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PubMed2004

Immunization with hepatitis C virus-like particles induces humoral and cellular immune responses in nonhuman primates.

We have previously reported the production of hepatitis C virus-like particles (HCV-LP) using a recombinant baculovirus containing the cDNA of the HCV structural proteins (core, E1, and E2). These particles resemble the putative HCV virions and are capable of inducing strong and broad humoral and cellular immune responses in mice. Here we present evidence on the immunogenicity of HCV-LP and the effects of novel adjuvant systems in a nonhuman primate model, the baboon. Three groups of four baboons were immunized with HCV-LP, HCV-LP and adjuvant AS01B (monophosphoryl lipid A and QS21), or HCV-LP and the combination of AS01B and CpG oligodeoxynucleotides 10105. After four immunizations over an 8-month period, all animals developed HCV-specific humoral and cellular immune responses including antibodies to HCV structural proteins and gamma interferon(+) (IFN-gamma(+))CD4(+) and IFN-gamma(+)CD8(+) T-cell responses. The immunogenicity of HCV-LP was only marginally enhanced by the use of adjuvants. The overall HCV-specific immune responses were broad and long lasting. Our results suggest that HCV-LP is a potent immunogen to induce HCV-specific humoral and cellular immune responses in primates and may be a promising approach to develop novel preventive and therapeutic modalities.

Adjuvants, Immunologic↗
PubMed1998

Long-term feeding of sodium saccharin to nonhuman primates: implications for urinary tract cancer.

BACKGROUND: It was observed in the early 1970s that saccharin produced bladder cancer in rats. However, it has been unclear whether sodium saccharin when consumed by humans poses a substantial carcinogenic hazard. Numerous epidemiologic studies have not shown any evidence of increased urothelial proliferation associated with ingestion of sodium saccharin. PURPOSE: Our purpose was to determine the effects of long-term feeding of sodium saccharin to three species of nonhuman primates. METHODS: Twenty monkeys of three species (six African green, seven rhesus, six cynomolgus, and one hybrid [of rhesus male and cynomolgus female parentage]) were treated with sodium saccharin (25 mg in the diet/kg body weight daily for 5 days a week) beginning within 24 hours after birth and continuing for up to 24 years. Sixteen monkeys (seven rhesus and nine cynomolgus) served as controls. During their last 2 years of life, urine was collected from selected treated and control animals and evaluated for various urinary chemistries and for the presence of calculi, microcrystalluria, and precipitate. Urinary bladders were examined by light microscopy and by scanning electron microscopy. RESULTS: Sodium saccharin treatment had no effect on the urine or urothelium in any of these monkeys. There was no evidence of increased urothelial cell proliferation, and there was no evidence of formation of solid material in the urine. CONCLUSION: Although the dose of sodium saccharin administered to these monkeys was only five to 10 times the allowable daily intake for humans, the results provide additional evidence that sodium saccharin is without a carcinogenic effect on the primate urinary tract.

Animals↗
PubMed2002

Intra-arterial 133Xe measurements suggest a dose-dependent increase in cerebral blood flow during intracarotid infusion of adenosine in nonhuman primates.

Intra-arterial vasodilators, such as papaverine, have been used to treat cerebrovascular insufficiency. The short biologic half-life, and the vasodilating and neuroprotective properties of adenosine could be useful during the treatment of cerebral ischemia. However, in human subjects a proposed intracarotid dose of 1 mg/min adenosine was ineffective in augmenting cerebral blood flow (CBF). The object of this experiment was to determine the dose-CBF response characteristics of intracarotid adenosine in nonhuman primates. Studies were conducted on five male baboons under isoflurane anesthesia. After transfemoral internal carotid artery cannulation, changes in CBF (intra-arterial 133Xe technique) were determined after intracarotid infusion of saline and three increasing doses of adenosine (0.5, 1.0, and 1.5 mg/min). Each infusion lasted 5 minutes. Data (mean +/- standard deviation) were analyzed by repeated-measure analysis of variance and the post hoc Tukey test. Intracarotid adenosine (0.5, 1.0, and 1.5 mg/min) resulted in a dose-dependent increase in CBF from 22.6 +/- 4 mL/100 g/min at baseline to 50 +/- 15, 65 +/- 22, and 83 +/- 31 mL/100 g/min respectively (n = 5, P < .05 each). No adverse hemodynamic side effects were noted, and animals recovered promptly from anesthesia. The authors conclude that intracarotid adenosine in the range of 0.5 to 1.5 mg/min results in a robust increase in CBF. Based on body weight, intracarotid adenosine in a dose range of 2.5 to 7.5 mg/min may be required to augment CBF in human subjects.

