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1.
Artigo em Inglês | MEDLINE | ID: mdl-37583705

RESUMO

Anxious temperament, characterized by heightened behavioral and physiological reactivity to potential threat, is an early childhood risk factor for the later development of stress-related psychopathology. Using a well-validated nonhuman primate model, we tested the hypothesis that the prefrontal cortex (PFC) is critical in regulating the expression of primate anxiety-like behavior, as well as the function of subcortical components of the anxiety-related neural circuit. We performed aspiration lesions of a narrow 'strip' of the posterior orbitofrontal cortex (OFC) intended to disrupt both cortex and axons entering, exiting and coursing through the pOFC, particularly those of the uncinate fasciculus (UF), a white matter tract that courses adjacent to and through this region. The OFC is of particular interest as a potential regulatory region because of its extensive reciprocal connections with amygdala, other subcortical structures and other frontal lobe regions. We validated this lesion method by demonstrating marked lesion-induced decreases in the microstructural integrity of the UF, which contains most of the fibers that connect the ventral PFC with temporal lobe structures as well as with other frontal regions. While the lesions resulted in modest decreases in threat-related behavior, they substantially decreased metabolism in components of the circuit underlying threat processing. These findings provide evidence for the importance of structural connectivity between the PFC and key subcortical structures in regulating the functions of brain regions known to be involved in the adaptive and maladaptive expression of anxiety.

2.
Magn Reson Med ; 89(2): 710-720, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36128887

RESUMO

PURPOSE: In current intraoperative MRI (IMRI) methods, an iterative approach is used to aim trajectory guides at intracerebral targets: image MR-visible features, determine current aim by fitting model to image, manipulate device, repeat. Infrequent updates are produced by such methods, compared to rapid optically tracked stereotaxy used in the operating room. Our goal was to develop a real-time interactive IMRI method for aiming. METHODS: The current trajectory was computed from two points along the guide's central axis, rather than by imaging the entire device. These points were determined by correlating one-dimensional spokes from a radial sequence with the known cross-sectional projection of the guide. The real-time platform RTHawk was utilized to control MR sequences and data acquisition. On-screen updates were viewed by the operator while simultaneously manipulating the guide to align it with the planned trajectory. Accuracy was quantitated in a phantom, and in vivo validation was demonstrated in nonhuman primates undergoing preclinical gene ( n = 5 $$ n=5 $$ ) and cell ( n = 4 $$ n=4 $$ ) delivery surgeries. RESULTS: Updates were produced at 5 Hz In 10 phantom experiments at a depth of 48 mm, the cannula tip was placed with radial error of (min, mean, max) = (0.16, 0.29, 0.68) mm. Successful in vivo delivery of payloads to all 14 targets was demonstrated across nine surgeries with depths of (min, mean, max) = (33.3, 37.9, 42.5) mm. CONCLUSION: A real-time interactive update rate was achieved, reducing operator fatigue without compromising accuracy. Qualitative interpretation of images during aiming was rendered unnecessary by objectively computing device alignment.


Assuntos
Neurocirurgia , Animais , Estudos Transversais , Imageamento por Ressonância Magnética/métodos , Imagens de Fantasmas , Imageamento Tridimensional
3.
Biol Reprod ; 107(6): 1517-1527, 2022 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-36018823

RESUMO

Identification of placental dysfunction in early pregnancy with noninvasive imaging could be a valuable tool for assessing maternal and fetal risk. Dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI) can be a powerful tool for interrogating placenta health. After inoculation with Zika virus or sham inoculation at gestation age (GA) 45 or 55 days, animals were imaged up to three times at GA65, GA100, and GA145. DCE MRI images were acquired at all imaging sessions using ferumoxytol, an iron nanoparticle-based contrast agent, and analyzed for placental intervillous blood flow, number of perfusion domains, and perfusion domain volume. Cesarean section was performed at GA155, and the placenta was photographed and dissected for histopathology. Photographs were used to align cotyledons with estimated perfusion domains from MRI, allowing comparison of estimated cotyledon volume to pathology. Monkeys were separated into high and low pathology groups based on the average number of pathologies present in the placenta. Perfusion domain flow, volume, and number increased through gestation, and total blood flow increased with gestation for both low pathology and high pathology groups. A statistically significant decrease in perfusion domain volume associated with pathology was detected at all gestational ages. Individual perfusion domain flow comparisons demonstrated a statistically significant decrease with pathology at GA100 and GA145, but not GA65. Since ferumoxytol is currently used to treat anemia during human pregnancy and as an off-label MRI contrast agent, future transition of this work to human pregnancy may be possible.


