| 1. |
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| 2. |
- Defer, G L, et al.
(författare)
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Core assessment program for surgical interventional therapies in Parkinson's disease (CAPSIT-PD)
- 1999
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Ingår i: Movement Disorders. - 0885-3185. ; 14:4, s. 84-572
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Tidskriftsartikel (refereegranskat)abstract
- In 1992 the Core Assessment Program for Intracerebral Transplantations (CAPIT) was published providing the minimal requirements for a common patient evaluation protocol. Despite the intent, the program was thought to be too laborious to carry out in large scale trials, and it also lacked evaluations of cognitive functions and quality of life. Moreover, the CAPIT was designed for neural transplantation only and has not been revised since. Since then, pallidotomy and deep brain stimulation have emerged as additional treatment modalities but there exists no common tool for evaluation of, and between, the techniques. In 1996, within the framework of NECTAR (Network for European CNS Transplantation and Restoration), a dedicated program entitled "Neurosurgical Interventions in Parkinson's Disease" (NIPD) was funded by the European Union Biomed 2 program to develop a new Core Assessment Program for Surgical Interventional Therapies in PD (CAPSIT-PD) and to establish an European registry for patients with PD subjected to functional neurosurgery. This article presents the recommendations of this new program.
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| 3. |
- Duan, W M, et al.
(författare)
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Addition of allogeneic spleen cells causes rejection of intrastriatal embryonic mesencephalic allografts in the rat
- 1997
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Ingår i: Neuroscience. - 0306-4522. ; 77:2, s. 599-609
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Tidskriftsartikel (refereegranskat)abstract
- To address the importance of antigen-presenting cells for the survival of intracerebral neural allografts, allogeneic spleen cells were added to the graft tissue before transplantation. Dissociated embryonic, dopamine-rich mesencephalic and adult spleen tissues were prepared from either inbred Lewis or Sprague-Dawley rats. A mixture of neural and spleen cells was sterotaxically transplanted into the right striatum of adult Sprague-Dawley rats. Controls were neural allografts without addition of allogeneic spleen cells and syngeneic neural grafts with or without the addition of syngeneic spleen cells. Six weeks after transplantation, brain sections were processed immunocytochemically for tyrosine hydroxylase, specific for grafted dopamine neurons, and a bank of markers for various components in the immune and inflammatory responses. The neural allografts which were mixed with allogeneic spleen cells were rejected. In these rats, there were high levels of expression of major histocompatibility complex class I and II antigens, intense cellular infiltration including macrophages and activated microglial cells, and a presence of cluster of differentiation 4- and 8-immunoreactive cells in the graft sites. Moreover, there were increased levels of intercellular adhesion molecule-1, tumour necrosis factor-alpha and interleukin-6 in and around the grafts which were undergoing rejection. In contrast, syngeneic neural grafts survived well regardless of whether they were mixed with syngeneic spleen cells or not, and control neural allografts also exhibited unimpaired survival. No significant difference was observed in the number of grafted dopamine neurons among these three latter groups. The levels of expression of the different markers for inflammation and rejection were generally lower in these grafts than in implants of combined allogeneic neural and spleen cells. In summary, intrastriatal neural allografts, which normally survive well in our animal model, were rejected if allogeneic spleen cells from the same donor were added to the graft tissue. The added spleen cells caused strong host immune and inflammatory responses. The study gave support to the notion that immunological privilege of the brain does not provide absolute protection to immunogenetically histoincompatible neural grafts.
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| 4. |
- Duan, W M, et al.
