20 results on '"Loftin SK"'
Search Results
2. Quantifying regional α -synuclein, amyloid β, and tau accumulation in lewy body dementia.
- Author
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Miller RL, Dhavale DD, O'Shea JY, Andruska KM, Liu J, Franklin EE, Buddhala C, Loftin SK, Cirrito JR, Perrin RJ, Cairns NJ, Campbell MC, Perlmutter JS, and Kotzbauer PT
- Subjects
- Aged, Aged, 80 and over, Autopsy, Humans, Neocortex metabolism, Alzheimer Disease metabolism, Amyloid beta-Peptides analysis, Brain metabolism, Lewy Body Disease metabolism, alpha-Synuclein analysis, tau Proteins analysis
- Abstract
Objective: Parkinson disease (PD) is defined by the accumulation of misfolded α-synuclein (α-syn) in Lewy bodies and Lewy neurites. It affects multiple cortical and subcortical neuronal populations. The majority of people with PD develop dementia, which is associated with Lewy bodies in neocortex and referred to as Lewy body dementia (LBD). Other neuropathologic changes, including amyloid β (Aβ) and tau accumulation, occur in some LBD cases. We sought to quantify α-syn, Aβ, and tau accumulation in neocortical, limbic, and basal ganglia regions., Methods: We isolated insoluble protein from fresh frozen postmortem brain tissue samples for eight brains regions from 15 LBD, seven Alzheimer disease (AD), and six control cases. We measured insoluble α-syn, Aβ, and tau with recently developed sandwich ELISAs., Results: We detected a wide range of insoluble α-syn accumulation in LBD cases. The majority had substantial α-syn accumulation in most regions, and dementia severity correlated with neocortical α-syn. However, three cases had low neocortical levels that were indistinguishable from controls. Eight LBD cases had substantial Aβ accumulation, although the mean Aβ level in LBD was lower than in AD. The presence of Aβ was associated with greater α-syn accumulation. Tau accumulation accompanied Aβ in only one LBD case., Interpretation: LBD is associated with insoluble α-syn accumulation in neocortical regions, but the relatively low neocortical levels in some cases suggest that other changes contribute to impaired function, such as loss of neocortical innervation from subcortical regions. The correlation between Aβ and α-syn accumulation suggests a pathophysiologic relationship between these two processes., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
- Published
- 2022
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3. Validation of diffusion tensor imaging measures of nigrostriatal neurons in macaques.
- Author
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Shimony JS, Rutlin J, Karimi M, Tian L, Snyder AZ, Loftin SK, Norris SA, and Perlmutter JS
- Subjects
- Animals, Corpus Striatum cytology, Disease Models, Animal, Humans, MPTP Poisoning diagnostic imaging, MPTP Poisoning pathology, Macaca, Male, Parkinson Disease diagnostic imaging, Parkinson Disease pathology, Positron-Emission Tomography methods, Reproducibility of Results, Substantia Nigra cytology, Tyrosine 3-Monooxygenase metabolism, Corpus Striatum diagnostic imaging, Diffusion Tensor Imaging methods, Dopaminergic Neurons metabolism, Substantia Nigra diagnostic imaging
- Abstract
Objective: Interpretation of diffusion MRI in the living brain requires validation against gold standard histological measures. We compared diffusion values of the nigrostriatal tract to PET and histological results in non-human primates (NHPs) with varying degrees of unilateral nigrostriatal injury induced by MPTP, a toxin selective for dopaminergic neurons., Methods: Sixteen NHPs had MRI and PET scans of three different presynaptic radioligands and blinded video-based motor ratings before and after unilateral carotid artery infusion of variable doses of MPTP. Diffusion measures of connections between midbrain and striatum were calculated. Then animals were euthanized to quantify striatal dopamine concentration, stereologic measures of striatal tyrosine hydroxylase (TH) immunostained fiber density and unbiased stereologic counts of TH stained nigral cells., Results: Diffusion measures correlated with MPTP dose, nigral TH-positive cell bodies and striatal TH-positive fiber density but did not correlate with in vitro nigrostriatal terminal field measures or in vivo PET measures of striatal uptake of presynaptic markers. Once nigral TH cell count loss exceeded 50% the stereologic terminal field measures reached a near zero floor effect but the diffusion measures continued to correlate with nigral cell counts., Conclusion: Diffusion measures in the nigrostriatal tract correlate with nigral dopamine neurons and striatal fiber density, but have the same relationship to terminal field measures as a previous report of striatal PET measures of presynaptic neurons. These diffusion measures have the potential to act as non-invasive index of the severity of nigrostriatal injury. Diffusion imaging of the nigrostriatal tract could potentially have diagnostic value in humans with Parkinson disease or related disorders., Competing Interests: The authors have declared that no competing interests exist.
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- 2018
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4. Dopaminergic, serotonergic, and noradrenergic deficits in Parkinson disease.
