For nearly 100 years neural tissue has been transplanted in animals. Transplantation of neural tissue into humans, however, began only a few years ago (1). It has been found in animals, that fetal brain grafts in damaged adult host brains reduce some of the functional deficits caused by brain lesions. Even though some neurons from the transplanted tissue survive and develop reciprocal connections with host brain tissue, this is not enough to completely replace damaged fibers and support behavioral recovery Usually the grafts will not develop a normal morphological appearance, but some metabolic activity can be found within the transplant. Release and diffusion of trophic substances from the transplant and the damaged host brain may partially restore neuronal and behavioral functions. It is hypothesized that this combination of fetal brain transplants and trophic substances may provide a better opportunity for recovery than either treatment given by itself. While this paper focuses on fetal brain grafts as a means to treat Parkinsonism, research is also being conducted in conjunction with Alzheimer’s Disease, visual, frontal, and motor cortex lesions, hippocampal lesions, and many others (2,3)
There are two current approaches to neural transplantation regarding Parkinson s; adrenal medullary and fetal brain grafts. Both methods suffer from limitations in tissue availability, cellular uniformity, and general applicability. The success of neural transplantation in animal models of Parkinson’s syndrome led to its clinical application in human patients with the syndrome. Each of the two methods mentioned has advantages and disadvantages. Transplantation of adrenal medullary tissue has the advantage of ready availability of human leukocyte antigen (matched cells), but has little potential for future use in diseases involving transmitter systems other than dopamine or other amines. Furthermore, adrenal medullary transplants have proved to be only minimally effective (4).
Fetal brain transplants have been more successful in animal and human studies, but ethical concerns have been raised. An alternative method using genetically engineered fibroblasts has been introduced. Although the fibroblasts may be used as a source of trophic factors or hormones, they lack neuronal properties that may be important in future development of neural transplants. A new technique has been devised to overcome these limitations: transplantation with temperature-sensitive immortalized clonal neural cells (4).
One example of this system was to use primary rat central nervous system cells immortalized with a temperature-sensitive Rous Sarcoma virus, cloned, and previously analyzed for neural and glial characteristics. The cells were not permissive for replication of the avian virus, however, expression of the viral genes did occur. The cells were transformed and immortalized at 34°C but differentiated at 38°C. Along with differentiation came a halt in cell division, extension of neurites, and the appearance of developmentally regulated molecules such as neural cell adhesion molecule (N-CAL1) and the cellular isoform of a prion protein (4).
There would be many theoretical advantages to a temperature- sensitive cell system. There would be unlimited availability of cells and application to any transmitter system. Also, cloned genes could be inserted into the cells prior to transplantation, allowing engineering of the cells. One setback with current research is that tumors often develop, therefore; each cell line must be evaluated individually (4).
Prior autopsy reports on patients with Parkinson’s disease who received adrenal medulla to caudate nucleus transplants have described short-term survival times and no, or minimal clinical benefit. No research group has been able to show surviving catecholamine-producing adrenal chromaffin cells within human striatal graft sites. Hirsch described an enhanced host-derived tyrosine hydroxylase fiber network near the graft site, and experimental data have demonstrated that implants of adrenal medulla can stimulate the sprouting or deregulation of residual host dopaminergic systems (5).
The following case reported by Kordower is the longest surviving and most improved transplant patient. The patient was a forty-eight year old white male. He had been diagnosed with Parkinson’s for 15 years prior to the transplant. He displayed no signs or symptoms of secondary Parkinsonism or multisystem degeneration. He was responding fairly well to 175 mg/day of carbidopa and 1,750 mg/day of levodopa. For most of the day, while on this medication, he could move around freely and complete simple tasks. During a small percentage of the day he would experience severe motor fluctuations forcing him to a wheelchair or bed. Because varying dosages and medications did not cure these
intermittent times of "Parkinson outbreaks" or "off time" during the day an adrenal medulla transplant was chosen for treatment.
His adrenal medulla was removed and replaced in a pocket in the caudate nucleus. Six months after surgery the patient began to improve. The percentage of "off time" decreased steadily and he was more ambulatory during the "off time." This improved state was maintained for the next 12 months. Eighteen months after surgery his motor function began to decline. At the time of his death, 30 months after surgery, the patient still showed less Parkinson symptoms than before the transplant.
An autopsy of the brain showed portions of the substantia nigra contained a significant amount of melanin containing neurons bilaterally within the pars compacts region. Many of these cells appeared healthy, but there were also several macrophages present that had incorporated the neuromelanin pigment. This suggested degeneration of the pars compacts was in progress. The tyrosine hydroxylase staining confirmed the presence of numerous dopamine -containing cells within the substantia nigra pars compacts and the ventral segmental area. (fig. 1)
Even though this patient improved greatly from the transplant, most other adrenal medulla patients do not improve. Because fetal grafts are so controversial, it is hoped that the adrenal transplant method can be worked out (6).
Fetal brain grafts are currently being tested in mice and in some isolated places with humans. It has been shown that dissociated intraparenchymal, intracavity, or intraventricular grafts of fetal substantia nigra to dopamine-denervated striatum can restore many of the behavioral dysfunction’s. This is especially important to patients with Parkinson’s disease. Histologically, dopamine containing fibers invade the adjacent areas of the striatum. It is this reinnervation that allows for the return of the behavioral functions (7).
One of the more major problems with fetal transplants is cell differentiation. They have been able to transfer the fetal cells into the adult brain for many years, but if one cell does not differentiate properly, then a tumor will develop. This along with its controversial nature make fetal grafts a hotly debated plan for treatment.
Much of the research, in America, has been hampered by laws restricting the use of fetal material for research. For many reasons, it seems logical that fetal material should be considered viable research material. Fetal research will have no bearing on the number of abortions done each year in this country. Women simply do not have abortion’s to supply research material. Secondly, the potential treatments that could come from fetal tissue research (not only Parkinson’s but several different brain lesion syndromes) seems to far outweigh the cost of using aborted fetal tissue. A true cure for Parkinson’s disease will not soon be found until restrictions of fetal tissue research are removed, or another method such as adrenal medulla or immortal cell transplants can be perfected.
erences
1. Hurtig, H. et. al. Postmortem Analysis of Adrenal -Medulla-to-Caudate Autograft in a Patient with Parkinson’s Disease. Ann. Neurol., 1989, 25: 607-614.
2. Lescaudron, L. et. al. Functional Recovery Following Transplants of Embryonic Brain Tissue In Rats with Lesions Of Visual, Frontal and Motor Cortex: Problems and Prospects For Future Research. Neuropsychologia, 1990, 28: 585-599.
3. Mickley, G. A. et. al. Neural grafts attenuate behavioral deficits produced by early radiation-induced hypoplasia of fascia dentate granule cells. Brain Research, 1990, 509: 280-292.
4. Bredesen, D. E. et. al. Neural Transplantation Using Temperature-sensitive Immortalized Neural Cells: A Preliminary Report. Ann. Neurol., 1990, 27: 205-207.
5. Hirsch, E. C. et. al. Does adrenal graft enhance recovery of dopaminergic neurons in Parkinson’s disease. Ann Neurol., 1990; 27: 676-682.
6. Kordower, J. H. et. al. Putative Chromaffin Cell Survival and Enhanced Host-derived TH-fiber Innervation Following a Functional Adrenal Medulla Autograft for Parkinson’s Disease. Ann Neurol., 1991; 29: 405-412.
7. Stromberg, I. et. al. Reinnervation of Dopamine-denervated striatum by Substantia Nigra Transplants. Neuroscience, 1985, 14: 981-990.