Benefits and risks of intranigral transplantation of GABA-producing cells subsequent to the establishment of kindling-induced seizures.
Neural transplantation has been investigated experimentally and clinically for the purpose of developing new treatment options for intractable epilepsy. In the present study we assessed the anticonvulsant efficacy and safety of bilateral allotransplantation of genetically engineered striatal GABAergic rat cell lines into the substantia nigra pars reticulata (SNr). Rats with previously-established seizures, induced by amygdala kindling, were used as a model of temporal lobe epilepsy. Three cell lines were transplanted: (1) immortalized GABAergic cells (M213-2O) derived from embryonic rat striatum; (2) M213-2O cells (CL4) transfected with human GAD67 cDNA to obtain higher GABA synthesis than the parent cell line; and (3) control cells (121-1I), also derived from embryonic rat striatum, but which did not show GAD expression. A second control group received injections of medium alone. Transplantation of M213-2O cells into the SNr of kindled rats resulted in significant but transient anticonvulsant effects. Neither control cells nor medium induced anticonvulsant effects. Strong tissue reactions were, however, induced in the host brain of kindled but not of non-kindled rats, and only in animals that received grafts of genetically modified CL4 cells. These tissue reactions included graft rejection, massive infiltration of inflammatory immune cells, and gliosis. The anticonvulsant effect of M213-2O cells emphasizes the feasibility of local manipulations of seizures by intranigral transplantation of GABA-producing cells. On the other hand, the present data suggest that kindling-induced activation of microglia in the SNr can enhance immune reactions to transplanted cells. In this case, under conditions of further immunological stimulation by CL4 cells, transfected with a human cDNA, substantial immune reactions occurred. Thus, it appears that the condition of the host brain and the production of foreign proteins by transplanted cells have to be considered in estimating the risks of rejection of transplants into the brain.
Nolte
Marc W
MW
Department of Pharmacology, Neuroscience Discovery Research, Abbott GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany.
Löscher
Wolfgang
W
Herden
Christiane
C
Freed
William J
WJ
Gernert
Manuela
M
D000818:Animals; D016380:Brain Tissue Transplantation / Q000009:adverse effects / Q000379:methods*; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D004827:Epilepsy / Q000378:metabolism* / Q000503:physiopathology / Q000601:surgery*; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005968:Glutamate Decarboxylase / Q000235:genetics; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D006801:Humans; D007696:Kindling, Neurologic / Q000378:metabolism; D017628:Microglia / Q000276:immunology; D009433:Neural Inhibition / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D051381:Rats; D017208:Rats, Wistar; D018570:Risk Assessment; D033581:Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods; D013378:Substantia Nigra / Q000378:metabolism* / Q000503:physiopathology / Q000601:surgery*; D014162:Transfection / Q000379:methods; D016896:Treatment Outcome; D015854:Up-Regulation / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis*
D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1