- Author
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Buddhala C, Loftin SK, Kuley BM, Cairns NJ, Campbell MC, Perlmutter JS, and Kotzbauer PT
- Abstract
Objective: People with Parkinson disease (PD) frequently develop dementia, which is associated with neocortical deposition of alpha-synuclein (α-syn) in Lewy bodies and Lewy neurites. In addition, neuronal loss and deposition of aggregated α-syn also occur in multiple subcortical nuclei that project to neocortical, limbic, and basal ganglia regions. Therefore, we quantified regional deficits in innervation from these PD-affected subcortical nuclei, by measuring the neurotransmitters and neurotransmitter transporter proteins originating from projections of dopaminergic neurons in substantia nigra pars compacta, serotonergic neurons in dorsal raphé nuclei, noradrenergic neurons in locus coeruleus, and cholinergic neurons in nucleus basalis of Meynert., Methods: High-performance liquid chromatography and novel enzyme-linked immunosorbent assays were performed to quantify dopaminergic, serotonergic, noradrenergic, and cholinergic innervation in postmortem brain tissue. Eight brain regions from 15 PD participants (with dementia and Braak stage 6 α-syn deposition) and six age-matched controls were tested., Results: PD participants compared to controls had widespread reductions of dopamine transporter in caudate, amygdala, hippocampus, inferior parietal lobule (IPL), precuneus, and visual association cortex (VAC) that exceeded loss of dopamine, which was only significantly reduced in caudate and amygdala. In contrast, PD participants had comparable deficits of both serotonin and serotonin transporter in caudate, middle frontal gyrus, IPL, and VAC. PD participants also had significantly reduced norepinephrine levels for all eight brain regions tested. Vesicular acetylcholine transporter levels were only quantifiable in caudate and hippocampus and did not differ between PD and control groups., Interpretation: These results demonstrate widespread deficits in dopaminergic, serotonergic, and noradrenergic innervation of neocortical, limbic, and basal ganglia regions in advanced PD with dementia.
- Published
- 2015
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5. In vivo measures of nigrostriatal neuronal response to unilateral MPTP treatment.
- Author
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Tian L, Karimi M, Brown CA, Loftin SK, and Perlmutter JS
- Subjects
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine pharmacology, Animals, Cell Count, Chromatography, High Pressure Liquid, Cocaine analogs & derivatives, Cocaine pharmacokinetics, Corpus Striatum drug effects, Disease Models, Animal, Dopamine Plasma Membrane Transport Proteins metabolism, Dopamine Uptake Inhibitors pharmacokinetics, Macaca, Male, Neurons metabolism, Parkinsonian Disorders diagnostic imaging, Positron-Emission Tomography, Protein Binding drug effects, Substantia Nigra drug effects, Tyrosine 3-Monooxygenase metabolism, Vesicular Monoamine Transport Proteins metabolism, Corpus Striatum pathology, Functional Laterality drug effects, Neurons drug effects, Parkinsonian Disorders chemically induced, Parkinsonian Disorders pathology, Substantia Nigra pathology
- Abstract
A single unilateral intracarotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into non-human primates causes injury to the nigrostriatal pathway including nigral cell bodies, axons and striatal terminal fields. In this model, motor parkinsonism correlates well with the loss of nigral dopaminergic cell bodies but only correlates with in vitro measures of nigrostriatal terminal fields when nigral cell loss does not exceed 50%. The goals of this study are to determine the relationship of motor parkinsonism with the degree of injury to nigrostriatal axons, as reflected by in vitro fiber length density measures, and compare in vivo with in vitro measures of striatal terminal fields. We determined axon integrity by measuring fiber length density with tyrosine hydroxylase (TH) immunohistology and dopamine transporter (DAT) density with DAT immunohistology. We then calculated the terminal arbor size and compared these measures with previously published data of quantified in vivo positron emission tomography (PET) measures of presynaptic dopaminergic neurons, autoradiographic measures of DAT and vesicular monoamine transporter type 2 (VMAT2), striatal dopamine, nigral cell counts, and parkinsonian motor ratings in the same animals. Our data demonstrate that in vivo and in vitro measures of striatal terminal fields correlate with each other regardless of the method of measurement. PET-based in vivo striatal measures accurately reflect in vitro measures of DAT and VMAT2. Terminal arbor size and other terminal field measures correlate with nigral TH immunoreactive (TH-ir) cell counts only when nigral TH-ir cell loss does not exceed 50%. Fiber length density was the only striatal measure that linearly correlated with motor ratings (Spearman: r=-0.81, p<0.001, n=16)., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
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6. Validation of midbrain positron emission tomography measures for nigrostriatal neurons in macaques.
