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H Widner

Publications and source records attributed to H Widner.

At least 73 records · Page 4Linked to original sources
PubMed1990

Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease.

Neural transplantation can restore striatal dopaminergic neurotransmission in animal models of Parkinson's disease. It has now been shown that mesencephalic dopamine neurons, obtained from human fetuses of 8 to 9 weeks gestational age, can survive in the human brain and produce marked and sustained symptomatic relief in a patient severely affected with idiopathic Parkinson's disease. The grafts, which were implanted unilaterally into the putamen by stereotactic surgery, restored dopamine synthesis and storage in the grafted area, as assessed by positron emission tomography with 6-L-[18F]fluorodopa. This neurochemical change was accompanied by a therapeutically significant reduction in the patient's severe rigidity and bradykinesia and a marked diminuation of the fluctuations in the patient's condition during optimum medication (the "on-off" phenomenon). The clinical improvement was most marked on the side contralateral to the transplant.

Brain↗
PubMed1989

Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson's disease. A detailed account of methodology and a 6-month follow-up.

By using stereotaxic surgical techniques, ventral mesencephalic tissues from aborted human fetuses of 8 to 10 weeks' gestational age were implanted unilaterally into the striata in two patients with advanced Parkinson's disease. The patients were treated with a cyclosporine, azathioprine, and steroid regimen to minimize the risk for graft rejection. They were examined for 6 months preoperatively and 6 months postoperatively and continued to receive the same doses of antiparkinsonian medication. There were no significant postoperative complications. No major therapeutic effect from the operation was observed. However, in the clinical tests, both patients showed small but significant increases of movement speed for repeated pronation-supination, fist clenching, and foot lifting. The rate of walking also increased in the one patient tested. For both patients, there was an initial worsening postoperatively, followed by improvement vs preoperative performance at 1 to 3 months. Both patients also showed significant improvement in the magnitude of response to a single dose of levodopa (L-dopa), but there was no increase in the duration of drug action. The motor readiness potential increased in both patients postoperatively, primarily over the operated hemisphere. Neurophysiological measurements also showed a more rapid performance of simple and complex arm and hand movements on the side contralateral to transplantation in one patient at 5 months postoperatively. Positron emission tomography demonstrated no increased uptake of 6-L-(18F)-fluorodopa in the transplanted striatum at 5 and 6 months. Taken together, these results suggest that the fetal nigral implants may have provided a modest improvement in motor function, consistent with the presence of small surviving grafts. Although our results support further scientific experimentation with transplantation in Parkinson's disease, widespread clinical trials with this procedure are probably not warranted at this time.

Contingent Negative Variation↗
PubMed1989

Intracerebral xenografts of dopamine neurons: the role of immunosuppression and the blood-brain barrier.

Fetal mesencephalic mouse tissue, rich in dopamine neurons, was xenografted as a dissociated cell suspension into the striatum of rats with unilateral 6-hydroxydopamine induced lesions of the mesostriatal pathway. The rats were either assigned to a 10-day, 21-day or 42-day Cyclosporin A (CyA) immunosuppression scheme, or given no immunosuppression. The functional effects of the grafts were followed over 6 months by monitoring changes in the recipient rats' amphetamine-induced turning behaviour. Without immunosuppression no grafts were functional at the end of the experiment. In the 10-, 21- and 42-day CyA treatment groups there was a significant reduction of rotational asymmetry at some timepoint following grafting in 26 of the 33 rats. However, by 6 months only 8 grafts remained functional suggesting that in several rats an immunological rejection took place following the termination of immunosuppression. This was supported by catecholamine histofluorescence analysis which revealed evidence of surviving grafts only in the few rats which had shown sustained functional graft effects at 6 months after grafting. In animals in which the grafts had undergone rejection, there was scar-like tissue in the striatum which appeared more extensive in rats that had lost their grafts after several weeks compared to rats in which the grafts were rejected at an early time-point. In a subgroup of the grafted animals the humoral antibody response against major transplantation antigens present on the grafted cells was investigated. All the studied rats were found to be immunized against the grafted mouse tissue following the intrastriatal implantation. This occurred irrespective of prior immunosuppressive treatment. In a parallel group of rats, the leakage of the blood-brain barrier was studied following intrastriatal implantation of a syngeneic fetal neural cell suspension. Evans Blue was infused into rats 3-12 days following transplantation surgery. At the early time-points there was a marked barrier leakage at the implantation site. This subsided with time such that there was minor leakage after 7-8 days and no leakage after 12 days. In summary, the results indicate the CyA is effective in promoting survival of intracerebral xenografts of fetal neural tissue, but that cessation of immunosuppressive treatment in most cases results in rejection of the grafted tissue. Temporary CyA treatment, even exceeding the time it takes for the blood-brain barrier to reform after transplantation surgery, is thus not sufficient to reliably support long term survival of xenografted dopamine neurons.