(författare)
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Immune reactions following systemic immunization prior or subsequent to intrastriatal transplantation of allogeneic mesencephalic tissue in adult rats
- 1995
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Ingår i: Neuroscience. - : Elsevier BV. - 0306-4522. ; 64:3, s. 41-629
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Tidskriftsartikel (refereegranskat)abstract
- We have previously found that dissociated mesencephalic tissue, which differs from the host at both major histocompatibility complex and non-major histocompatibility complex gene loci, can survive stereotaxic transplantation to the striatum of adult rats. We have now studied the outcome of intrastriatal neural allografts in rats that were systemically immunized by an orthotopic skin allograft either prior or subsequent to intracerebral implantation surgery. Dissociated mesencephalic tissue from Lewis rat embryos was stereotaxically injected into the dopamine-depleted striatum of hemi-parkinsonian Sprague-Dawley rats. One group was immunized by an orthotopic allogeneic skin graft of the same genetic origin as the neural graft, six weeks before the neural transplantation (the pre-immunized group). Another group was post-immunized by an orthotopic skin allograft, six weeks after the neural transplantation (the post-immunized group). A control group of rats was not challenged by a skin allograft. Marked behavioural recovery was observed in six of seven rats in the control group, in six of eight rats in the post-immunized group, and in none of the pre-immunized rats. Tyrosine hydroxylase-immunopositive cells were found in rats from the two behaviourally compensated groups, but not in the pre-immunized group. The immune responses were evaluated by OX-18 (monoclonal antibody against major histocompatibility complex class I antigen), OX-6 (major histocompatibility complex class II antigen), OX-42 (microglia and macrophages), glial fibrillary acidic protein (astrocytes), OX-8 (cytotoxic T-lymphocytes) and W3/25 (helper T-lymphocytes) immunocytochemistry. All the neural allografts in the pre-immunized group were rejected, leaving scars only. There were more intense immune responses to the allografts in the post-immunized group than the control group, in terms of immunocytochemically higher expression of major histocompatibility complex class I and II antigens and more intense cellular reactions consisting of macrophages, activated microglia and astrocytes, in addition to CD8- and CD4-positive lymphocytes. In summary, the results show the following: (i) systemic pre-immunization leads to complete rejection of intrastriatal neural allografts, implying that the status of the host immune system before transplantation determines the outcome for intrastriatal neural allografts; (ii) established intrastriatal neural allografts can survive for at least six weeks after systemic immunization, in spite of increased host immune responses in and around the allografts; (iii) there are no marked immune reactions against intrastriatal neural allografts 13 weeks after implantation in rats which have not been systemically immunized by a skin allograft; (iv) pre-immunized rats may provide a very useful animal model to investigate the role of inflammatory lymphokines in immune rejection and to test alternative immunosuppressive drugs.
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| 5. |
- Duan, W M, et al.
(författare)
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Methylprednisolone prevents rejection of intrastriatal grafts of xenogeneic embryonic neural tissue in adult rats
- 1996
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Ingår i: Brain Research. - : Elsevier BV. - 0006-8993. ; 712:2, s. 199-212
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Tidskriftsartikel (refereegranskat)abstract
- We studied the effects of high-dose methylprednisolone on the survival of intrastriatal neural xenografts and the host responses against them. Dissociated mesencephalic tissue from inbred mouse (CBA-strain) embryos was transplanted to the intact striatum of adult Sprague-Dawley rats. The rats received either daily injections of methylprednisolone (30 mg/kg), or cyclosporin A (10 mg/kg), or no immunosuppressive treatment. Two or six weeks after transplantation, there was good survival of xenografts in both the methylprednisolone- and cyclosporin A-treated rats. In contrast, the xenografts in untreated control rats were all rejected by six weeks. There was no marked difference in the degree of expression of MHC class I and II antigens and the accumulation of activated astrocytes and microglial cells/macrophages between the three groups. However, both methylprednisolone and cyclosporin A reduced infiltration of T lymphocytes to the transplantation sites. The expression of pro-inflammatory cytokines (interferon-gamma, tumour necrosis factor-alpha, interleukin-6) in and around the grafts was lower in the methylprednisolone- and cyclosporin A-treated groups than in untreated control rats. Although high-dose methylprednisolone caused significant body weight loss, we conclude that this treatment can prevent rejection of intrastriatal grafts of xenogeneic embryonic neural tissue in the adult.
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| 6. |
- Duan, W M, et al.
