title: Cell Therapy for Parkinson's Disease: A Translational Approach to Assess the Role of Local and Systemic Immunosuppression.
abstract: 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 WT 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 mo. Recovery was associated with restoration of dopaminergic activity detected both by positron emission tomography imaging and histological examination. Local infiltration by T cells and CD80/86+ 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.
authors.affiliation: MIRCen, CEA UMR 9199, Fontenay-aux-Roses, France.
authors.forename: R
authors.initials: R
authors.lastname: Aron Badin
authors.affiliation: CORIT (Consortium for Research in Organ Transplantation), Padua, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Vadori
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR1064, Nantes, France.|CHU de Nantes, Institut de Transplantation Urologie Néphrologie, Université de Nantes, Nantes, France.
authors.forename: B
authors.initials: B
authors.lastname: Vanhove
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR1064, Nantes, France.
authors.forename: V
authors.initials: V
authors.lastname: Nerriere-Daguin
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR913, Nantes, France.
authors.forename: P
authors.initials: P
authors.lastname: Naveilhan
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR913, Nantes, France.
authors.forename: I
authors.initials: I
authors.lastname: Neveu
authors.affiliation: MIRCen, CEA UMR 9199, Fontenay-aux-Roses, France.
authors.forename: C
authors.initials: C
authors.lastname: Jan
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR1064, Nantes, France.
authors.forename: X
authors.initials: X
authors.lastname: Lévèque
authors.affiliation: INRA Physio Reproduction Femelle CR de Tours, Nouzilly, France.
authors.forename: E
authors.initials: E
authors.lastname: Venturi
authors.affiliation: INRA Physio Reproduction Femelle CR de Tours, Nouzilly, France.
authors.forename: P
authors.initials: P
authors.lastname: Mermillod
authors.affiliation: MIRCen, CEA UMR 9199, Fontenay-aux-Roses, France.
authors.forename: N
authors.initials: N
authors.lastname: Van Camp
authors.affiliation: CEA, I²BM, Service Hospitalier Frédéric Joliot, Orsay, France.
authors.forename: F
authors.initials: F
authors.lastname: Dollé
authors.affiliation: MIRCen, CEA UMR 9199, Fontenay-aux-Roses, France.
authors.forename: M
authors.initials: M
authors.lastname: Guillermier
authors.affiliation: Neurosciences, University of Padua, Padua, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Denaro
authors.affiliation: Neurosciences, University of Padua, Padua, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Manara
authors.affiliation: Neurosciences, University of Padua, Padua, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Citton
authors.affiliation: Neurosciences, University of Padua, Padua, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Simioni
authors.affiliation: Neurosciences, University of Padua, Padua, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Zampieri
authors.affiliation: Neurosciences, University of Padua, Padua, Italy.
authors.forename: D
authors.initials: D
authors.lastname: D'avella
authors.affiliation: Nuclear Medicine, S. Maria della Misericordia Hospital, Rovigo, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Rubello
authors.affiliation: CORIT (Consortium for Research in Organ Transplantation), Padua, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Fante
authors.affiliation: CORIT (Consortium for Research in Organ Transplantation), Padua, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Boldrin
authors.affiliation: Department of Animal Medicine, Production and Health, University of Padua, Legnaro, Italy.
authors.forename: G M
authors.initials: GM
authors.lastname: De Benedictis
authors.affiliation: Department of Comparative Biomedicine and Food Science, University of Padua, Legnaro, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Cavicchioli
authors.affiliation: Transplant Infectious Disease Unit, Padua University Hospital, Padua, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Sgarabotto
authors.affiliation: Department of Laboratory Medicine, Padua University Hospital, Padua, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Plebani
authors.affiliation: Istituto Zooprofilattico Sperimentale delle Venezie, Legnaro, Italy.
authors.forename: A L
authors.initials: AL
authors.lastname: Stefani
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR1064, Nantes, France.
authors.forename: P
authors.initials: P
authors.lastname: Brachet
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR1064, Nantes, France.|CHU de Nantes, Institut de Transplantation Urologie Néphrologie, Université de Nantes, Nantes, France.
authors.forename: G
authors.initials: G
authors.lastname: Blancho
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR1064, Nantes, France.
authors.forename: J P
authors.initials: JP
authors.lastname: Soulillou
authors.affiliation: MIRCen, CEA UMR 9199, Fontenay-aux-Roses, France.
authors.forename: P
authors.initials: P
authors.lastname: Hantraye
authors.affiliation: CORIT (Consortium for Research in Organ Transplantation), Padua, Italy.|Transplant Immunology Unit, Padua University Hospital, Padua, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Cozzi
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D060908:CTLA-4 Antigen / Q000276:immunology*; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002478:Cells, Cultured; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D064593:Heterografts; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008213:Lymphocyte Activation; D008252:Macaca fascicularis; D008297:Male; D009474:Neurons / Q000166:cytology* / Q000276:immunology; D010300:Parkinson Disease / Q000276:immunology / Q000628:therapy*; D034421:Sus scrofa; D013601:T-Lymphocytes / Q000276:immunology*; D014183:Transplantation, Heterologous
chemical_list: D060908:CTLA-4 Antigen; D007166:Immunosuppressive Agents
keywords: immunosuppressant; immunosuppression/immune modulation; other; rejection; translational research/science; xenotransplantation