title: Influence of chronic L-DOPA treatment on immune response following allogeneic and xenogeneic graft in a rat model of Parkinson's disease.
abstract: Although intrastriatal transplantation of fetal cells for the treatment of Parkinson's disease had shown encouraging results in initial open-label clinical trials, subsequent double-blind studies reported more debatable outcomes. These studies highlighted the need for greater preclinical analysis of the parameters that may influence the success of cell therapy. While much of this has focused on the cells and location of the transplants, few have attempted to replicate potentially critical patient centered factors. Of particular relevance is that patients will be under continued L-DOPA treatment prior to and following transplantation, and that typically the grafts will not be immunologically compatible with the host. The aim of this study was therefore to determine the effect of chronic L-DOPA administered during different phases of the transplantation process on the survival and function of grafts with differing degrees of immunological compatibility. To that end, unilaterally 6-OHDA lesioned rats received sham surgery, allogeneic or xenogeneic transplants, while being treated with L-DOPA before and/or after transplantation. Irrespective of the L-DOPA treatment, dopaminergic grafts improved function and reduced the onset of L-DOPA induced dyskinesia. Importantly, although L-DOPA administered post transplantation was found to have no detrimental effect on graft survival, it did significantly promote the immune response around xenogeneic transplants, despite the administration of immunosuppressive treatment (cyclosporine). This study is the first to systematically examine the effect of L-DOPA on graft tolerance, which is dependent on the donor-host compatibility. These findings emphasize the importance of using animal models that adequately represent the patient paradigm.
authors.affiliation: School of Pharmacy & Pharmaceutical Sciences, Redwood Building, King Edward VII Avenue, CF10 3NB Cardiff, UK; Brain Repair Group, Cardiff School of Biosciences, Museum Avenue, CF10 3AX Cardiff, UK. Electronic address: Lu.Breger@icloud.com.
authors.forename: Ludivine S
authors.initials: LS
authors.lastname: Breger
authors.affiliation: School of Pharmacy & Pharmaceutical Sciences, Redwood Building, King Edward VII Avenue, CF10 3NB Cardiff, UK. Electronic address: kienle@ie-freiburg.mpg.de.
authors.forename: Korbinian
authors.initials: K
authors.lastname: Kienle
authors.affiliation: Brain Repair Group, Cardiff School of Biosciences, Museum Avenue, CF10 3AX Cardiff, UK. Electronic address: Gaynor.Smith@umassmed.edu.
authors.forename: Gaynor A
authors.initials: GA
authors.lastname: Smith
authors.affiliation: Brain Repair Group, Cardiff School of Biosciences, Museum Avenue, CF10 3AX Cardiff, UK. Electronic address: Dunnettsb@cardiff.ac.uk.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Dunnett
authors.affiliation: School of Pharmacy & Pharmaceutical Sciences, Redwood Building, King Edward VII Avenue, CF10 3NB Cardiff, UK. Electronic address: LaneEL@cardiff.se.uk.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Lane
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D017690:Cell Transplantation; D003131:Combined Modality Therapy; D005260:Female; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D007110:Immunity, Active / Q000187:drug effects*; D007980:Levodopa / Q000008:administration & dosage* / Q000627:therapeutic use; D010302:Parkinson Disease, Secondary / Q000188:drug therapy / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000978:Antiparkinson Agents; D007980:Levodopa
keywords: Dyskinesia; Immune response; L-DOPA; Parkinson’s disease; Stem cell; Transplant