(författare)
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Quinolinic acid-induced inflammation in the striatum does not impair the survival of neural allografts in the rat
- 1998
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X. ; 10:8, s. 606-2595
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Tidskriftsartikel (refereegranskat)abstract
- It has been suggested that inflammation related to intracerebral transplantation surgery can affect the survival of intrastriatal neural allografts. To test this hypothesis, we transplanted dissociated embryonic mesencephalic tissue from one of two rat strains, Lewis (allogeneic grafts) or Sprague-Dawley (syngeneic grafts), to the striatum of Sprague-Dawley rats. The target striatum was either intact or had received a local injection of quinolinic acid 9 days earlier, in order to induce a marked inflammation. At 6 or 12 weeks after transplantation, there was no significant difference between the different groups regarding the number of surviving grafted tyrosine hydroxylase immunoreactive neurons. However, the graft volume of both the syngeneic and allogeneic implants was significantly larger in the quinolinate-lesioned than in the intact striatum. There were dramatically increased levels of expression of major histocompatibility complex class I and II antigens, marked infiltrates of macrophages, activated microglia and astrocytes, and accumulation of large numbers of CD4 and CD8 positive T-lymphocytes in the quinolinate-lesioned striatum. In contrast, these immunological markers were much less abundant around both syngeneic and allogeneic grafts placed in intact striatum. We conclude that severe inflammation caused by quinolinic acid does not lead to rejection of intrastriatal neural allografts.
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| 7. |
- Duan, W M, et al.
(författare)
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Rat intrastriatal neural allografts challenged with skin allografts at different time points
- 1997
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 148:1, s. 47-334
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Tidskriftsartikel (refereegranskat)abstract
- The present study was designed to address two questions. First, can an intrastriatal neural allograft exhibit long-term survival (18 weeks) if the host is immunized by an orthotopic skin graft 6 weeks after neural transplantation (the 6w-Long group)? Second, can an intrastriatal neural allograft survive when the host is challenged by an orthotopic skin allograft either simultaneously (Sim) with the intracerebral graft surgery or 2 (2w) weeks later? Dissociated embryonic ventral mesencephalic tissue from Lewis rats was stereotaxically injected into the striatum of Sprague-Dawley rats with unilateral 6-hydroxydopamine lesions. Six weeks after neural grafting, no reduction in amphetamine-induced motor asymmetry was observed in the Sim and 2w groups. At 6 weeks after skin grafting, the mean motor asymmetry scores had returned to the initial pretransplantation levels in the 6w-Long group. All the neural allografts in the Sim group were completely rejected, and the mean number of tyrosine hydroxylase immunoreactivity neurons in the grafts was significantly reduced in the 2w and the 6w-Long group, when compared to the no-skin control group. There were very high levels of expression of MHC class I and II antigens, marked cellular infiltrates containing macrophages and T-lymphocytes, and several activated microglia and astrocytes in and around the surviving intracerebral transplants in the 2w and the 6w-Long groups. The results suggest that intrastriatal neural allografts are more likely to be rejected rapidly if the host is efficiently immunized with the same alloantigens simultaneously or soon after the neural transplantation than at a later time point. When established neural allografts are subjected to a strong immunological challenge, they undergo protracted rejection.
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| 8. |
- Duan, W M, et al.
(författare)
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Temporal pattern of host responses against intrastriatal grafts of syngeneic, allogeneic or xenogeneic embryonic neuronal tissue in rats
- 1995
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Ingår i: Experimental Brain Research. - 0014-4819. ; 104:2, s. 42-227
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Tidskriftsartikel (refereegranskat)abstract
- The host response to immunologically incompatible intrastriatal neural grafts was studied using immunohistochemical techniques. Dissociated ventral mesencephalic tissue from embryonic donors of either syngeneic, allogeneic or xenogeneic (mouse) origin was stereotaxically implanted into adult rats. The brains were analysed 4 days, 2 weeks or 6 weeks after grafting with antibodies against the following antigenic structures: major histocompatibility complex (MHC) class I antigens; MHC class II antigens; complement receptor (CR) 3 (marker for microglia and macrophages); helper T-lymphocyte antigen-cluster of differentiation (CD) 4; cytotoxic T-lymphocyte antigen-CD8; tyrosine hydroxylase (TH) (marker for transplanted dopaminergic neurons). The number of surviving TH-positive cells was not different at the various time points in either the syngeneic or allogeneic groups, whereas the xenogeneic cells were all rejected by 6 weeks. The host reactions were similar in character in the syngeneic and allogeneic groups. At 4 days after implantation, there were increased levels of expression of MHC class I and II antigens. In and around the grafts, there were cellular infiltrates consisting of activated microglia, macrophages, CD4- and CD8-positive lymphocytes. At 6 weeks, MHC expression was reduced and the cellular infiltrates had subsided with only low numbers of activated microglia cells and CD8-positive lymphocytes remaining. In the xenogeneic group, at 4 days, some grafts contained cavities, possibly reflecting acute rejection. At later stages, the xenografts were heavily infiltrated by macrophages, activated microglial cells and T-lymphocytes, and at 6 weeks all the xenografts were rejected. Taken together, the results suggest that there is an inflammation caused by the implantation process which leads to an accumulation of host defence cells. This, in turn, leads to increased MHC expression in and around the grafts. In syngeneic grafts, these reactions are short lasting and weak; for allografts slightly more pronounced and longer lasting than syngeneic grafts, but not sufficient to cause rejection. For xenografts, the reactions are more intense and lead to transplant rejection. Thus, a strong sustained inflammatory response may be an important determinator for the failure of histoincompatible neural grafts. It can be speculated that a short-term anti-inflammatory treatment of graft recipients may be a sufficient immunosuppressive regimen to allow long-term graft survival.