Assuntos
Infecção por Zika virus , Zika virus , Animais , Gravidez , Feminino , Humanos , Lactente , Placenta/irrigação sanguínea , Óxido Ferroso-Férrico , Macaca mulatta , Meios de Contraste , Cotilédone , Cesárea , Imageamento por Ressonância Magnética/métodos , Perfusão , Infecção por Zika virus/patologia
4.
Neurobiol Dis ; 127: 554-562, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30951850

RESUMO

Apoptosis is triggered in the developing mammalian brain by sedative, anesthetic or antiepileptic drugs during late gestation and early life. Whether human children are vulnerable to this toxicity mechanism remains unknown, as there are no imaging techniques to capture it. Apoptosis is characterized by distinct structural features, which affect the way damaged tissue scatters ultrasound compared to healthy tissue. We evaluated whether apoptosis, triggered by the anesthetic sevoflurane in the brains of neonatal rhesus macaques, can be detected using quantitative ultrasound (QUS). Neonatal (n = 15) rhesus macaques underwent 5 h of sevoflurane anesthesia. QUS images were obtained through the sagittal suture at 0.5 and 6 h. Brains were collected at 8 h and examined immunohistochemically to analyze apoptotic neuronal and oligodendroglial death. Significant apoptosis was detected in white and gray matter throughout the brain, including the thalamus. We measured a change in the effective scatterer size (ESS), a QUS biomarker derived from ultrasound echo signals obtained with clinical scanners, after sevoflurane-anesthesia in the thalamus. Although initial inclusion of all measurements did not reveal a significant correlation, when outliers were excluded, the change in the ESS between the pre- and post-anesthesia measurements correlated strongly and proportionally with the severity of apoptotic death. We report for the first time in vivo changes in QUS parameters, which may reflect severity of apoptosis in the brains of infant nonhuman primates. These findings suggest that QUS may enable in vivo studies of apoptosis in the brains of human infants following exposure to anesthetics, antiepileptics and other brain injury mechanisms.


Assuntos
Apoptose/fisiologia , Encéfalo/diagnóstico por imagem , Sevoflurano/farmacologia , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Feminino , Macaca mulatta , Masculino , Neurônios/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Ultrassonografia
5.
Transplantation ; 103(9): 1821-1833, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30964836

RESUMO

BACKGROUND: Brain death (BD)-associated inflammation has been implicated in decreased kidney allograft function and survival, but the underlying mechanisms have not been well distinguished from the conditions of critical care itself. We have developed a clinically translatable model to separate and investigate strategies to improve donor management and critical care. METHODS: Brain-dead (n = 12) and sham (n = 5) rhesus macaques were maintained for 20 hours under intensive care unit-level conditions. Samples were collected for immunophenotyping, analysis of plasma proteins, coagulation studies, and gene analysis for changes in immune and metabolic profile with comparison to naive samples (n = 10). RESULTS: We observed an increase in circulating leukocytes and cytokines, activation of complement and coagulation pathways, and upregulation of genes associated with inflammation in both brain-dead and sham subjects relative to naïve controls. Sham demonstrated an intermediate phenotype of inflammation compared to BD. Analysis of gene expression in kidneys from BD kidneys revealed a similar upregulation of inflammatory profile in both BD and sham subjects, but BD presented a distinct reduction in metabolic and respiratory processes compared to sham and naïve kidneys. CONCLUSION: BD is associated with activation of specific pathways of the innate immune system and changes to metabolic gene expression in renal tissue itself; however, sham donors presented an intermediate inflammatory response attributable to the critical care environment. The early onset and penetrating impact of this inflammatory response underscores the need for early intervention to prevent perioperative tissue injury to transplantable organs.