- Author
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Brown CA, Karimi MK, Tian L, Flores H, Su Y, Tabbal SD, Loftin SK, Moerlein SM, and Perlmutter JS
- Subjects
- Animals, Carbon Isotopes, Disease Models, Animal, Fluorodeoxyglucose F18, MPTP Poisoning diagnostic imaging, Macaca mulatta, Magnetic Resonance Imaging, Male, Substantia Nigra diagnostic imaging, Tetrabenazine analogs & derivatives, MPTP Poisoning pathology, Mesencephalon pathology, Neurons physiology, Positron-Emission Tomography, Substantia Nigra pathology
- Abstract
Objective: Development of an effective therapy to slow the inexorable progression of Parkinson disease requires a reliable, objective measurement of disease severity. In the present study, we compare presynaptic positron emission tomography (PET) tracer uptake in the substantia nigra (SN) to cell loss and motor impairment in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primates., Methods: Presynaptic PET tracers 6-[(18)F]-fluorodopa (FD), [(11)C]-2β-methoxy-3β-4-fluorophenyltropane (CFT), and [(11)C]-dihydrotetrabenazine (DTBZ) were used to measure specific uptake in the SN and striatum before and after a variable dose of MPTP in nonhuman primates. These in vivo PET-based measures were compared with motor impairment, as well as postmortem tyrosine hydroxylase-positive cell counts and striatal dopamine concentration., Results: We found the specific uptake of both CFT and DTBZ in the SN had a strong, significant correlation with dopaminergic cell counts in the SN (R(2) = 0.77, 0.53, respectively, p < 0.001), but uptake of FD did not. Additionally, both CFT and DTBZ specific uptake in the SN had a linear relationship with motor impairment (rs = -0.77, -0.71, respectively, p < 0.001), but FD uptake did not., Interpretation: Our findings demonstrate that PET-measured binding potentials for CFT and DTBZ for a midbrain volume of interest targeted at the SN provide faithful correlates of nigral neuronal counts across a full range of lesion severity. Because these measures correlate with both nigral cell counts and parkinsonian ratings, we suggest that these SN PET measures are relevant biomarkers of nigrostriatal function., (© 2013 American Neurological Association.)
- Published
- 2013
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7. Validation of nigrostriatal positron emission tomography measures: critical limits.
- Author
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Karimi M, Tian L, Brown CA, Flores HP, Loftin SK, Videen TO, Moerlein SM, and Perlmutter JS
- Subjects
- Animals, Cocaine analogs & derivatives, Corpus Striatum diagnostic imaging, Disease Models, Animal, Fluorodeoxyglucose F18, MPTP Poisoning diagnostic imaging, Macaca mulatta, Magnetic Resonance Imaging, Male, Positron-Emission Tomography, Protein Binding drug effects, Radiopharmaceuticals, Reproducibility of Results, Substantia Nigra diagnostic imaging, Tetrabenazine analogs & derivatives, Corpus Striatum pathology, MPTP Poisoning pathology, Substantia Nigra pathology
- Abstract
Objective: Molecular imaging and clinical endpoints are frequently discordant in Parkinson disease clinical trials, raising questions about validity of these imaging measures to reflect disease severity. We compared striatal uptake for 3 positron emission tomography (PET) tracers with in vitro measures of nigral cell counts and striatal dopamine in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys., Methods: Sixteen macaques had magnetic resonance imaging and baseline PETs using 6-[18F]fluorodopa (FD), [11C]dihydrotetrabenazine (DTBZ), and 2beta-[11 C]carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT). MPTP (0-0.31 mg/kg) infused unilaterally via the internal carotid artery produced stable hemiparkinsonism by 3 weeks. After 8 weeks, PETs were repeated and animals were euthanized for striatal dopamine measurements and unbiased counts of tyrosine hydroxylase-stained nigral cells., Results: Striatal uptake for each radiotracer (FD, DTBZ, CFT) correlated with stereologic nigral cell counts only for nigral loss<50% (r2=0.84, r2=0.86, r2=0.87, p<0.001 respectively; n=10). In contrast, striatal uptake correlated with striatal dopamine over the full range of dopamine depletion (r2=0.95, r2=0.94, r2=0.94, p<0.001; n=16). Interestingly, indices of striatal uptake of FD, DTBZ, and CFT correlated strongly with each other (r2=0.98, p<0.001)., Interpretation: Tracer uptake correlated with nigral neurons only when nigral loss was <50%. This along with previous work demonstrating that nigral cell counts correlate strongly with parkinsonism ratings may explain discordant results between neuroimaging and clinical endpoints. Furthermore, strong correlations among striatal uptake for these tracers support lack of differential regulation of decarboxylase activity (FD), vesicular monoamine transporter type 2 (DTBZ), and dopamine transporter (CFT) within 2 months after nigrostriatal injury., (Copyright © 2013 American Neurological Association.)
- Published
- 2013
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8. Low nigrostriatal reserve for motor parkinsonism in nonhuman primates.
- Author
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Tabbal SD, Tian L, Karimi M, Brown CA, Loftin SK, and Perlmutter JS
- Subjects
- Animals, Chromatography, High Pressure Liquid, Corpus Striatum metabolism, Dopaminergic Neurons metabolism, Dopaminergic Neurons pathology, Immunohistochemistry, Macaca, Male, Parkinsonian Disorders metabolism, Corpus Striatum chemistry, Dopamine analysis, Parkinsonian Disorders pathology, Substantia Nigra pathology
- Abstract
Objective: Nigrostriatal reserve refers to the threshold of neuronal injury to dopaminergic cell bodies and their terminal fields required to produce parkinsonian motor deficits. Inferential studies have estimated striatal dopamine reserve to be at least 70%. Knowledge of this threshold is critical for planning interventions to prevent symptom onset or reverse nigrostriatal injury sufficient to restore function in people with Parkinson disease. In this study, we determine the nigrostriatal reserve in a non-human primate model that mimics the motor manifestations of Parkinson disease., Methods: Fifteen macaque monkeys received unilateral randomized doses of the selective dopaminergic neuronal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We compared blinded validated ratings of parkinsonism to in vitro measures of striatal dopamine and unbiased stereologic counts of nigral neurons after tyrosine hydroxylase immunostaining., Results: The percent of residual cell counts in lesioned nigra correlated linearly with the parkinsonism score at 2 months (r=-0.87, p<0.0001). The parkinsonism score at 2 months correlated linearly with the percent residual striatal dopamine (r=-0.77, p=0.016) followed by a flooring effect once nigral cell loss exceeded 50%. A reduction of about 14 to 23% of nigral neuron counts or 14% to 37% of striatal dopamine was sufficient to induce mild parkinsonism., Conclusions: The nigral cell body and terminal field injury needed to produce parkinsonian motor manifestations may be much less than previously thought., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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9. Dopamine pathway loss in nucleus accumbens and ventral tegmental area predicts apathetic behavior in MPTP-lesioned monkeys.