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| 9. |
- Larsson, Lena C, et al.
(författare)
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Discordant neural tissue xenografts survive longer in immunoglobulin deficient mice
- 1999
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Ingår i: Transplantation. - 0041-1337. ; 68:8, s. 60-1153
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The immune response against discordant xenografts in the brain is incompletely understood and remains a major obstacle for future clinical applications of xenogeneic neural tissue transplants in neurodegenerative disorders. To determine the role of antibodies in the rejection process, we compared graft survival and immune reactions between immunoglobulin deficient (IgKO) and normal mice.METHODS: A cell suspension of embryonic porcine ventral mesencephalon was injected into the striatum of adult normal and IgKO mice. Graft sizes and number of infiltrating CD4- and CD8-positive lymphocytes were determined by stereological methods at 4 days and 2, 4, and 6 weeks after the transplants. Microglial accumulation was determined using the optical densitometrical method. Intraparenchymal deposition of IgG was investigated at 4 days and 2 weeks.RESULTS: The majority of IgKO mice had surviving grafts for up to 4 weeks, whereas survival was minimal in control mice beyond 4 days. Graft sizes differed significantly between IgKO and control mice at 2 weeks (P<0.01, Kruskal Wallis ANOVA, followed by Mann Whitney test). The majority of infiltrating lymphocytes were CD4-positive in control mice but CD8-positive in IgKO mice. Microglial accumulation was strong around surviving grafts in IgKO mice at 4 weeks. Prominent staining of IgG, diffuse in the transplanted hemisphere and specific on grafted neurons, was found in control mice.CONCLUSIONS: Our results suggest that immunoglobulins play an initiating role in rejection of discordant neural xenografts. After a prolonged graft survival of approximately 4 weeks, a cellular response with a large proportion CD8-positive cells leads to rejection in IgKO mice.
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| 10. |
- Larsson, L C, et al.
(författare)
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Discordant xenografts : different outcome after mouse and rat neural tissue transplantation to guinea-pigs
- 1999
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Ingår i: Brain Research Bulletin. - 0361-9230. ; 49:5, s. 76-367
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Tidskriftsartikel (refereegranskat)abstract
- Embryonic neural tissue obtained from other species has been considered as a donor tissue source in repair strategies for human neurodegenerative disorders. The neuro- and immunobiology of distantly related species combinations, discordant xenografts, need to be characterised. For this purpose, a small animal model would be an important research tool. Adult guinea-pigs, and adult rats as controls, received intrastriatal grafts of either mouse or rat embryonic ventral mesencephalic tissue. The survival rates and types of host immune response were assessed at 2 weeks after grafting using stereological techniques and semi-quantitative evaluations. In the mouse-to-guinea-pig group, all transplants were rejected and no tyrosine hydroxylase-immuno reactive (TH-IR) cells remained. In the rat-to-guinea-pig group, there was good survival of TH-IR cells (5050 SEM+/-1550), similar to that in the rat-to-rat group (4900 SEM+/-1540). In the mouse-to-rat group, half of the animals had no surviving TH-IR cells (520 SEM+/-230 for the whole group). These species combinations offer inexpensive, efficient, and suitable conditions to study important survival factors for discordant xenogeneic neural tissue transplants. The factors responsible for the divergent graft outcomes between the two combinations might provide clues on how to manipulate xenogeneic tissue to increase survival rates in the future.
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| 11. |
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| 12. |
- Nakao, Naoyuki, et al.
