Cell therapy for Parkinson's disease: A translational approach to assess the role of local and systemic immunosuppression
2016
Aron Badin, R. | Vadori, M. | Vanhove, B. | Nerriere-Daguin, V. | Naveilhan, P. | Neveu, I. | Jan, C. | Lévèque, X. | Venturi, Eric | Mermillod, Pascal | van Camp, N. | Dollé, F. | Guillermier, M. | Denaro, L. | Manara, R. | Citton, V. | Simioni, P. | Zampieri, P. | d'Avella, D. | Rubello, D. | Fante, F. | Boldrin, M. | de Benedictis, G.M. | Cavicchioli, L. | Sgarabotto, D. | Plebani, M. | Stefani, A.L. | Brachet, P. | Blancho, G. | Soulillou, J.P. | Hantraye, P. | Cozzi, E. | Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN) ; Molecular Imaging Research Center [Fontenay-aux-Roses] (MIRCEN) ; Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB) ; Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB) ; Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS) | Consorzio per la Ricerca sul Trapianto d'Organ = Consortium for Research in Organ Transplantation (CORIT) | Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE) ; Université de Nantes (UN)-Université de Nantes (UN) | Institut de Transplantation Urologie Néphrologie ; Université de Nantes (UN) | Université de Nantes (UN) | The Enteric Nervous System in gut and brain disorders [U1235] (TENS) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE) ; Université de Nantes (UN)-Université de Nantes (UN) | Unité Expérimentale de Physiologie Animale de l‘Orfrasiére (UE PAO) ; Institut National de la Recherche Agronomique (INRA) | Physiologie de la reproduction et des comportements [Nouzilly] (PRC) ; Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS) | Neurosciences ; Università degli Studi di Padova = University of Padua (Unipd) | Nuclear Medicine ; Ospedale "Santa Maria della Misericordia" = University Hospital "Santa Maria della Misericordia" | Department of Animal Medicine, Production and Health ; Università degli Studi di Padova = University of Padua (Unipd) | Department of Comparative Biomedicine and Food Science ; Università degli Studi di Padova = University of Padua (Unipd) | Transplant Infectious Disease Unit ; Università degli Studi di Padova = University of Padua (Unipd) | Department of Laboratory Medicine ; University of Alberta | Istituto Zooprofilattico Sperimentale delle Venezie (IZSVe) | Transplant Immunology Unit ; Università degli Studi di Padova = University of Padua (Unipd)
Neural transplantation is a promising therapeutic approach for neurodegenerative diseases. However, many patients receiving intracerebral fetal allografts exhibit signs of immunization to donor antigens that could compromise the graft. In this context, we intracerebrally transplanted mesencephalic pig xenografts into primates to identify a suitable strategy to enable long-term cell survival, maturation and differentiation. Parkinsonian primates received wild-type or CTLA4-Ig transgenic porcine xenografts and different durations of peripheral immunosuppression to test whether systemic plus graft-mediated local immunosuppression might avoid rejection. A striking recovery of spontaneous locomotion was observed in primates receiving systemic plus local immunosuppression for 6 months. Recovery was associated with restoration of dopaminergic activity detected both by PET imaging and histological examination. Local infiltration by T-cells and CD80/86-positive microglial cells expressing indoleamine 2,3-dioxigenase were observed only in CTLA4-Ig recipients. Results suggest that, in this primate neurotransplantation model, peripheral immunosuppression is indispensable to achieve the long-term survival of porcine neuronal xenografts that is required to study the beneficial immunomodulatory effect of local blockade of T-cell costimulation. This article is protected by copyright.
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