- Author
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Brown CA, Campbell MC, Karimi M, Tabbal SD, Loftin SK, Tian LL, Moerlein SM, and Perlmutter JS
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- Animals, MPTP Poisoning diagnostic imaging, MPTP Poisoning psychology, Macaca fascicularis, Macaca nemestrina, Male, Neural Pathways pathology, Nucleus Accumbens diagnostic imaging, Predictive Value of Tests, Radionuclide Imaging, Ventral Tegmental Area diagnostic imaging, Apathy physiology, Dopaminergic Neurons pathology, MPTP Poisoning pathology, Nucleus Accumbens pathology, Ventral Tegmental Area pathology
- Abstract
Apathy, primarily defined as a lack of motivation, commonly occurs in people with Parkinson disease (PD). Although dysfunction of basal ganglia pathways may contribute to apathy, the role of dopamine remains largely unknown. We investigated the role of dopaminergic pathways in the manifestation of apathetic behaviors by measuring the effects of the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on monkeys' willingness to attempt goal directed behaviors, distinct from their ability to perform tasks. Fifteen macaques received variable doses of MPTP, had PET scans with [(11)C]-dihydrotetrabenazine (DTBZ), [(11)C]-2β-3β-4-fluorophenyltropane (CFT), and [(18)F]-fluorodopa (FD) and performed tasks to assess apathetic behaviors and motor impairment. At 8 weeks post-MPTP, primates were euthanized and stereological cell counts and dopamine measurements were done. Apathy scores were compared to motor scores, in vitro and in vivo dopaminergic measures. Apathy scores increased following MPTP and correlated with DTBZ (r(S) = -0.85), CFT (r(S) = -0.87), and FD (r(S) = -0.85) specific uptake in nucleus accumbens (NAcc,) and dopaminergic cell counts in ventral tegmental area (VTA, r(S) = -0.80). Dopaminergic cell loss in VTA provided significant predictive power for apathy scores after controlling for the influence of cell loss in SN. Additionally, forward step-wise regression analyses indicated that neuropathological changes in the VTA-NAcc pathway predict apathetic behavior better than motor impairment or neuropathological changes in the nigrostriatal network. Our findings suggest that dopaminergic dysfunction within the VTA-NAcc pathway plays a role in the manifestation of apathetic behaviors in MPTP-lesioned primates. Similar changes in people with PD may contribute to apathy., (Copyright © 2012 Elsevier Inc. All rights reserved.)
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- 2012
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10. No differential regulation of dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) binding in a primate model of Parkinson disease.
- Author
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Tian L, Karimi M, Loftin SK, Brown CA, Xia H, Xu J, Mach RH, and Perlmutter JS
- Subjects
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine pharmacology, Animals, Autoradiography, Binding Sites, Corpus Striatum, Disease Models, Animal, Haplorhini, Neurons, Substantia Nigra, Tyrosine 3-Monooxygenase, Dopamine Plasma Membrane Transport Proteins metabolism, Parkinson Disease metabolism, Vesicular Monoamine Transport Proteins metabolism
- Abstract
Radioligands for DAT and VMAT2 are widely used presynaptic markers for assessing dopamine (DA) nerve terminals in Parkinson disease (PD). Previous in vivo imaging and postmortem studies suggest that these transporter sites may be regulated as the numbers of nigrostriatal neurons change in pathologic conditions. To investigate this issue, we used in vitro quantitative autoradioradiography to measure striatal DAT and VMAT2 specific binding in postmortem brain from 14 monkeys after unilateral internal carotid artery infusion of 1-Methyl-4-Phenyl-1,2,3,6-tetrahydropyridine (MPTP) with doses varying from 0 to 0.31 mg/kg. Quantitative estimates of the number of tyrosine hydroxylase (TH)-immunoreactive (ir) neurons in substantia nigra (SN) were determined with unbiased stereology, and quantitative autoradiography was used to measure DAT and VMAT2 striatal specific binding. Striatal VMAT2 and DAT binding correlated with striatal DA (r(s) = 0.83, r(s) = 0.80, respectively, both with n = 14, p<0.001) but only with nigra TH-ir cells when nigral cell loss was 50% or less (r = 0.93, n = 8, p = 0.001 and r = 0.91, n = 8, p = 0.002 respectively). Reduction of VMAT2 and DAT striatal specific binding sites strongly correlated with each other (r = 0.93, n = 14, p<0.0005). These similar changes in DAT and VMAT2 binding sites in the striatal terminal fields of the surviving nigrostriatal neurons demonstrate that there is no differential regulation of these two sites at 2 months after MPTP infusion.
