ABSTRACT
Neurodegenerative diseases are characterized by the progressive loss of defi ned neuronal populations within the central nervous system (CNS), leading to neurological dysfunction. Some clinical features respond to symptomatic drugs, providing relief to the patient early in the disease process. However, the symptomatic benefits do not persist, because neuronal loss often is not abated. In the attempt to reduce or reverse the cell loss, neurotrophic factors, such as ciliary neurotrophic factor (CNTF) and glial-cell-line-derived neurotrophic factor (GDNF), were successfully administrated in primate models of Huntington’s disease (HD; Mittoux et al., 2000) and Parkinson’s disease (PD; Kordower et al., 2000), respectively, but such an approach would require early diagnosis of the disease to be
1INSERM UMR 643/1064, Nantes, France. 2ITUN CHU HOTEL DIEU Nantes, Nantes, France. 3INSERM UMR U913, Institut des Maladies de l’Appareil Digestif, Nantes, France. 4UFR de Médecine, Université de Nantes, Nantes, France. 5Centre Hospitalier-Universitaire (CHU) de Nantes, Nantes, France. *Corresponding author: Isabelle.Neveu@univ-nantes.fr
clinically relevant for it. Another alternative is the transplantation of cells that would replace those that are lost as part of the disease process. In this regard, PD and HD are appropriate targets for cell transplantation strategies, given the well-defined core pathology of theses chronic, progressive neurodegenerative diseases. PD is characterized by a continuous loss of dopaminergic neurons in the substantia nigra pars compacta, causing a signifi cant defi cit in producing suffi cient dopamine needed by the target area, the neostriatum, which leads to such hallmark clinical symptoms as tremor, rigidity, and bradykinesia (Lang and Lozano, 1998). HD is an autosomal dominant disease characterized by the prevalent loss of efferent GABAergic medium spiny neurons in the striatum (Vonsattel et al., 1985). Typically, patients with HD show progressive movement disorders, psychiatric abnormalities, and gradual impairment of the mental processes (Harper, 1991). Even if a more widespread degeneration occurs in the brain as the disease progresses, specifi c loss of nigral dopaminergic neurons (PD) and striatal output GABAergic neurons (HD) at the early stages of the diseases favored the development of cell replacement strategies. Success in reconstructing neuronal circuitry and in providing missing neurotransmitter is still considered an important issue for PD and HD patients, but also for those affected by central disorders, such as Alzheimer, ischemia or trauma. In the perspective of replacing lost neurons, fetal brain tissue, derived from the ventral mesencephalon (PD) or from the ganglionic eminence (HD), have been transplanted into both animal models and, subsequently, into the striatum of patients (Olanow et al., 1996; Kordower et al., 1998; Freed et al., 2001; Mendez et al., 2008; Bachoud-Levi et al., 2000; Freeman et al., 2000; Hauser et al., 2002; Bachoud-Levi et al., 2006). The clinical benefi ts observed in some patients provide the “proof-of-principle” for cell replacement, but the large variability in outcomes and the observation of motoric side effects in some patients, emphasize the necessity for an optimization of this therapeutic strategy, including the possibility of using other cell sources (Lindvall and Bjorklund, 2004). Indeed, utilization of human fetal tissue rises ethical and practical concerns that might be partially or totally overcome by the use of stem cells, as these cells can be expanded in vitro before their transplantation into the brain. Cells derived from adult, and embryonic stem cells, have been proposed for cell replacement in neurodegenerative diseases. However, whatever the selected source, special care needs to be paid to the host immune response. Even if the CNS is still considered as an immuno-privileged site for transplantation, due to the absence of conventional lymphatic vessels, the rare professional antigen-presenting cells, and to its isolation by the blood-brain barrier, this privilege is not absolute, and immune rejection has been observed after the transplantation of allogenic neural cells into the brain of a patient with Huntington’s disease (Krystkowiak et al., 2007). So, besides benefi cial effects in term of cell
replacement or restorative functions, one has to be careful about a possible host immune response that would jeopardize the survival of transplanted cells. Knowing this, immune characteristics of transplanted cells have to be considered. This is particularly important if immunosuppression is planned. In this regard, it is instructive to know how different types of stem cells may cause a variety of immunological responses following transplantation. The present chapter reviews the immune and infl ammatory host responses to intracerebral stem cell transplantation.