Adenosine↗
PubMed2001

Ebola virus glycoprotein demonstrates differential cellular localization in infected cell types of nonhuman primates and guinea pigs.

BACKGROUND: In vitro studies have previously shown that Ebola virus glycoprotein (GP) is rapidly processed and largely released from infected cells, whereas other viral proteins, such as VP40, accumulate within cells. OBJECTIVE: To determine infected cell types in which Ebola virus GP and VP40, individually, localize in vivo. METHODS: Immunohistochemistry and in situ hybridization using GP- and VP40-specific antibodies and genetic probes were used to analyze archived tissues of experimentally infected nonhuman primates and guinea pigs and Vero E6 and 293 cells infected in vitro. RESULTS: The GP antigen was consistently present in hepatocytes, adrenal cortical cells, fibroblasts, fibroblastic reticular cells, ovarian thecal cells, and several types of epithelial cells, but was not detected in macrophages and blood monocytes of animals, nor in Vero cells and 293 cells. All GP-positive and GP-negative cell types analyzed contained VP40 antigen and both GP and VP40 RNAs. CONCLUSIONS: Ebola virus GP appears to selectively accumulate in many cell types infected in vivo, but not in macrophages and monocytes. This finding suggests that many cell types may have a GP-processing pathway that differs from the pathway described by previous in vitro studies. Differential cellular localization of GP could be relevant to the pathogenesis of Ebola hemorrhagic fever.

Animals↗
PubMed2000

Prolonged high-level detection of retrovirally marked hematopoietic cells in nonhuman primates after transduction of CD34+ progenitors using clinically feasible methods.

Low-level retroviral transduction and engraftment of hematopoietic long-term repopulating cells in large animals and humans remain primary obstacles to the successful application of hematopoietic stem cell (HSC) gene transfer in humans. Recent studies have reported improved efficiency by including stromal cells (STR), or the fibronectin fragment CH-296 (FN), and various cytokines such as flt3 ligand (FLT) during ex vivo culture and transduction in nonhuman primates. In this work, we extend our studies using the rhesus competitive repopulation model to further explore optimal and clinically feasible peripheral blood (PB) progenitor cell transduction methods. First, we compared transduction in the presence of either preformed autologous STR or immobilized FN. Long-term clinically relevant gene marking levels in multiple hematopoietic lineages from both conditions were demonstrated in vivo by semiquantitative PCR, colony PCR, and genomic Southern blotting, suggesting that FN could replace STR in ex vivo transduction protocols. Second, we compared transduction on FN in the presence of IL-3, IL-6, stem cell factor (SCF), and FLT (our best cytokine combination in prior studies) with a combination of megakaryocyte growth and development factor (MGDF), SCF, and FLT. Gene marking levels were equivalent in these animals, with no significant effect on retroviral gene transfer efficiency assessed in vivo by the replacement of IL-3 and IL-6 with MGDF. Our results indicate that SCF/G-CSF-mobilized PB CD34+ cells are transduced with equivalent efficiency in the presence of either STR or FN, with stable long-term marking of multiple lineages at levels of 10-15% and transient marking as high as 54%. These results represent an advance in the field of HSC gene transfer using methods easily applied in the clinical setting.

Animals↗
PubMed2003

Human, nonhuman primate, and rat pancreatic islets express erythropoietin receptors.

BACKGROUND: Erythropoietin (EPO) promotes survival in a variety of cells by mediating antiapoptotic signals through the EPO receptor (R). The authors examined pancreatic islets for the presence of EPO-R to determine whether these cells are protected by EPO from cytokine-induced apoptosis. METHODS: Reverse-transcriptase polymerase chain reaction, immunohistology, and Western blots were used to establish the presence and localization of EPO-R on rat, nonhuman primate, and human islets. Islets were exposed to cytokines in the presence and absence of recombinant EPO and apoptosis was measured using a terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay followed by fluorescence-activated cell sorter analysis. Glucose stimulation indices were measured to assess the effect of EPO on islet function. RESULTS: The presence of EPO-R was demonstrated on islets regardless of species. Recombinant EPO protected islets in culture from cytokine-induced apoptosis in a dose-dependent manner. Furthermore, the presence of EPO in the media does not adversely affect islet function. CONCLUSIONS: This is the first demonstration that pancreatic islets express EPO-R and that EPO may prevent islet-cell apoptosis in culture. In vivo trials to evaluate the potential of long-term expression of EPO to augment islet survival in transplantation are underway.

Animals↗
PubMed2003

The deafferented nonhuman primate is not a reliable model of intractable pain.