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- 2012
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11. Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of B and T lymphocyte attenuator required for association with protein tyrosine phosphatases SHP-1 and SHP-2.
- Author
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Gavrieli M, Watanabe N, Loftin SK, Murphy TL, and Murphy KM
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- Amino Acid Motifs, Amino Acid Sequence, Animals, Binding Sites, Cells, Cultured, Cytoplasm metabolism, Humans, Intracellular Signaling Peptides and Proteins, Jurkat Cells, Mice, Molecular Sequence Data, Mutation, Phosphotyrosine, Protein Binding, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Receptors, Immunologic classification, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Sequence Homology, Species Specificity, Structure-Activity Relationship, Protein Tyrosine Phosphatases chemistry, Protein Tyrosine Phosphatases metabolism, Receptors, Immunologic chemistry, Receptors, Immunologic metabolism, T-Lymphocytes chemistry, T-Lymphocytes metabolism
- Abstract
B and T lymphocytes express receptors providing positive and negative co-stimulatory signals. We recently identified a novel co-stimulatory molecule, B and T lymphocyte attenuator (BTLA), which exerts inhibitory effects on B and T lymphocytes. The cytoplasmic domain of murine and human BTLA share three conserved tyrosine-based signaling motifs, a Grb-2 recognition consensus, and two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Phosphorylation of the cytoplasmic domain of BTLA induced the association with the protein tyrosine phosphatases SHP-1 and SHP-2. Association of SHP-1 and SHP-2 to other receptors can involve recruitment to either a single receptor ITIM or to two receptor ITIMs. Here, we analyzed the requirements of BTLA interaction with SHP-1 and SHP-2 in a series of murine and human BTLA mutants. For human BTLA, mutations of either Y257 or Y282, but not Y226, abrogated association with both SHP-1 and SHP-2. For murine BTLA, mutation of either Y274 or Y299, but not Y245, also abrogated association with both SHP-1 and SHP-2. These results indicate that for both murine and human BTLA, association with SHP-1 or SHP-2 requires both of conserved ITIM motifs and does not involve the conserved Grb-2 consensus. Thus, similar to the bisphosphoryl tyrosine-based activation motif (BTAM) by which the Grb-2 associated binder (Gab1), PDGF receptor, and PECAM-1 recruit SHP-2, BTLA also relies on dual ITIMs for its association with the phosphatases SHP-1 and SHP-2.
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- 2003
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12. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1.
- Author
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Watanabe N, Gavrieli M, Sedy JR, Yang J, Fallarino F, Loftin SK, Hurchla MA, Zimmerman N, Sim J, Zang X, Murphy TL, Russell JH, Allison JP, and Murphy KM
- Subjects
- Abatacept, Amino Acid Sequence, Animals, Antigens, CD, Apoptosis Regulatory Proteins, B7-1 Antigen physiology, CTLA-4 Antigen, Encephalomyelitis, Autoimmune, Experimental immunology, Interleukin-2 biosynthesis, Intracellular Signaling Peptides and Proteins, Mice, Molecular Sequence Data, Phosphorylation, Programmed Cell Death 1 Receptor, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases physiology, RNA, Messenger analysis, Receptors, Immunologic chemistry, Receptors, Immunologic genetics, Antigens, Differentiation physiology, Antigens, Surface, Immunoconjugates, Lymphocyte Activation, Proteins physiology, Receptors, Immunologic physiology, T-Lymphocytes immunology
- Abstract
During activation, T cells express receptors for receiving positive and negative costimulatory signals. Here we identify the B and T lymphocyte attenuator (BTLA), an immunoglobulin domain-containing glycoprotein with two immunoreceptor tyrosine-based inhibitory motifs. BTLA is not expressed by naive T cells, but it is induced during activation and remains expressed on T helper type 1 (T(H)1) but not T(H)2 cells. Crosslinking BTLA with antigen receptors induces its tyrosine phosphorylation and association with the Src homology domain 2 (SH2)-containing protein tyrosine phosphatases SHP-1 and SHP-2, and attenuates production of interleukin 2 (IL-2). BTLA-deficient T cells show increased proliferation, and BTLA-deficient mice have increased specific antibody responses and enhanced sensitivity to experimental autoimmune encephalomyelitis. B7x, a peripheral homolog of B7, is a ligand of BTLA. Thus, BTLA is a third inhibitory receptor on T lymphocytes with similarities to cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1).
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- 2003
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13. Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients.
