Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of primary human fetal tissue in the treatment of neurodegenerative disorders, while promising, faces several difficult technical and ethical issues. An alternative approach that would obviate these problems would be to use immortalized cell lines of human fetal central nervous system origin. An immortalized human fetal astrocyte cell line (SVG) has been established (45) and herein we describe the in vitro and in vivo characteristics of this cell line which suggest that it may be a useful vehicle for neural transplantation. The SVG cell line is vimentin, GFAP, Thy 1.1 and MHC class I positive, and negative for neurofilament and neuron specific enolase, consistent with its glial origin. To determine whether the cell line could be used as a drug delivery system, a cDNA expression vector for tyrosine hydroxylase was constructed (phTH/Neo) and stably expressed in the SVG cells for over 18 months as demonstrated by immunohistochemistry and Western blotting of the stable transfectants. HPLC analysis of the supernatant from these cells, termed SVG-TH, consistently found 4-6 pmol/ml/min of l-dopa produced with the addition of BH4 to the media. Furthermore, in cocultivation experiments with hNT neurons, PC-12 cells and primary rat fetal mesencephalic tissue, both the SVG and SVG-TH cells demonstrated neurotrophic potential, suggesting that they constituitively express factors with neuroregenerative potential. To determine the viability of these cells in vivo, SVG-TH cells were grafted into the striatum of Sprague-Dawley rats and followed over time. A panel of antibodies was used to unequivocally differentiate the engrafted cells from the host parenchyma, including antibodies to: SV40 large T antigen (expressed in the SVG-TH cells), human and rat MHC class 1, vimentin, GFAP, and tyrosine hydroxylase. While the graft was easily identified with the first week, over the course of a four week period of time the engrafted cells decreased in number. Concomittantly, rat CD4 and CD8 expression in the vicinity of the graft increased, consistent with xenograft rejection. When the SVG-TH cells were grafted to the lesioned striatum of a 6-hydroxydopamine lesioned rats, rotational behavior of the rat decreased as much as 80% initially, then slowly returned to baseline over the next four weeks, parallelling graft rejection. Thus, the SVG-TH cells can induce a functional recovery in an animal model of Parkinson's disease, however as a xenograft, the SVG cells are recognized by the immune system.
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PMID:Expression of tyrosine hydroxylase in an immortalized human fetal astrocyte cell line; in vitro characterization and engraftment into the rodent striatum. 868 28

Transplantation of neural tissue from other species has the potential to improve function in patients with neurodegenerative disorders. We investigated the functional effects of embryonic porcine dopaminergic neurons transplanted in a rat model of Parkinson's disease and the immune responses to the grafts in immunosuppressed and nonimmunosuppressed hosts. Twenty-three rats with unilateral 6-hydroxydopamine lesions received dissociated, 27-day-old embryonic porcine ventral mesencephalic tissue in the right striatum. Eighteen rats received cyclosporine (10 mg/kg, IP, daily) during the whole period of 14 weeks, in combination with prednisolone (20 mg/kg, IP, daily) the first 4 days. Five rats served as nonimmunosuppressed controls. All rats were tested for amphetamine-induced rotational behavior at 3-week intervals. Two immunosuppressed rats were excluded due to severe side effects of the treatment. Functional recovery was seen in 9 of 16 immunosuppressed rats at 12 weeks. Six animals remained functionally recovered at 14 weeks and contained an average of 5750+/-1450 (SEM) dopaminergic neurons. Between 9 and 14 weeks, three immunosuppressed rats rejected their grafts, based on rotation scores and immunohistochemical demonstration of cell infiltrates. One additional immunosuppressed rat showed evidence of ongoing rejection at 14 weeks. The striata in animals with ongoing or recent rejection contained large numbers of CD4- and CD8-positive lymphocytes, NK cells, macrophages, and microglia cells, whereas scar tissue was found in rats with grafts rejected at earlier time points (n = 11). Embryonic porcine ventral mesencephalic tissue matures in the adult rat striatum, reinnervates the host brain, and restores behavioral defects. Immunosuppressive treatment was necessary for long-term graft survival and functional recovery, but did not sufficiently protect from rejection mechanisms. Porcine neural tissue is an interesting alternative to embryonic human tissue for intracerebral transplantation in neurodegenerative diseases. However, to achieve stable graft survival in discordant xenogeneic combinations, an appropriate immunosuppressive treatment or donor tissue modifications are needed.
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PMID:Intrastriatal ventral mesencephalic xenografts of porcine tissue in rats: immune responses and functional effects. 1081 98