(författare)
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Antioxidant treatment protects striatal neurons against excitotoxic insults
- 1996
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Ingår i: Neuroscience. - : Elsevier BV. - 0306-4522. ; 73:1, s. 185-200
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Tidskriftsartikel (refereegranskat)abstract
- It has been suggested that oxidative stress plays an important role in mediating excitotoxic neuronal death. We have therefore investigated the protective effects of antioxidants against excitotoxic injury in the rat on striatal neurons both in vitro and in vivo. In the first part of the study, we determined whether two different types of antioxidants, the spin trapping agent, alpha-phenyl-tert-butyl nitrone and an inhibitor of lipid peroxidation, U-83836E, could protect cultured striatal neurons against either hypoglycemic injury or N-methyl-D-aspartate-induced excitotoxicity. Dopamine- and cyclic AMP-regulated phosphoprotein, which is enriched in medium-sized spiny neurons, was chosen as a marker for striatal neurons. alpha-Phenyl-t-butyl nitrone and U-83836E both significantly reduced cell death induced by these insults as indicated by an increased number of surviving dopamine- and cyclic AMP-regulated phospho-protein-positive neurons. The two antioxidants also promoted the survival of cultured striatal neurons grown at low cell density under serum-free culture conditions. In an in vivo experiment systemically administered alpha-phenyl-t-butyl nitrone exerted neuroprotective effects in the rat striatum following injection of the excitotoxin quinolinic acid. Apomorphine-induced rotation tests revealed that alpha-phenyl-t-butyl nitrone-treated animals were significantly less asymmetric in their motor behavior than control rats. Treatment with alpha-phenyl-t-butyl nitrone significantly reduced the size of the quinolinic acid-induced striatal lesions, as assessed by the degree of sparing of dopamine- and cyclic AMP-regulated phospho-protein-positive and nicotinamide adenine dinucleotide phosphate-diaphorase-positive neurons, and of microtubule-associated protein-2-immunorective areas. Furthermore, lesion-induced morphological changes in the substantia nigra pars reticulate, i.e. loss of dopamine- and cyclic AMP-regulated phosphoprotein-positive afferent fibers and atrophic changes due to transsynaptic degeneration, were also less extensive in the alpha-phenyl-t-butyl nitrone-treated animals. The results support the hypothesis that oxygen-free radicals contribute to excitotoxic neuronal injury. The in vivo cytoprotective effects of alpha-phenyl-t-butyl nitrone against striatal excitotoxic lesions suggest that antioxidants could be used as potential neuroprotective agents in Huntington's disease, which has been suggested to involve excitotoxicity.
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| 13. |
- Nakao, Naoyuki, et al.
(författare)
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DARPP-32-rich zones in grafts of lateral ganglionic eminence govern the extent of functional recovery in skilled paw reaching in an animal model of Huntington's disease
- 1996
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Ingår i: Neuroscience. - : Elsevier BV. - 0306-4522. ; 74:4, s. 70-959
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Tidskriftsartikel (refereegranskat)abstract
- Grafts of striatal tissue comprise two different types of tissue: regions with (P-zones) and without (NP-zones) neurons that express markers characteristic of the striatum, such as dopamine- and cyclic AMP-regulated phosphoprotein with a mol. wt of 32,000 (DARPP-32). It remains unclear whether P-zones alone play a crucial role in functional effects of striatal grafts in an animal model of Huntington's disease. The present study has been performed to determine: (i) the yield of DARPP-32-positive neurons in grafts of lateral ganglionic eminence; (ii) whether treatment of graft tissue with the spin-trapping agent alpha-phenyl-tert-butyl nitrone enhances the survival of implanted DARPP-32-positive neurons; and (iii) the relationship between the number of DARPP-32-positive neurons in the grafts and functional effects of the grafts on paw-reaching ability in rats with unilateral quinolinic acid lesions of the striatum. Dissociated tissue derived from the lateral ganglionic eminence of rat embryos (embryonic day 14), with or without addition of alpha-phenyl-tert-butyl nitrone (3 mM), was implanted into the quinolinic acid-lesioned striatum. Compared to unlesioned normal animals, rats with striatal lesions showed substantial impairment in paw-reaching ability, particularly on the side contralateral to the lesion, as judged from the number of pellets retrieved by each paw. Intrastriatal grafts gave rise to a significant improvement in paw-reaching ability. The mean total number of surviving DARPP-32-positive cells in grafts without alpha-phenyl-tert-butyl nitrone treatment was estimated at 115 x 10(3), which did not significantly differ from that in alpha-phenyl-tert-butyl nitrone-treated grafts. The paw-reaching scores were significantly correlated with the volumes of P-zones and the number of DARPP-32-positive neurons, but with neither the volumes of NP-zones nor the total graft volume. The results suggest that P-zones in striatal grafts mediate graft-derived functional recovery in a complex task such as skilled forelimb use. Although the antioxidant treatment with alpha-phenyl-tert-butyl nitrone failed to promote graft survival, the positive correlation between the yield of DARPP-32-positive cells in the graft and the extent of the functional recovery highly warrants further attempts to increase the yield of the striatal component in the graft.