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Rooney CM, Smith CA, Ng CY, Loftin SK, Sixbey JW, Gan Y, Srivastava DK, Bowman LC, Krance RA, Brenner MK, and Heslop HE
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- Adolescent, Adult, Burkitt Lymphoma therapy, Burkitt Lymphoma virology, Child, Child, Preschool, DNA, Viral blood, Female, Genetic Markers, Herpesvirus 4, Human genetics, Herpesvirus 4, Human immunology, Humans, Infant, Infusions, Intravenous, Male, Remission Induction, Bone Marrow Transplantation, Burkitt Lymphoma prevention & control, Immunotherapy, Adoptive, T-Lymphocytes, Cytotoxic immunology
- Abstract
Epstein-Barr virus (EBV) causes potentially lethal immunoblastic lymphoma in up to 25% of children receiving bone marrow transplants from unrelated or HLA-mismatched donors. Because this complication appears to stem from a deficiency of EBV-specific cytotoxic T cells, we assessed the safety and efficacy of donor-derived polyclonal (CD4(+) and CD8(+)) T-cell lines as immunoprophylaxis and treatment for EBV-related lymphoma. Thirty-nine patients considered to be at high risk for EBV-induced lymphoma each received 2 to 4 intravenous infusions of donor-derived EBV-specific T lymphocytes, after they had received T-cell-depleted bone marrow from HLA-matched unrelated donors (n = 33) or mismatched family members (n = 6). The immunologic effects of this therapy were monitored during and after the infusions. Infused cells were identified by detection of the neo marker gene. EBV-specific T cells bearing the neo marker were identified in all but 1 of the patients. Serial analysis of DNA detected the marker gene for as long as 18 weeks in unmanipulated peripheral blood mononuclear cells and for as long as 38 months in regenerated lines of EBV-specific cytotoxic T cells. Six patients (15.5%) had greatly increased amounts of EBV-DNA on study entry (>2, 000 genome copies/10(6) mononuclear cells), indicating uncontrolled EBV replication, a complication that has had a high correlation with subsequent development of overt lymphoma. All of these patients showed 2 to 4 log decreases in viral DNA levels within 2 to 3 weeks after infusion and none developed lymphoma, confirming the antiviral activity of the donor-derived cells. There were no toxic effects that could be attributed to prophylactic T-cell therapy. Two additional patients who did not receive prophylaxis and developed overt immunoblastic lymphoma responded fully to T-cell infusion. Polyclonal donor-derived T-cell lines specific for EBV proteins can thus be used safely to prevent EBV-related immunoblastic lymphoma after allogeneic marrow transplantation and may also be effective in the treatment of established disease., (Copyright 1998 by The American Society of Hematology.)
- Published
- 1998
14. Adoptive immunotherapy for Epstein-Barr virus-related lymphoma.
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Smith CA, Ng CY, Loftin SK, Li C, Heslop HE, Brenner MK, and Rooney CM
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- Child, Humans, Immunity, Cellular, Immunocompromised Host, Lymphoma, B-Cell immunology, T-Lymphocytes, Cytotoxic immunology, Herpesviridae Infections immunology, Herpesviridae Infections therapy, Herpesvirus 4, Human, Immunotherapy, Adoptive, Lymphoma, B-Cell therapy, Lymphoma, B-Cell virology, Tumor Virus Infections immunology, Tumor Virus Infections therapy
- Abstract
Epstein-Barr virus (EBV) causes opportunistic B cell lymphomas in patients whose cellular immunity is compromised. We have been investigating whether infusions of donor-derived, EBV-specific cytotoxic T cells can prevent and/or treat EBV-related lymphoproliferative disease in children receiving T cell-depleted bone marrow from HLA-matched, unrelated or HLA-mismatched, related donors. In this review, we discuss the rationale for this therapeutic approach, describe our experiences with the regimen thus far, and consider some future directions in immunotherapy.
- Published
- 1996
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15. Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes.
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Heslop HE, Ng CY, Li C, Smith CA, Loftin SK, Krance RA, Brenner MK, and Rooney CM
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- CD4-Positive T-Lymphocytes transplantation, CD8-Positive T-Lymphocytes transplantation, Cell Survival, Child, Preschool, Hematopoietic Stem Cell Transplantation, Humans, Male, Bone Marrow Transplantation immunology, Herpesviridae Infections prevention & control, Herpesvirus 4, Human immunology, Immunotherapy, Adoptive methods, T-Lymphocytes, Cytotoxic transplantation, Tumor Virus Infections prevention & control
- Abstract
Adoptive transfer of antigen-specific cytotoxic T lymphocytes (CTLs) offers safe and effective therapy for certain viral infections and could prove useful in the eradication of tumor cells. Whether or not the infused T cells persist for extended periods, retaining their ability to expand in response to antigenic stimulation, is not known. We now report long-term detection of gene-marked Epstein-Barr virus (EBV)-specific CTLs in immunocompromised patients at risk for the development of EBV lymphoproliferative disease. Infusions of CTLs not only restored cellular immune responses against EBV, but also established populations of CTL precursors that could respond to in vivo or ex vivo challenge with the virus for as long as 18 months. Our findings support wider use of antigen-specific CTLs in adoptive immunotherapy.
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- 1996
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16. Production of genetically modified Epstein-Barr virus-specific cytotoxic T cells for adoptive transfer to patients at high risk of EBV-associated lymphoproliferative disease.
