CNS IMMUNOLOGICAL MODULATION OF NEURAL GRAFT-REJECTION AND SURVIVAL

Neural transplantation therapy as a possible alternative treatment for neurological movement disorders, such as in Parkinson's disease (PD) has accentuated research interest on the immune status of the central nervous system (CNS). Most animal studies concerned with neural transp lantation for the treatment of PD have utilized dopamine (DA) neurons from tissues of the embryonic ventral mesencephalon. Rat embryonic DA neurons, grafted either as solid blocks or dissociated into a cell sus pension and stereotaxically injected intraparenchymally into a rat les ion model of PD, have been shown to survive and form connections with the host brain, and ameliorate the behavioral deficits of PD. Similarl y, studies on nonhuman primate models of PD provide considerable suppo rt for neural transplantation of DA neurons as an experimental clinica l procedure for the treatment of PD. To this end, experimental clinica l trials have been centered upon transplantation of the embryonic vent ral mesencephalic cells for PD patients. Although not conclusive, the findings from clinical studies have provided some evidence that most p atients with marked increases in fluorodopa uptake (indicating graft s urvival) have been immunosuppressed. Furthermore, immune reactions hav e been observed in rats xenografted with human embryonic tissue. Of no te, embryonic ventral mesencephalic tissues compared to adult tissues produce better morphological and long-lasting behavioral amelioration of the neurobehavioral deficits of PD, thus advocating the use of graf ts from young donors (embryo) to circumvent the CNS immune rejection. The possible graft rejection due to CNS immune reactions, coupled with the social and ethical problems surrounding the use of embryonic neur al tissue, and the logistical problems concerning tissue availability have prompted the development of alternative sources of DA-secreting c ells. To circumvent these obstacles, several methods have been suggest ed including the use of immunosuppressants such as Cyclosporine-A, tra nsplantation of autografts, polymer-encapsulated DA-secreting cells, c o-culturing and co-transplantation of DA-secreting cells with microcar rier beads, with Sertoli cells, or with fragments of a monoclonal anti body that can mask the MHC class I antigens, and genetically modifying cells that can withstand CNS immune reactions. Some of these techniqu es allow transplantation of allograft (same species transplantation), or even xenograft (cross species transplantation) without immunosuppre ssion of the recipient. We discuss recent CNS immunosuppression techni ques that pose some promise for enhanced survival of neural grafts. Wh en possible, advantages and disadvantages of each method are presented . Hopefully, such critical analysis of different immunosuppression tec hniques will produce innovated ideas that will lead to a better unders tanding of CNS immune response and its modulatory function on graft re jection and survival.