Amphetamines↗
PubMed1989

Survival and immunogenicity of dissociated allogeneic fetal neural dopamine-rich grafts when implanted into the brains of adult mice.

The survival of grafts of dissociated allogeneic fetal neural dopamine (DA) rich tissue in the striatum has been studied after transplantation between inbred strains of mice differing at defined immunogenetical loci between donor and recipient. Six to 7 weeks and 15 weeks after grafting, surviving grafted DA neurons were found in the brains of all the recipients, albeit with a large variation in numbers, located either within the striatum or within the adjacent lateral ventricle. The mean number of surviving DA neurons did not differ between the syngeneic controls and the histoincompatible donor-host combinations, and there was no difference in survival between grafts that differed at single or multiple major histocompatibility complex (MHC) loci, and those that differed at multiple non-MHC loci. The amount of inflammatory cells in the graft area did not differ between the groups, and none of the animals showed massive infiltration of inflammatory cells. The in situ immunogenicity of the grafted neural tissue after intracerebral implantation was monitored by means of Simonsen's alloimmunization test, at 6-7 weeks after transplantation, which provides a sensitive measure primarily of the cellular immunological response. Most, but not all, graft recipients showed immunization with a Spleen Index (S.I.) close to that seen in recipients of an orthotopical skin graft of the same histoincompatibility combination. In contrast to the prolonged survival of the intracerebral neural transplants, none of the skin grafts survived longer than 3 weeks, thus demonstrating the immunologically privileged status of the brain. We conclude that intracerebrally grafted allogeneic neural tissue is capable of provoking a cellular immune response. Despite host immunization, however, the dissociated fetal neural allografts survived for at least 15 weeks without any overt signs of rejection, regardless of the donor-host combination used.

Animals↗
PubMed1988

Human fetal basal forebrain neurons grafted to the denervated rat hippocampus produce an organotypic cholinergic reinnervation pattern.

The septal/diagonal band (SDB) area, obtained from a 9- to 10-week-old aborted human fetus, was grafted to the hippocampal formation of adult, immunosuppressed rats subjected to an aspirative lesion of the fimbria-fornix. Nineteen weeks after transplantation, microscopical analysis revealed large, partly acetylcholinesterase (AChE)-positive grafts in the hippocampus in 3 of the 5 recipients. The AChE-positive grafts gave rise to a reinnervation of the host hippocampus and an AChE-positive lamination of the different hippocampal subfields with the same characteristics as the normal septum-derived innervation. Immunological evaluation of host sera revealed that all rats were immunized by the graft. This indicates that grafted human cholinergic SDB neurons can respond to or interact with factors that regulate and guide the innervation of the rat hippocampus.

Acetylcholinesterase↗
PubMed1988

Human fetal dopamine neurons grafted in a rat model of Parkinson's disease: immunological aspects, spontaneous and drug-induced behaviour, and dopamine release.

We have used a rat model of Parkinson's disease (PD) to address issues of importance for a future clinical application of dopamine (DA) neuron grafting in patients with PD. Human mesencephalic DA neurons, obtained from 6.5-8 week old fetuses, were found to survive intracerebral cell suspension xenografting to the striatum of rats immunosuppressed with Cyclosporin A. The grafts produced an extensive new DA-containing terminal network in the previously denervated caudate-putamen, and they normalized amphetamine-induced, apomorphine-induced and spontaneous motor asymmetry in rats with unilateral lesions of the mesostriatal DA pathway. Grafts from an 11.5-week old donor exhibited a lower survival rate and smaller functional effects. As assessed with the intracerebral dialysis technique the grafted DA neurons were found to restore spontaneous DA release in the reinnervated host striatum to normal levels. The neurons responded with large increases in extracellular striatal DA levels after the intrastriatal administration of the DA-releasing agent d-amphetamine and the DA-reuptake blocker nomifensine, although not to the same extent as seen in striata with an intact mesostriatal DA system. DA fiber outgrowth from the grafts was dependent on the localization of the graft tissue. Thus, grafts located within the striatum gave rise to an extensive axonal network throughout the whole host striatum, whereas grafted DA neurons localized in the neocortex had their outgrowing fibers confined within the grafts themselves. In contrast to the good graft survival and behavioural effects obtained in immunosuppressed rats, there was no survival, or behavioural effects, of human DA neurons implanted in rats that did not receive immunosuppression. In addition, we found that all the graft recipients were immunized, having formed antibodies against antigens present on human T-cells. This supports the notion that the human neurons grafted to the non-immunosuppressed rats underwent immunological rejection. Based on an estimation of the survival rate and extent of fiber outgrowth from the grafted human fetal DA neurons, we suggest that DA neurons that can be obtained from one fetus may be sufficient to restore significant DA neurotransmission unilaterally, in one putamen, in an immunosuppressed PD patient.

