion protein; PrPSc, scrapie prion protein; wt, wild type.
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