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. Abbreviations: ( 18

Xenotransplantation: Current Status in Preclinical Research

“…Martin et al produced transgenic pigs with neuronal expression of hCTLA4-Ig and demonstrated that hCTLA4-Ig protein reduced the proliferation of human T cells against porcine cells (103). The beneficial effect of hCTL4-Ig expression extended xenograft survival time in a rat skin transplantation model (104) and a NHP neuronal transplantation model (137). These in vivo evidence also suggested that the expression of hCTLA4-Ig alone could not prevent xenograft rejection, which is consistent with the result blocking costimulatory pathway against B7-CD28 only.…”

Regulation of Clinical Xenotransplantation—Time for a Reappraisal

“…13–17 Genetically engineered mesencephalic pig cells have reduced the physical features of a Parkinson-like disease in monkeys for more than 1 year. 18 Even in the difficult pig-to-baboon liver transplantation model, there has been significant improvement in graft survival, to almost 1 month in 2 recent instances. 19–21 …”

Neuroimmunomodulatory properties of DPSCs in an in vitro model of Parkinson's disease

“…One of them include the neuroinflammation that gave rise to their death . Post mortem studies have substantially confirmed the involvement of innate as well as adaptive immunity in the affected brain regions in PD patients . Furthermore, activated microglial cells and T lymphocytes have also been detected in the substantia nigra of patients concomitantly with an increased expression of proinflammatory mediators .…”