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| 14. |
- Nakao, Naoyuki, et al.
(författare)
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Overexpressing Cu/Zn superoxide dismutase enhances survival of transplanted neurons in a rat model of Parkinson's disease
- 1995
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Ingår i: Nature Medicine. - 1078-8956. ; 1:3, s. 31-226
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Tidskriftsartikel (refereegranskat)abstract
- A high survival rate of grafted dopamine neurons is crucial for reversing neurological deficits following brain tissue transplantation in Parkinson's disease. For unknown reasons the survival rate of transplanted dopamine neurons is only around 10% in experimental animals. The hypothesis that oxidative stress causes the loss of transplanted neurons was tested by grafting neurons from transgenic mice that overexpress Cu/Zn superoxide dismutase. Compared with the survival of those taken from non-transgenic littermates, the survival was 4 times higher for the transgenic dopamine neurons with a concomitant more extensive functional recovery. The results provide direct support for the free radical hypothesis of dopaminergic neuron death in brain tissue grafting.
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| 15. |
- Schierle, G S, et al.
(författare)
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Differential effects of Bcl-2 overexpression on fibre outgrowth and survival of embryonic dopaminergic neurons in intracerebral transplants
- 1999
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X. ; 11:9, s. 81-3073
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Tidskriftsartikel (refereegranskat)abstract
- The causes of death of transplanted neurons are not known in detail, but apoptotic mechanisms involving caspase activation are likely to play a role. We examined whether overexpression of the anti-apoptotic protein Bcl-2 may enhance the survival of dopaminergic [tyrosine hydroxylase (TH)-immunoreactive] grafted neurons. For this purpose, we prepared cells from embryonic day 13 ventral mesencephalon (VM) of mice overexpressing human Bcl-2, or from their wild-type littermates. The bcl-2 transgene was strongly expressed in these cells, and resulted in protection of neuronal cultures from death triggered by serum deprivation or exposure to staurosporine. To model pretransplantation stress more closely in vitro, we stored dissociated embryonic mesencephalic cells for 8 h in the same type of medium used for intracerebral transplantation. This resulted in massive cell death as quantified by lactate dehydrogenase (LDH) release, and increased DNA fragmentation. Although this cell loss was strongly reduced by a caspase inhibitor, Bcl-2 had no significant protective effect. Finally, mesencephalic cell suspensions were xenografted into the striatum of immunosuppressed hemiparkinsonian rats. Neither the survival of TH-immunopositive transplanted neurons nor the functional recovery of the rats was improved by Bcl-2, although the Bcl-2 protein was strongly expressed in transgenic grafts 5 weeks after implantation, and dopaminergic fibre outgrowth from the grafts was significantly improved. These data suggest that cell death in neuronal transplants involves apoptotic mechanisms that can bypass negative regulation by Bcl-2.
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| 16. |
- Sumitran-Holgersson, S, et al.