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Smith CA, Ng CY, Heslop HE, Holladay MS, Richardson S, Turner EV, Loftin SK, Li C, Brenner MK, and Rooney CM
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- Adolescent, Adult, Cell Line, Transformed transplantation, Cell Transformation, Viral, Child, Child, Preschool, Female, Herpesviridae Infections virology, Herpesvirus 4, Human immunology, Humans, Immunophenotyping, Infant, Lymphoproliferative Disorders virology, Male, Middle Aged, Risk Factors, T-Lymphocytes, Cytotoxic immunology, Tumor Virus Infections prevention & control, Tumor Virus Infections virology, Bone Marrow Transplantation adverse effects, Herpesviridae Infections prevention & control, Herpesvirus 4, Human physiology, Immunotherapy, Adoptive methods, Lymphoproliferative Disorders prevention & control, T-Lymphocytes, Cytotoxic transplantation
- Abstract
EBV-induced lymphoproliferative disease (EBV-LPD) is a disorder most commonly associated with the immunocompromise that follows allogeneic organ transplantation. In patients receiving T cell-depleted bone marrow from HLA-mismatched or HLA-matched unrelated donors, the incidence of EBV-LPD is particularly high, ranging from 5 to 30%. Administration of EBV-specific cytotoxic T lymphocytes may be one means of preventing and treating this disease. We now describe a method that allows the routine and timely preparation of large numbers of such cells to allow their safe administration to bone marrow transplant recipients. We also describe how these cells may be genetically marked before infusion, to determine their fate and disposition in vivo.
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- 1995
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17. Early identification of Epstein-Barr virus-associated post-transplantation lymphoproliferative disease.
- Author
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Rooney CM, Loftin SK, Holladay MS, Brenner MK, Krance RA, and Heslop HE
- Subjects
- Adolescent, B-Lymphocytes pathology, Blotting, Southern, Cell Division, Cell Transformation, Viral, Cells, Cultured, Child, Child, Preschool, DNA, Viral blood, Female, Humans, Leukemia, Myeloid therapy, Lymphoproliferative Disorders blood, Lymphoproliferative Disorders virology, Male, Time Factors, Bone Marrow Transplantation adverse effects, Herpesviridae Infections diagnosis, Herpesvirus 4, Human isolation & purification, Lymphoproliferative Disorders diagnosis, Tumor Virus Infections diagnosis
- Abstract
Epstein-Barr virus-associated lymphoproliferative disease (EBV-LPD) is a common, usually fatal, complication developing after transplantation of bone marrow from HLA-mismatched or HLA-matched unrelated donors. Prompted by recent reports of successful treatment of EBV-LPD, we investigated methods which could result in early identification of patients at high risk for this disorder, thus improving the likelihood of successful therapeutic interventions. Both the outgrowth of transformed B lymphocytes ex vivo (100% correlation) and the detection of EBV DNA by a PCR method (80% correlation) showed statistically significant association with the histopathological diagnosis of EBV-LPD. Because these abnormalities can be detected prior to the onset of clinical disease. It should now be possible to use a combination of the methods described here to identify patients at high risk of developing EBV-LPD, thus enabling early therapeutic intervention.
- Published
- 1995
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18. Factors that influence the therapeutic activity of 5-fluorouracil [6RS]leucovorin combinations in colon adenocarcinoma xenografts.
- Author
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Houghton JA, Williams LG, Loftin SK, Cheshire PJ, Morton CL, Houghton PJ, Dayan A, and Jolivet J
- Subjects
- Animals, Fluorouracil administration & dosage, Fluorouracil blood, Humans, Leucovorin administration & dosage, Leucovorin analogs & derivatives, Leucovorin analysis, Mice, Mice, Inbred CBA, Neoplasm Transplantation, Tetrahydrofolates analysis, Adenocarcinoma drug therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Colonic Neoplasms drug therapy, Fluorouracil therapeutic use
- Abstract
The therapeutic activity of FUra alone or combined with [6RS]LV doses ranging from 50 to 1,000 mg/m2 was examined in eight colon adenocarcinoma xenografts, of which five were established from adult neoplasms (HxELC2, HxGC3, HxVRC5, HxHC1, and HxGC3/c1TK-c3 selected for TK deficiency) and three were derived from adolescent tumors (HxSJC3A, HxSJC3B, and HxSJC2). The growth-inhibitory effects of FUra were potentiated by higher doses of [6RS]LV (500-1,000 mg/m2) in three lines (HxGC3/c1TK-c3, HxSJC3A, and HxSJC3B) and by a low dose of [6RS]LV in only one tumor (HxVRC5). Expansion of pools of CH2-H4PteGlun+H4PteGlun (greater than or equal to 2.4-fold) in response to higher doses of [6RS]LV was obtained in all lines except HxHC1. Metabolism of [6RS]LV was high in HxVRC5, with high levels of 5-CH3-H4PteGlu being detected, but not in HxHC1, in which levels of 5-CH3-H4PteGlu and CH = H4PteGlu+10-CHO-H4PteGlu remained relatively low. In the adolescent tumors, levels of CH = H4PteGlu+10-CHO-H4PteGlu were consistently higher than those of 5-CH3-H4PteGlu following [6RS]LV administration, and in HxSJC3A, in which pools of CH2-H4PteGlun+H4PteGlun were significantly expanded, 5-CH3-H4PteGlu concentrations were lower than those observed in the other two lines. The sensitivity of tumors to FUra +/- [6RS]LV and the characteristics of [6S]LV metabolism did not correlate with the activity of CH = H4PteGlu synthetase, the enzyme responsible for the initial cellular metabolism of [6S]LV to CH = H4PteGlu. Thus, no single metabolic phenotype correlated with the [6RS]LV-induced expansion of CH2-H4PteGlun+H4PteGlun pools. Potentiation of the therapeutic efficacy of FUra by [6RS]LV was observed in HxGC3/c1TK-c3 xenografts but not in parent HxGC3 tumors, demonstrating the influence of dThd salvage capability in the response to FUra-[6RS]LV combinations. Plasma dThd concentrations in CBA/CaJ mice were high (1.1 microM). The present data therefore demonstrate the importance of (1) higher doses of [6RS]LV, (2) expansion of pools of CH2-H4PteGlun+H4PteGlun, and (3) dThd salvage capability in potentiation of the therapeutic efficacy of FUra in colon adenocarcinoma xenografts. The plasma levels of FUra achieved in mice are presented.
