Improvement of Neurological Deficits in 6-hydroxydopamine-Lesioned Rats after Transplantation with Allogeneic Simian Virus 40 Large Tumor Antigen Gene-Induced Immortalized Dopamine Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 95; no. 3; pp. 1265 - 1270
• Main Authors: Clarkson, Edward D., La Rosa, Francisco G., Edwards-Prasad, Judith, Weiland, David A., Witta, Samir E., Freed, Curt R., Prasad, Kedar N.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 03-02-1998; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Animals; Antigen presenting cells; Antigens, Polyomavirus Transforming - genetics; Biological Sciences; Brain; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Differentiation; Cell growth; Cell lines; Cells, Cultured; Cellular differentiation; Corpus Striatum - drug effects; Dopamine - physiology; Dopamine Plasma Membrane Transport Proteins; Graft rejection; Male; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Neurologic manifestations; Neurology; Neurons; Neurons - transplantation; Neurons - virology; Oxidopamine - toxicity; Rats; Rats, Sprague-Dawley; RNA, Messenger - metabolism; Rodents; Simian virus 40 - immunology; Tissue grafting; Tissue transplantation; Transplantation; Tumors; Tyrosine 3-Monooxygenase - genetics; Tyrosine 3-Monooxygenase - metabolism; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.95.3.1265

The replacement of dopamine (DA) by DA neuron transplants in the treatment of advanced Parkinson disease (PD) is a rational approach. Because of limitations associated with fetal tissue transplants, a clone (1RB3AN27) of simian virus 40 large tumor antigen (LTa) gene-induced immortalized DA neurons were used in this study. These allogeneic immortalized dopamine neurons, when grafted into striata of normal rats, did not divide, did not form tumors, did not produce LTa, did not extend neurites to host neurons, and were not rejected, for as long as 13 months after transplantation. Grafted cells when recultured in vitro resumed cell proliferation and LTa production, suggesting the presence of a LTa gene-inhibiting factor in the brain. The grafting of undifferentiated and differentiated 1RB3AN27cells or differentiated murine neuroblastoma (NBP2) cells into striata of 6-hydroxydopamine-lesioned rats (an animal model of PD) caused a time-dependent improvement in neurological deficits (reduction in the methamphetamine-induced turning rate). At 3 months after transplantation, 100% of the animals receiving differentiated 1RB3AN27cells, 63% of the animals receiving undifferentiated 1RB3AN27cells, 56% of the animals receiving differentiated NBP2cells, and 0% of the sham-transplanted animals showed improvements in neurological deficits. At 6 months after transplantation, there was a progressive increase in spontaneous recovery in sham-transplanted animals. These results suggest that immortalized DA neurons should be further studied for their potential use in transplant therapy in advanced PD patients.