Cell therapy for Parkinson׳s disease: Functional role of the host immune response on survival and differentiation of dopaminergic neuroblasts

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder, whose cardinal pathology is the loss of dopaminergic neurons in the substantia nigra. Current treatments for PD have side effects in the long term and do not halt disease progression or regenerate dopaminergic cell loss. Attempts to compensate neuronal cell loss by transplantation of dopamine-producing cells started more than 30 years ago, leading to several clinical trials. These trials showed safety and variable efficacy among patients. In addition to variability in efficacy, several patients developed graft-induced dyskinesia. Nevertheless, they have provided a proof of concept that motor symptoms could be improved by cell transplantation. Cell transplantation in the brain presents several immunological challenges. The adaptive immune response should be abolished to avoid graft rejection by the host. In addition, the innate immune response will always be present after transplanting cells into the brain. Remarkably, the innate immune response can have dramatic effects on the survival, differentiation and proliferation of the transplanted cells, but has been hardly investigated. In this review, we analyze data on the functional effects of signals from the innate immune system on dopaminergic differentiation, survival and proliferation. Then, we discussed efforts on cell transplantation in animal models and PD patients, highlighting the immune response and the immunomodulatory treatment strategies performed. The analysis of the available data lead us to conclude that the modulation of the innate immune response after transplantation can increase the success of future clinical trials in PD by enhancing cell differentiation and survival. This article is part of a Special Issue entitled SI: PSC and the brain.

Microglia affect α-synuclein cell-to-cell transfer in a mouse model of Parkinson’s disease

“…Intrastriatal neural grafting is an experimental therapy that, in the best cases, has provided long-term relief of motor symptoms in some PD patients [28]. Notably, Lewy pathology has been documented in a small percentage of the grafted neurons of these patients [29–33].…”

Effect of dental pulp stem cells in MPTP‐induced old‐aged mice model

“…In addition, transplanted stem cells are also expected to modulate the inflammatory processes that take place in the targeted area to facilitate regeneration and cell renewal. Although studies have reported the homing capacity of stem cells in transplanted area, their secondary effects, however, are not thoroughly investigated .…”

Pluripotent stem cell-based therapy for Parkinson’s disease: Current status and future prospects

“…The use of an immunosuppressive regimen in experimental PD models is usually necessary to sustain long-term survival of allo- or xenografts. This issue, however, has not been systematically analyzed in any of the clinical trials to date (Wenker et al, 2016). Immune rejection in the brain has been a concern not only for graft survival, but also because of significant side effects of the immunosuppressive drugs used to suppress it.…”

“…There have been other attempts to induce tolerance to tissue grafted into the brain, such as co-transplantation of porcine neuroblasts with syngeneic mesenchymal stem cells (MSCs) in the rat striatum (Leveque et al, 2015), or the use of immune-modulatory molecules (Uchida et al, 2001; Wennberg et al, 2001). The exact mechanisms of graft rejection in the brain are not well understood and may include both cellular and humoral immune responses (Cicchetti et al, 2003; Krystkowiak et al, 2007; Porfirio et al, 2015; Wenker et al, 2016). There is hope that strategies utilizing autologous cell sources, because they are derived from host tissue, will avoid the host immune response and, thus, obviate the need for immunosuppressive treatments altogether.…”