Assuntos
Morte Encefálica/imunologia , Morte Encefálica/metabolismo , Metabolismo Energético/genética , Imunidade Inata/genética , Inflamação/imunologia , Inflamação/metabolismo , Rim/metabolismo , Animais , Biomarcadores/sangue , Coagulação Sanguínea/genética , Fatores de Coagulação Sanguínea/genética , Fatores de Coagulação Sanguínea/metabolismo , Ativação do Complemento/genética , Cuidados Críticos , Citocinas/sangue , Citocinas/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Inflamação/sangue , Inflamação/genética , Macaca mulatta , Fatores de Tempo
6.
NPJ Parkinsons Dis ; 4: 22, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30038956

RESUMO

Loss of cardiac postganglionic sympathetic innervation is a characteristic pathology of Parkinson's disease (PD). It progresses over time independently of motor symptoms and is not responsive to typical anti-parkinsonian therapies. Cardiac sympathetic neurodegeneration can be mimicked in animals using systemic dosing of the neurotoxin 6-hydroxydopamine (6-OHDA). As in PD, 6-OHDA-induced neuronal loss is associated with increased inflammation and oxidative stress. To assess the feasibility of detecting changes over time in cardiac catecholaminergic innervation, inflammation, and oxidative stress, myocardial positron emission tomography with the radioligands [11C]meta-hydroxyephedrine (MHED), [11C]PBR28 (PBR28), and [61Cu]diacetyl-bis(N(4))-methylthiosemicarbazone (ATSM) was performed in 6-OHDA-intoxicated adult, male rhesus macaques (n = 10; 50 mg/kg i.v.). The peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone, which is known to have anti-inflammatory and anti-oxidative stress properties, was administered to five animals (5 mg/kg, PO); the other five were placebo-treated. One week after 6-OHDA, cardiac MHED uptake was significantly reduced in both groups (placebo, 86% decrease; pioglitazone, 82%); PBR28 and ATSM uptake increased in both groups but were attenuated in pioglitazone-treated animals (PBR28 Treatment × Level ANOVA p < 0.002; ATSM Mann-Whitney p = 0.032). At 12 weeks, partial recovery of MHED uptake was significantly greater in the pioglitazone-treated group, dependent on left ventricle circumferential region and axial level (Treatment × Region × Level ANOVA p = 0.034); 12-week MHED uptake significantly correlated with tyrosine hydroxylase immunoreactivity across cardiac anatomy (p < 0.000002). PBR28 and ATSM uptake returned to baseline levels by 12 weeks. These radioligands thus hold potential as in vivo biomarkers of mechanisms of cardiac neurodegeneration and neuroprotection.

7.
PLoS Pathog ; 13(10): e1006692, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29073258

RESUMO

Human pegivirus (HPgV) protects HIV+ people from HIV-associated disease, but the mechanism of this protective effect remains poorly understood. We sequentially infected cynomolgus macaques with simian pegivirus (SPgV) and simian immunodeficiency virus (SIV) to model HIV+HPgV co-infection. SPgV had no effect on acute-phase SIV pathogenesis-as measured by SIV viral load, CD4+ T cell destruction, immune activation, or adaptive immune responses-suggesting that HPgV's protective effect is exerted primarily during the chronic phase of HIV infection. We also examined the immune response to SPgV in unprecedented detail, and found that this virus elicits virtually no activation of the immune system despite persistently high titers in the blood over long periods of time. Overall, this study expands our understanding of the pegiviruses-an understudied group of viruses with a high prevalence in the global human population-and suggests that the protective effect observed in HIV+HPgV co-infected people occurs primarily during the chronic phase of HIV infection.


Assuntos
Coinfecção/virologia , Infecções por Flaviviridae/imunologia , Infecções por Flaviviridae/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Animais , Coinfecção/imunologia , Modelos Animais de Doenças , Vírus GB C , Macaca fascicularis , Vírus da Imunodeficiência Símia
8.
Sci Transl Med ; 7(305): 305ra144, 2015 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-26378244

RESUMO

Human pegivirus (HPgV)-formerly known as GB virus C and hepatitis G virus-is a poorly characterized RNA virus that infects about one-sixth of the global human population and is transmitted frequently in the blood supply. We create an animal model of HPgV infection by infecting macaque monkeys with a new simian pegivirus (SPgV) discovered in wild baboons. Using this model, we provide a high-resolution, longitudinal picture of SPgV viremia where the dose, route, and timing of infection are known. We detail the highly variable acute phase of SPgV infection, showing that the viral load trajectory early in infection is dependent on the infecting dose, whereas the chronic-phase viremic set point is not. We also show that SPgV has an extremely low propensity for accumulating sequence variation, with no consensus-level variants detected during the acute phase of infection and an average of only 1.5 variants generated per 100 infection-days. Finally, we show that SPgV RNA is highly concentrated in only two tissues: spleen and bone marrow, with bone marrow likely producing most of the virus detected in plasma. Together, these results reconcile several paradoxical observations from cross-sectional analyses of HPgV in humans and provide an animal model for studying pegivirus biology.