Amphetamine↗
PubMed1988

Immune response in deep cervical lymph nodes and spleen in the mouse after antigen deposition in different intracerebral sites.

Brain interstitial and cerebrospinal fluid drainage into the lymphatics was studied by injections of 5 microliters of packed sheep red blood cells (SRBC) injected into the caudate nucleus, the occipital lobe, and the lateral ventricle of the brain in mice. The number of plaque-forming cells (PFC) was determined in the deep cervical lymph nodes, the axillary lymph nodes, and the spleen, and the number of PFC was compared with the response in the same tissues after intravenous immunization with 0.1 ml 10% SRBC. The weight of the deep cervical lymph nodes increased 3.0 times on day 3 after injection in the brain parenchyma compared with the weight of these nodes after intravenous immunization. The antigen-specific response peaked on day 5, 392 +/- 37 PFC/10(6) for IgG in the deep cervical lymph nodes after antigen deposition in the caudate nucleus, whereas only a minor peak in the antigen-specific response was obtained after intraventricular antigen deposition, 127 +/- 79 PFC x 10(6) for IgG on day 6. There were no increased PFC in any of the lymph nodes after intravenous immunization. The experiments show an antigen-specific response in the deep cervical lymph nodes after intracerebral antigen deposition, whereas antigens deposited in the lateral ventricles drain preferentially to the blood, with a high response in the spleen.

Animals↗
PubMed1987

Scintigraphic method to quantify the passage from brain parenchyma to the deep cervical lymph nodes in rats.

In order to investigate the kinetics of the passage from the brain parenchyma to the lymphatic system in vivo a high resolution scintillation camera technique was developed. Albumin, albumin colloids and dextran labelled with 99mTc were injected into the right side of the thalamus of anesthetized rats. Continuous measurement of the activity distribution in head and neck were performed for 70 min. Rate constants were calculated by means of a computer program for compartment analysis. The animals were killed 10 h postinjection, to measure the activity in tissue samples. For some animals, images were registered up to 24 h after injection. This work presents an in vivo technique to clarify the particle flow paths in the brain and make quantification possible. The method is simple and does not require continuous blood or lymph sampling. Our work shows that there is a substantial flow of injected material from the brain via lamina cribriformis to the lymphatic system. This route is of great interest for the drainage of the interstitial fluid of the brain. We have also shown a difference in flow for dextran particles with different charge.

Albumins↗
PubMedDate not supplied

Neural tissue xenotransplantation: what is needed prior to clinical trials in Parkinson's disease? Neural Tissue Xenografting Project.

Embryonic allografted human tissue in patients with Parkinson's disease has been shown to survive and ameliorate many of the symptoms of this disease. Despite this success, the practical problems of using this tissue coupled to the ethical restrictions of using aborted human fetal tissue have lead to an exploration for alternative sources of suitable material for grafting, including xenogeneic embryonic dopaminergic-rich neural tissue. Nevertheless, xenografted neural tissue itself generates a number of practical, ethical, safety, and immunological issues that have to be addressed prior to any clinical xenotransplant program. In this article we review these critical issues and set out the criteria that we consider need to be met in the development of our clinical xenotransplantation research programs. We advocate that these, or similar, criteria should be adopted and made explicit by other centers contemplating similar clinical trials.

Animals↗
PubMedDate not supplied

Intrastriatal ventral mesencephalic xenografts of porcine tissue in rats: immune responses and functional effects.

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.

Animals↗