The effects of music therapy on natural killer (NK) cell count and activity (NKCA) were studied in 19 persons. Alzheimer's disease, cerebrovessel disease and Parkinson's disease subjects were assigned to a music therapy. Blood samples were drawn at rest and after completion of music therapy. Music therapy did not change the number of circulating lymphocytes. The percentage of NK cells increased during music therapy, along with an increase in the NK cell activity. The proportion of T cells, CD4 and CD8 did not change significantly during music therapy. One hour after the music therapy session, plasma adrenaline increased but cortisol and noradrenalin did not change. The results indicate that music therapy can significantly increase NK cell count and activity. The change in NK cell and function were independent of neuro-degenerative diseases.
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PMID:[Music therapy induced alternations in natural killer cell count and function]. 1130 34

Transplantation of embryonic porcine neurons may restore neurological function in patients with Parkinson's disease, if immunological rejection could be prevented. This study was performed to investigate the role of natural killer cells (NK cells) and NK1.1+ T cells (NK T cells) in the rejection of neural xenografts. A cell suspension was prepared from the ventral mesencephalon of 26-27-day-old pig embryos, and 2 microl was implanted in the right striata of mutant CD1d1 null (CD1.1-/-) mice, NK1.1-depleted mice, and controls. The CD1.1-/- mice are deficient in NK T cells and the antigen-presenting molecule CD1d1. Graft survival and host responses were determined immunohistochemically using markers for dopamine neurons, CD4-, CD8- cells, microglia, and macrophages. At 2 weeks, the grafts were significantly larger in CD1.1-/- mice, 0.09 +/- 0.02 microl (mean +/- SEM), compared with controls, 0.05 +/- 0.01 microl. There was no significant difference between NK1.1-depleted mice, 0.02 +/- 0.01 microl, and controls. At 5 weeks, two grafts were still present in the CD1-/- mice, whereas only scars remained in the controls and in the NK1.1-depleted mice. Immune reactions were strong at 2 weeks and less pronounced at 5 weeks in all groups. Microglial activation was lower in NK-depleted mice than in the controls at 2 weeks. In contrast to organ xenografting, NK1.1+ cells do not seem to be important mediators of the rejection of discordant cellular neural xenografts. However, our results suggest that the antigen-presenting molecule CD1d1 may be involved in the rejection process.
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PMID:Enhanced survival of porcine neural xenografts in mice lacking CD1d1, but no effect of NK1.1 depletion. 1143 75

Embryonic ventral mesencephalic tissue from the pig is a potential alternative donor tissue for neural transplantation to Parkinson's disease patients. For stable graft survival, the host immune response has to be prevented. This study was performed in order to analyze the mechanisms and dynamics of neural xenograft rejection, as well as neurobiological properties of the donor tissue. Adult normal mice and rats, and cyclosporin A-treated rats, received intrastriatal transplants of dissociated embryonic ventral mesencephalic pig tissue that was 27 or 29 embryonic days of age (E27 and E29). The animals were perfused at 2, 4, 6, and 12 weeks after grafting and the brains were processed for immunohistochemistry of dopaminergic (tyrosine hydroxylase positive) neurons, CD4(+) and CD8(+) lymphocytes, natural killer cells, macrophages, microglia, and astrocytes. Thirty-five rats received daily injections of BrdU for 5 consecutive days at different time points after transplantation and were perfused at 6 weeks. These animals were analyzed for proliferation of cells in the donor tissue, both in healthy and in rejecting grafts. No tyrosine hydroxylase-positive cells proliferated after grafting. Our results demonstrated that E27 was superior to E29 donor tissue for neurobiological reasons. Cyclosporin A immunosuppression was protective only during the first weeks and failed to protect the grafts in a long-term perspective. Grafts in mice were invariably rejected between 2 and 4 weeks after transplantation, while occasional grafts in untreated rats survived up to 12 weeks without signs of an ongoing rejection process. CD8(+) lymphocytes and microglia cells are most likely important effector cells in the late, cyclosporin A-resistant rejection process.
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PMID:Porcine neural xenografts in rats and mice: donor tissue development and characteristics of rejection. 1168 44