Assuntos
Medula Óssea/virologia , Modelos Animais de Doenças , Infecções por Flaviviridae/complicações , Vírus GB C , Tropismo Viral , Síndrome da Imunodeficiência Adquirida/prevenção & controle , Animais , Medula Óssea/patologia , Evolução Molecular , Feminino , Variação Genética , Infecções por HIV/virologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Funções Verossimilhança , Macaca , Masculino , Papio , Filogenia , RNA Viral/sangue , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Carga Viral , Viremia
9.
Invest Ophthalmol Vis Sci ; 55(11): 7499-507, 2014 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-25324280

RESUMO

PURPOSE: To identify stem cells in the chamber angle of the monkey eye by detection of 5-bromo-2'-deoxyuridine (BrdU) long-term retention. METHODS: Four cynomolgus monkeys were treated with BrdU via subcutaneous pumps for 4 weeks. The eyes of two animals were processed immediately thereafter (group 1) while in the other animals, BrdU treatment was discontinued for 4 weeks to allow identification of cells with long-term BrdU retention (group 2). The number of BrdU-positive nuclei was quantified, and the cells were characterized by immunohistochemistry and transmission electron microscopy (TEM). RESULTS: The number of BrdU-positive cells was higher at Schwalbe's line covering the peripheral end of Descemet's membrane than in Schlemm's canal (SC) endothelium, trabecular meshwork (TM), and scleral spur (SS). Labeling with BrdU in SC, TM, and SS was less intense and the number of labeled cells was smaller in group 2 than in group 1. In contrast, in cells of Schwalbe's line the intensity of BrdU staining and the number of BrdU-positive cells was similar when group 1 and 2 monkeys were compared with each other, indicating long-term BrdU retention. Cells that were BrdU-positive in Schwalbe's line region stained for the stem cell marker OCT4. Details of a stem cell niche in Schwalbe's line region were identified by TEM. CONCLUSIONS: We provide evidence for a niche in the Schwalbe's line region harboring cells with long-term BrdU retention and OCT4 immunoreactivity. The cells likely constitute a population of adult stem cells with the capability to compensate for the loss of TM and/or corneal endothelial cells.


Assuntos
Células-Tronco Adultas/ultraestrutura , Câmara Anterior/citologia , Bromodesoxiuridina , Células-Tronco Adultas/metabolismo , Animais , Câmara Anterior/metabolismo , Bromodesoxiuridina/farmacocinética , Macaca fascicularis , Macaca mulatta , Microscopia Eletrônica de Transmissão , Reprodutibilidade dos Testes , Tomografia de Coerência Óptica
10.
PLoS One ; 7(4): e35371, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22539969

RESUMO

Parkinson's disease presents nonmotor complications such as autonomic dysfunction that do not respond to traditional anti-parkinsonian therapies. The lack of established preclinical monkey models of Parkinson's disease with cardiac dysfunction hampers development and testing of new treatments to alleviate or prevent this feature. This study aimed to assess the feasibility of developing a model of cardiac dysautonomia in nonhuman primates and preclinical evaluations tools. Five rhesus monkeys received intravenous injections of 6-hydroxydopamine (total dose: 50 mg/kg). The animals were evaluated before and after with a battery of tests, including positron emission tomography with the norepinephrine analog (11)C-meta-hydroxyephedrine. Imaging 1 week after neurotoxin treatment revealed nearly complete loss of specific radioligand uptake. Partial progressive recovery of cardiac uptake found between 1 and 10 weeks remained stable between 10 and 14 weeks. In all five animals, examination of the pattern of uptake (using Logan plot analysis to create distribution volume maps) revealed a persistent region-specific significant loss in the inferior wall of the left ventricle at 10 (P<0.001) and 14 weeks (P<0.01) relative to the anterior wall. Blood levels of dopamine, norepinephrine (P<0.05), epinephrine, and 3,4-dihydroxyphenylacetic acid (P<0.01) were notably decreased after 6-hydroxydopamine at all time points. These results demonstrate that systemic injection of 6-hydroxydopamine in nonhuman primates creates a nonuniform but reproducible pattern of cardiac denervation as well as a persistent loss of circulating catecholamines, supporting the use of this method to further develop a monkey model of cardiac dysautonomia.