(författare)
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Human natural antibodies cytotoxic to pig embryonic brain cells recognize novel non-Galalpha1,3Gal-based xenoantigens
- 1999
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 159:2, s. 61-347
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Tidskriftsartikel (refereegranskat)abstract
- Transplantation of porcine embryonic brain cells, including dopaminergic neurons, from ventral mesencephalon (VM) is considered a potential treatment for patients with Parkinson's disease. In the present study, we characterized the distribution among VM cells of the major porcine endothelial xenoantigen, the Galalpha1,3Gal epitope, and evaluated the cytotoxic effect of anti-Galalpha1,3Gal antibody-depleted and nondepleted human AB serum on VM cells. Overall levels of Galalpha1,3Gal-epitope expression was very low on the VM cell population using Bandeiraea simplicifolia IB(4) lectin staining of resuspended VM cells in flow cytometric analyses or staining of SDS-PAGE-separated, solubilized VM cell membrane proteins in Western blot analyses. Lectin-histochemical staining of sections of pig embryonal VM regions with BSA IB(4) lectin showed staining restricted to endothelial cells and microglia. In the presence of complement, both nondepleted and anti-Galalpha1,3Gal antibody-depleted AB sera were shown to be cytotoxic to VM cells as assessed in microcytotoxicity- and flow cytometry-based cytotoxicity assays. Purified IgM and IgG were both cytotoxic in the presence of complement. Three major VM cell membrane antigens of approximately 210, 105, and 50 kDa were reactive with natural IgM antibodies present in pooled human AB sera. Thus, antibody-dependent cytotoxicity may contribute to pig to human brain cell xenorejection, necessitating donor tissue modifications prior to a more widespread utilization of neural tissue xenografting.
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| 17. |
- Sumitran-Holgersson, S, et al.
(författare)
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Porcine embryonic brain cell cytotoxicity mediated by human natural killer cells
- 1999
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Ingår i: Cell Transplantation. - : SAGE Publications. - 0963-6897 .- 1555-3892. ; 8:6, s. 10-601
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Tidskriftsartikel (refereegranskat)abstract
- Intracerebral transplantation of porcine embryonic dopamine-producing neurons has been suggested as a method to treat patients with Parkinson's disease. Even though the brain is an immunologically privileged site, neuronal xenografts are usually rejected within a few weeks. T cells are important for this process, but the exact cellular events leading to rejection are poorly characterized. Brain cells from ventral mesencephalon of 26-27-day-old pig embryos were used as target cells in flow cytometry-assessed cytotoxicity assays using non- and IL-2-activated CD3- CD16+ CD56+ human natural killer (NK) cells as effector cells. The ability of human NK cells to kill pig embryonic brain cells by antibody-dependent cellular cytotoxicity (ADCC) in the presence of nondepleted and anti-Gal alpha1,3Gal antibody-depleted human blood group AB serum (AB serum) was evaluated using the same assay. Both nondepleted and anti-Gal alpha1,3Gal antibody-depleted AB serum could mediate ADCC of pig embryonic VM cells when human NK cells were used as effector cells. Nonactivated NK cells did not show any direct cytotoxic effect on freshly isolated VM cells, whereas IL-2-activated NK cells killed approximately 50% of the VM cells at an effector-to-target ratio of 50:1 in a 4-h cytotoxicity assay. Activation of VM cells by TNF-alpha did not change their sensitivity to human NK cell cytotoxicity. Human NK cells may thus contribute to a cellular rejection of pig neuronal xenografts by ADCC, or following IL-2 activation, by a direct cytotoxic effect.
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| 18. |
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| 19. |
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| 20. |
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| 21. |
- Widner, H
(författare)
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The case for neural tissue transplantation as a treatment for Parkinson's disease
- 1999
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Ingår i: Advances in neurology. - 0091-3952. ; 80, s. 9-641
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Forskningsöversikt (refereegranskat)abstract
- Neural tissue grafting can be highly effective and constitutes a potentially curative approach for progressive neurodegenerative disorders such as PD. Virtually all signs and symptoms of PD have been shown to improve after grafting but not necessarily simultaneously in one patient. Several technical aspects require improvement before widespread use of neural tissue implants can be recommended. These include better definition of donor tissue in terms of infectious risks, the need and duration of immunosuppressive treatment, and the minimal amount of tissue needed for definite benefit. Somatotropism within the basal ganglia system (with specific targeted grafts) aimed at relieving certain symptoms need to be elucidated experimentally. Interaction with the underlying disease process is also important to consider, and the role of intracerebral grafts in differing patterns of parkinsonism needs to be addressed. Grafting is potentially a very powerful therapeutic approach that may evolve to be the ideal treatment for patients with young-onset disease who, when starting to experience fluctuations, may have a life expectancy of 25 years with the disease. For these patients, grafting is likely to be both effective and long-lasting. For these patients, it is likely to become an efficient and also economically sound treatment for the patients and society. Provided that the transplantation procedure is performed judiciously and with strict adherence to basic principles defined from animal and human experimentation, more patients are likely to benefit from the procedure.
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