- Published
- 1992
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19. Accumulation, intracellular metabolism, and antitumor activity of high- and low-dose methotrexate in human osteosarcoma xenografts.
- Author
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Meyer WH, Loftin SK, Houghton JA, and Houghton PJ
- Subjects
- Animals, Carbon Radioisotopes, DNA metabolism, Dose-Response Relationship, Drug, Formates metabolism, Humans, Liver metabolism, Mice, Neoplasm Transplantation, Polyglutamic Acid analogs & derivatives, Polyglutamic Acid metabolism, Transplantation, Heterologous, Tritium, Body Fluids metabolism, Intracellular Fluid metabolism, Methotrexate analogs & derivatives, Methotrexate metabolism, Methotrexate pharmacokinetics, Methotrexate pharmacology, Osteosarcoma drug therapy
- Abstract
High doses of methotrexate with leucovorin rescue are routinely used in the treatment of patients with osteosarcoma; the rationale for this application is controversial. Using human osteosarcoma xenografts growing in mice as a clinically relevant model, we compared the accumulation, intracellular metabolism, and tumor response of methotrexate administered as either high-dose (2400 mg/kg) or low-dose (150 mg/kg) infusions. The high-dose regimen, which included i.v. hydration and leucovorin rescue, resulted in plasma methotrexate levels that approximated those in patients receiving the drug at 12 g/m2. The low-dose infusion produced essentially the same toxicity as the higher dose level, without use of leucovorin. The HxOs33 tumor line was moderately sensitive to the high-dose infusion (55-day delay in tumor volume doubling time), whereas the second line, HxOs2, did not respond. Neither xenograft had a measurable response to low-dose methotrexate. Methotrexate was present in both tumors for up to 72 hr post-infusion, regardless of the dosage regimen. Only shorter-chain polyglutamates (MTXglu2 and MTXglu3) were detected over this period in the high-dose trial, and levels of these derivatives were uniformly higher in the resistant HxOs2 xenograft. Low-dose infusions were associated with formation of longer-chain polyglutamate species, with more abundant production in the HxOs2 line. Methotrexate polyglutamates exceeded baseline [3H]MTX binding of dihydrofolate reductase, as measured in tumor homogenates, at all testing intervals through 72 hr in both tumor lines. Nonetheless, high-dose methotrexate-induced suppression of [14C]formate incorporation into DNA was greater in the drug-sensitive HxOs33 tumor than in HxOs2. These results suggest a therapeutic advantage for high-dose methotrexate regimens in the treatment of human osteosarcoma but show that formation of tumor MTX polyglutamates is not the sole determinant of response to this agent.
- Published
- 1990
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20. Photolysis of the lysosomal neuraminidase in cultured human skin fibroblasts in the presence of a photoreactive competitive inhibitor.
- Author
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Warner TG and Loftin SK
- Subjects
- Binding, Competitive, Cells, Cultured, Fibroblasts enzymology, Humans, Kinetics, Neuraminidase radiation effects, Photolysis, Azides pharmacology, Lysosomes enzymology, Neuraminidase antagonists & inhibitors, Skin enzymology, Sugar Acids pharmacology
- Abstract
Photolysis of the lysosomal neuraminidase in crude homogenates of cultured human skin fibroblasts was carried out using the potent competitive enzyme inhibitor, 9-S-(4-azido-2-nitrophenyl)-5-acetamido-2,6-anhydro-2,3,5,9-tetradeoxy-9 -thio-D - glycero-D-galacto-non-2-enonic acid (9-PANP-2,3-D-NANA). Irradiation of the homogenate and the inhibitor (2 min, pH 4.3, 10 degrees C) with a medium pressure mercury lamp resulted in about a 24% reduction of enzyme activity compared to irradiated controls that did not contain additives. No significant loss of activity was observed with homogenate that contained a photoreactive thioglycoside of sialic acid that was not an inhibitor of the enzyme. Similarly, the enzyme activity was not affected when 2-deoxy-2,3-dehydro-N-acetyl neuraminic acid was photolyzed with the homogenate. The latter is a potent competitive inhibitor but it is not photoreactive. Also, the products obtained by prephotolyzing 9-PANP-2,3-D-NANA gave similar enzyme levels under standard assay conditions when compared with the nonirradiated material. Together, these results demonstrate that the photoinactivation is highly specific and both the aryl azide and the unsaturated pyran portion of the molecule are required for inactivation. The title compound may be useful as a potential photolabeling reagent which may facilitate purification of the enzyme and permit further characterization of the mutation in sialidosis patients.
- Published
- 1989
- Full Text
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