Assuntos
Efedrina/análogos & derivados , Coração/diagnóstico por imagem , Oxidopamina/toxicidade , Compostos Radiofarmacêuticos , Ácido 3,4-Di-Hidroxifenilacético/sangue , Animais , Pressão Sanguínea/efeitos dos fármacos , Radioisótopos de Carbono/química , Dopamina/sangue , Ecocardiografia , Efedrina/sangue , Efedrina/química , Feminino , Macaca mulatta , Masculino , Neurônios/efeitos dos fármacos , Norepinefrina/sangue , Oxidopamina/química , Tomografia por Emissão de Pósitrons , Disautonomias Primárias/diagnóstico , Compostos Radiofarmacêuticos/química
11.
Nature ; 458(7241): 1034-8, 2009 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-19262509

RESUMO

Although there has been great progress in treating human immunodeficiency virus 1 (HIV-1) infection, preventing transmission has thus far proven an elusive goal. Indeed, recent trials of a candidate vaccine and microbicide have been disappointing, both for want of efficacy and concerns about increased rates of transmission. Nonetheless, studies of vaginal transmission in the simian immunodeficiency virus (SIV)-rhesus macaque (Macacca mulatta) model point to opportunities at the earliest stages of infection in which a vaccine or microbicide might be protective, by limiting the expansion of infected founder populations at the portal of entry. Here we show in this SIV-macaque model, that an outside-in endocervical mucosal signalling system, involving MIP-3alpha (also known as CCL20), plasmacytoid dendritic cells and CCR5(+ )cell-attracting chemokines produced by these cells, in combination with the innate immune and inflammatory responses to infection in both cervix and vagina, recruits CD4(+) T cells to fuel this obligate expansion. We then show that glycerol monolaurate-a widely used antimicrobial compound with inhibitory activity against the production of MIP-3alpha and other proinflammatory cytokines-can inhibit mucosal signalling and the innate and inflammatory response to HIV-1 and SIV in vitro, and in vivo it can protect rhesus macaques from acute infection despite repeated intra-vaginal exposure to high doses of SIV. This new approach, plausibly linked to interfering with innate host responses that recruit the target cells necessary to establish systemic infection, opens a promising new avenue for the development of effective interventions to block HIV-1 mucosal transmission.


Assuntos
Lauratos/farmacologia , Macaca mulatta/virologia , Monoglicerídeos/farmacologia , Mucosa/efeitos dos fármacos , Mucosa/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Síndrome de Imunodeficiência Adquirida dos Símios/transmissão , Doença Aguda , Animais , Líquidos Corporais/metabolismo , Líquidos Corporais/virologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Proteínas de Ciclo Celular/metabolismo , Colo do Útero/efeitos dos fármacos , Colo do Útero/imunologia , Colo do Útero/virologia , Quimiocina CCL20/imunologia , Quimiocina CCL20/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Proteínas Ligadas por GPI , Perfilação da Expressão Gênica , HIV-1/fisiologia , Interleucina-8/metabolismo , Proteínas de Membrana/metabolismo , Mucosa/imunologia , RNA Viral/sangue , Receptores CCR5/imunologia , Receptores CCR5/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/genética , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/crescimento & desenvolvimento , Vírus da Imunodeficiência Símia/fisiologia , Fatores de Tempo , Vagina/efeitos dos fármacos , Vagina/virologia
12.
Antimicrob Agents Chemother ; 52(12): 4448-54, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18838587