Immune reaction-related inflammation may be important in the pathogenesis of Parkinson disease (PD). To elucidate peripheral immunologic alterations in PD, we characterized extended peripheral T-lymphocyte populations in 33 patients with PD and 34 normal subjects. Patients with PD had significantly decreased CD4+:CD8(+)T-cell ratios (P<0.001), fewer CD4(+)CD25(+)T cells (P<0.01), and significantly increased ratios of IFN-gamma-producing to IL-4-producing T cells (P<0.001). The characteristics of predominant expression of CD8(+)T cells, depletion of CD4(+)CD25(high) cells, and a shift to a T(H)1-type immune response in the peripheral immune system in PD patients may reflect an immune reaction-associated inflammatory process in the brain.
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PMID:Alterations of T-lymphocyte populations in Parkinson disease. 1615 92

Currently, regulation of immune response after grafting has become a hot topic in Parkinson's disease (PD) transplantation research. Interleukin-10 (IL-10) is an important regulator of immune system. Presently, we transplanted c17.2 neural stem cells transfected with pcDNA3.1-Hygro-IL-10 vector (IL-10-c17.2 cells) or Mock-c17.2 cells (c17.2 cells transfected with pcDNA3.1-Hygro vector) into the brains of 6-hydroxydopamine-lesioned PD model rats. From days 10 to 60 after grafting, double immunohistochemistry showed that IL-10 expression was detected in IL-10-c17.2 cells in vivo. Further immunohistochemistry analyses revealed that intracerebral cellular (ED1 and CD8) and humoral (C3 and IgM) immune responses were down-regulated in the rats treated with IL-10-c17.2 cells compared with controls treated with Mock-c17.2 cells. The reduction in ED1 immunostaining in the rats treated with IL-10-c17.2 cells remained significant until day 60 after transplantation. Our results suggest the potential application value of IL-10 in the transplantation treatment of PD.
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PMID:Effect of transplantation of c17.2 cells transfected with interleukin-10 gene on intracerebral immune response in rat model of Parkinson's disease. 1767 68

The migration of peripheral bone-marrow-derived cells (BMDCs) to the brain was studied in a chronic mouse model of Parkinson's disease (PD). BMDCs expressing the enhanced green fluorescent protein (GFP) were aseptically obtained from C57 BL/6-EGFP-Tg mice and intravenously injected into C57 BL/6j mice which had received a total body irradiation of 8 Gy to induce bone marrow ablation. Implanted GFP-BMDCs replenished the bone marrow of irradiated mice, and progressively crossed the blood-brain barrier (BBB), penetrating different mesencephalic and telencephalic brain regions in the following months. The progressive degeneration of dopamine (DA) cells with a small daily dose (4 mg/kg/day for 20 days) of 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) increased the penetration of GFP-BMDCs into the brain, particularly into those regions with marked DA innervation and which showed the clearest DA cell loss. BMDC penetration increased before the DA cell loss was evident and persisted for a long time after MPTP withdrawal. Under these conditions, most BMDCs differentiated into microglia (CD68 expression was observed in 50% of GFP cells 60 days after MPTP administration). BMDC-derived microglia showed morphological characteristics of cell activation, with the glial cell line-derived neurotrophic factor only being expressed in 3% of the cells. No differentiation into neurons (NeuN expression), astrocites (GFAP), cytotoxic lymphocytes (CD8) and T-helper lymphocytes (CD4) was observed. Taken together, the present data suggest that a significant portion of microglial cells is of a peripheral origin. Bearing in mind that microglial reaction is a significant part of the degenerative process in PD, the increase of BMDC penetration into DA-rich areas during DA cell degeneration and their differentiation into microglia suggest that cells coming across the BBB may participate in the neurodegeneration process. The precise role of such a cell inflow into the brain requires further study. Nevertheless, this may represent an opportunity to develop neuroprotective therapeutic strategies for PD.
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PMID:Bone-marrow-derived cell differentiation into microglia: a study in a progressive mouse model of Parkinson's disease. 1789 35

Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of dopamine-containing neurons. Mounting evidence suggests that dopaminergic cell death is influenced by the innate immune system. However, the pathogenic role of the adaptive immune system in PD remains enigmatic. Here we showed that CD8+ and CD4+ T cells but not B cells had invaded the brain in both postmortem human PD specimens and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD during the course of neuronal degeneration. We further demonstrated that MPTP-induced dopaminergic cell death was markedly attenuated in the absence of mature T lymphocytes in 2 different immunodeficient mouse strains (Rag1-/- and Tcrb-/- mice). Importantly, similar attenuation of MPTP-induced dopaminergic cell death was seen in mice lacking CD4 as well as in Rag1-/- mice reconstituted with FasL-deficient splenocytes. However, mice lacking CD8 and Rag1-/- mice reconstituted with IFN-gamma-deficient splenocytes were not protected. These data indicate that T cell-mediated dopaminergic toxicity is almost exclusively arbitrated by CD4+ T cells and requires the expression of FasL but not IFNgamma. Further, our data may provide a rationale for targeting the adaptive arm of the immune system as a therapeutic strategy in PD.
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PMID:Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. 1910 49

Sequence variants at or near the leucine-rich repeat kinase 2 (LRRK2) locus have been associated with susceptibility to three human conditions: Parkinson's disease (PD), Crohn's disease and leprosy. As all three disorders represent complex diseases with evidence of inflammation, we hypothesized a role for LRRK2 in immune cell functions. Here, we report that full-length Lrrk2 is a relatively common constituent of human peripheral blood mononuclear cells (PBMC) including affinity isolated, CD14(+) monocytes, CD19(+) B cells, and CD4(+) as well as CD8(+) T cells. Up to 26% of PBMC from healthy donors and up to 43% of CD14(+) monocytes were stained by anti-Lrrk2 antibodies using cell sorting. PBMC lysates contained full-length (>260 kDa) and higher molecular weight Lrrk2 species. The expression of LRRK2 in circulating leukocytes was confirmed by microscopy of human blood smears and in sections from normal midbrain and distal ileum. Lrrk2 reactivity was also detected in mesenteric lymph nodes and spleen (including in dendritic cells), but was absent in splenic mononuclear cells from lrrk2-null mice, as expected. In cultured bone marrow-derived macrophages from mice we made three observations: (i) a predominance of higher molecular weight lrrk2; (ii) the reduction of autophagy marker LC3-II in (R1441C)lrrk2-mutant cells (<31%); and (iii) a significant up-regulation of lrrk2 mRNA (>fourfold) and protein after exposure to several microbial structures including bacterial lipopolysaccharide and lentiviral particles. We conclude that Lrrk2 is a constituent of many cell types in the immune system. Following the recognition of microbial structures, stimulated macrophages respond with altered lrrk2 gene expression. In the same cells, lrrk2 appears to co-regulate autophagy. A pattern recognition receptor-type function for LRRK2 could explain its locus' association with Crohn's disease and leprosy risk. We speculate that the role of Lrrk2 in immune cells may also be relevant to the susceptibility of developing PD or its progression.
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PMID:Parkinson's disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures. 2155 86


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