Transplantation Of Fetal Neurons Research Articles

Immune response after striatal engraftment of fetal neuronal cells in patients with Huntington’s disease: Consequences for cerebral transplantation programs

Objectives: Striatal transplantation of human fetal neurones as a therapeutic approach to treat Huntington’s disease is under investigation. The allogeneic graft material raises questions of immune response and immunosuppressive treatment. No data is available on how the human brain reacts immunologically over time to neuronal transplantation. Methods: We measured post-engraftment immune responses as assessed by the development of anti-human leukocyte antigen (HLA)-antibodies to allogeneic intrastriatal transplantation of fetal neurons in Huntington’s disease patients. Results: Out of 10 patients without HLA-antibodies before engraftment, five developed HLA-antibodies of class I and II. The time between transplantation and development of HLA-antibodies was variable, with detection either immediately after engraftment, during immunosuppressive therapy or months to years after immunosuppressive drugs were discontinued. There are no typical changes in magnetic resonance imaging that distinguish the different immune behaviors. Positive clinical responses to engraftment might not be reflected in the 18F-deoxyglucose positron emission tomography images as expected. Conclusions: There is indeed an immune response from the human brain, but the time between transplantation and development of anti-HLA-antibodies is variable and unpredictable. A long-term, post-engraftment immunosuppressant therefore cannot be justified. The impact of the emergence of HLA-antibodies on graft survival and clinical efficacy cannot be ascertained at this stage. Given the projected clinical trials of cell transplantation in neurodegenerative disorders, the findings are of practical significance. (Clin. Exp. Neuroimmunol. doi: 10.1111/j.1759-1961.2011.00018.x, May 2011)

Glial and endothelial cell response to a fetal transplant of purified neurons

Astrocytes, microglia and endothelial cells display very specific phenotypic characteristics in the intact adult CNS, which appear quite versatile when grown in culture without neurons. Indirect evidence from in vitro co-culture studies and analysis of the effects of specific neuronal removal in vivo, does accordingly favour a role of neurons for the phenotypic repression of these cells in the intact brain. In order to provide more direct evidence for such neuronal influence, we attempted to induce, in the rat brain, a reversal of the post-lesional activation of astrocytes, microglia and endothelial cells by transplantation of fetal neurons purified by immunopanning. Host microglial cells which have been activated by the lesion process, penetrated the neuronal graft during the few days after the transplantation. Reactive astrocytes began to appear in the lesioned parenchyma and gathered around the transplant. Thereafter they first sent their processes in the direction of the neuronal graft, before they migrated into the graft a few days later. At this time, which was at the end of the first week post-transplantation, the host endothelial cells sprouted “streamers” of basal lamina within the graft forming small capillaries. During the second week post-transplantation, numerous astrocytes and microglial cells, both displaying a reactive hypertrophied morphology, were observed throughout the grafts. Finally, by the end of the first month, the activated cells differentiated towards a quiescent, resting morphology. At this time the grafts contained a vascular network with morphological characteristics comparable to those observed in the intact brain parenchyma. The results indicate that the interaction of activated astroglia and microglia and endothelial cells with neurons causes the cells to re-differentiate and regain phenotypic features characteristic of intact brain parenchyma, strongly suggesting that neurons play an essential role in the phenotypic restriction of glial and endothelial cells in the adult central nervous system.

Neural grafting as a tool for the study and reversal of neurobehavioral birth defects

The transplantation of fetal neurons has gained notoriety in recent years for its perceived potential to reverse neurological deficits caused by loss of one or another neuronal population. The present paper describes a neural grafting approach employed by our laboratory to gain more insight into the drug-induced neurobehavioral teratogenicity. Mice were exposed prenatally to phenobarbital by feeding the barbiturate to the pregnant dam on gestation days 9–18. Heroin exposure was accomplished by injecting dams during the same gestational period. At maturity, the drug-exposed offspring displayed profound deficits in specific behavioral tasks, suggesting alterations in the septohippocampal cholinergic pathway. Biochemically, we observed increased presynaptic activity in the pathway, which was not accompanied by a corresponding reduction in postsynaptic activity. Rather, there was a general hyperactivation along the different postsynaptic phases. In contrast, we noted a desensitization of protein kinase C activity in response to the exposure of a cholinergic agonist to the drug-exposed offspring. Subsequent transplantation of embryonic cholinergic cells from normal mice to the impaired hippocampus reversed the behavioral deficits, whereas sham-operated controls exhibited no improvement. Concomitantly, all the biochemical alterations studied, both presynaptic and postsynaptic, were either partially or completely reversed following grafting.

Chapter 25 Transplantation of fetal dopamine neurons in primate brain reverses MPTP induced parkinsonism

Parkinsonian signs were produced in the African Green monkeys by the administration of the toxin, 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP). The transplantation of fetal neurons from the substantia nigra into two monkeys with severe symptoms of hypokinesia, postural and resting tremor, the episodes of movement freezing, and difficulty in initiating movements resulted in a reversal of these symptoms. The functional degree of recovery corresponded with the immunohistochemical observation of tyrosine hydroxylase (TH) positive neurons in the host caudate nucleus and putamen in these two animals. Dopamine metabolite levels in cerebrospinal fluid (CSF) were also elevated in these monkeys. A third monkey with parkinsonian signs received nigral tissue into a control site, the cingulate cortex. This animal failed to show recovery from the toxin-induced parkinsonism. Both early and late gestational tissue survived and showed growth of neurites, which suggested a wide developmental window in the primate brain. The combination of morphological evidence of survival and growth, the elevated neurochemical indices, and the reversal of behavioral motor impairment following the transplantation of fetal neurons into monkeys with parkinsonian signs may provide therapeutic insights into the treatment of Parkinson's disease.