RESUMO

Glycerol monolaurate (GML) is a fatty acid monoester that inhibits growth and exotoxin production of vaginal pathogens and cytokine production by vaginal epithelial cells. Because of these activities, and because of the importance of cytokine-mediated immune activation in human immunodeficiency virus type 1 (HIV-1) transmission to women, our laboratories are performing studies on the potential efficacy of GML as a topical microbicide to interfere with HIV-1 transmission in the simian immunodeficiency virus-rhesus macaque model. While GML is generally recognized as safe by the FDA for topical use, its safety for chronic use and effects on normal vaginal microflora in this animal model have not been evaluated. GML was therefore tested both in vitro for its effects on vaginal flora lactobacilli and in vivo as a 5% gel administered vaginally to monkeys. In vitro studies demonstrated that lactobacilli are not killed by GML; GML blocks the loss of their viability in stationary phase and does not interfere with lactic acid production. GML (5% gel) does not quantitatively alter monkey aerobic vaginal microflora compared to vehicle control gel. Lactobacilli and coagulase-negative staphylococci are the dominant vaginal aerobic microflora, with beta-hemolytic streptococci, Staphylococcus aureus, and yeasts sporadically present; gram-negative rods are not part of their vaginal flora. Colposcopy and biopsy studies indicate that GML does not alter normal mucosal integrity and does not induce inflammation; instead, GML reduces epithelial cell production of interleukin 8. The studies suggest that GML is safe for chronic use in monkeys when applied vaginally; it does not alter either mucosal microflora or integrity.


Assuntos
Lactobacillus/efeitos dos fármacos , Lauratos , Monoglicerídeos , Tensoativos , Vagina , Cremes, Espumas e Géis Vaginais , Administração Intravaginal , Animais , Feminino , Humanos , Lactobacillus/crescimento & desenvolvimento , Lauratos/administração & dosagem , Lauratos/efeitos adversos , Lauratos/farmacologia , Macaca mulatta , Modelos Animais , Monoglicerídeos/administração & dosagem , Monoglicerídeos/efeitos adversos , Monoglicerídeos/farmacologia , Tensoativos/administração & dosagem , Tensoativos/efeitos adversos , Tensoativos/farmacologia , Vagina/efeitos dos fármacos , Vagina/microbiologia , Cremes, Espumas e Géis Vaginais/administração & dosagem , Cremes, Espumas e Géis Vaginais/efeitos adversos , Cremes, Espumas e Géis Vaginais/farmacologia
13.
Transplantation ; 76(3): 524-30, 2003 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-12923438

RESUMO

BACKGROUND: Unlike acute and hyperacute rejection, chronic rejection (CR) still constitutes a poorly understood process. The onset is insidious, occurs in a period of months to years and, because the pathophysiology is not well understood, is untreatable. A reliable large-animal model for renal allograft CR is needed and has not been reported in the literature yet. METHODS: CR biopsy changes were studied in major histocompatibility complex-mismatched renal allografts performed in nine rhesus monkeys that received CD3 T-lymphocyte depletion therapy with immunotoxin on the day of the transplantation (n=7) or 7 days before transplant (n=2). RESULTS: Mean graft survival time was 613.77 days. Biopsy changes of CR were identified as soon as 84 days after transplant (mean, 336 days; range, 84-896 days). Most of the experimental animals had severe interstitial fibrosis, tubular atrophy, chronic transplant glomerulopathy, and chronic vascular rejection changes at the time of necropsy. A significant positive correlation between the severity of CR and the degree of CD68+ macrophage infiltrate of renal parenchyma and the degree of anemia and serum creatinine level elevations were also observed. CONCLUSIONS: Our findings are similar to those seen in human renal chronic allograft nephropathy, but in contrast, our model excludes all the nonimmune factors associated with chronic allograft nephropathy, including donor disease, injury from prolonged preservation, drug toxicity, and underlying recipient disease. Immunotoxin-treated rhesus monkeys emerge as an outstanding animal model for assisting us in understanding the pathophysiology of CR.


Assuntos
Anticorpos Monoclonais/farmacologia , Toxina Diftérica/farmacologia , Rejeição de Enxerto/imunologia , Imunotoxinas/farmacologia , Transplante de Rim/imunologia , Proteínas Recombinantes de Fusão/farmacologia , Animais , Doença Crônica , Creatinina/sangue , Modelos Animais de Doenças , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Imuno-Histoquímica , Rim/patologia , Macaca mulatta , Masculino , Fatores de Tempo , Transplante Homólogo
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