Before extending the application of motor cortex stimulation it is important to investigate the intimate mechanisms by which it alleviates intractable pain and to consider possible side effects. Self-mutilation in animals following extensive neurectomy or posterior rhizotomy of a limb is thought to reveal severe dysesthesias in the deafferented zone suggesting its usefulness as an animal model of chronic pain in humans. We here show in deafferented nonhuman primates that the autotomy behavior immediately follows the surgery and disappears after 28 days. In keeping with the experience of Y. Lamarre, the simple but careful care of all wounds is sufficient to abolish this behavior. Our results do not exclude the possibility that the deafferentiation is still painful for the monkeys, but they definitely rule out that autotomy is a consistent response to deafferentation.

Animals↗
PubMed2006

Differential effects of HOXB4 on nonhuman primate short- and long-term repopulating cells.

BACKGROUND: Hematopoietic stem cells (HSCs) or repopulating cells are able to self-renew and differentiate into cells of all hematopoietic lineages, and they can be enriched using the CD34 cell surface marker. Because of this unique property, HSCs have been used for HSC transplantation and gene therapy applications. However, the inability to expand HSCs has been a significant limitation for clinical applications. Here we examine, in a clinically relevant nonhuman primate model, the ability of HOXB4 to expand HSCs to potentially overcome this limitation. METHODS AND FINDINGS: Using a competitive repopulation assay, we directly compared in six animals engraftment of HOXB4GFP (HOXB4 green fluorescent protein) and control (yellow fluorescent protein [YFP])-transduced and expanded CD34+ cells. In three animals, cells were infused after a 3-d transduction culture, while in three other animals cells were infused after an additional 6-9 d of ex vivo expansion. We demonstrate that HOXB4 overexpression resulted in superior engraftment in all animals. The most dramatic effect of HOXB4 was observed early after transplantation, resulting in an up to 56-fold higher engraftment compared to the control cells. At 6 mo after transplantation, the proportion of marker gene-expressing cells in peripheral blood was still up to 5-fold higher for HOXB4GFP compared to YFP-transduced cells. CONCLUSIONS: These data demonstrate that HOXB4 overexpression in CD34+ cells has a dramatic effect on expansion and engraftment of short-term repopulating cells and a significant, but less pronounced, effect on long-term repopulating cells. These data should have important implications for the expansion and transplantation of HSCs, in particular for cord blood transplantations where often only suboptimal numbers of HSCs are available.

Animals↗
PubMed2005

Live attenuated recombinant vaccine protects nonhuman primates against Ebola and Marburg viruses.

Vaccines and therapies are urgently needed to address public health needs stemming from emerging pathogens and biological threat agents such as the filoviruses Ebola virus (EBOV) and Marburg virus (MARV). Here, we developed replication-competent vaccines against EBOV and MARV based on attenuated recombinant vesicular stomatitis virus vectors expressing either the EBOV glycoprotein or MARV glycoprotein. A single intramuscular injection of the EBOV or MARV vaccine elicited completely protective immune responses in nonhuman primates against lethal EBOV or MARV challenges. Notably, vaccine vector shedding was not detectable in the monkeys and none of the animals developed fever or other symptoms of illness associated with vaccination. The EBOV vaccine induced humoral and apparent cellular immune responses in all vaccinated monkeys, whereas the MARV vaccine induced a stronger humoral than cellular immune response. No evidence of EBOV or MARV replication was detected in any of the protected animals after challenge. Our data suggest that these vaccine candidates are safe and highly efficacious in a relevant animal model.

Animals↗
PubMed1994

In vivo high intrinsic efficacy of triazolam: a positron emission tomography study in nonhuman primates.

The triazolobenzodiazepine triazolam is a central-type benzodiazepine receptor (BZR) ligand that is widely prescribed as a hypnotic agent. Triazolam produces its effects through potentiation of gamma-aminobutyric acid-mediated neurotransmission. Findings reported from in vitro binding studies showed some discrepancies concerning the pharmacological characteristics of triazolam. The present study aims to characterize in vivo the biochemical properties of triazolam, i.e., cerebral pharmacokinetics, interaction with BZR, potency, and intrinsic efficacy. Triazolam was studied in living nonhuman primates using positron emission tomography. Two different studies were carried out: (a) a direct study using [11C]triazolam and (b) an indirect competition study using the radiolabeled BZR antagonist 1C]flumazenil. Results showed that, in the brain in vivo, triazolam binds specifically and competitively to the BZR. Its rapid cerebral kinetics is consistent with a hypnotic profile (maximal binding after 23 min, elimination half-life of 202 min). Triazolam is very potent in displacing [11C]flumazenil (ID50 = 28 +/- 6 micrograms/kg). Hill analysis of the displacement curve does not show obvious binding-site heterogeneity. Triazolam is 20 times more potent in displacing [11C]flumazenil and 50 times more potent in inhibiting pentylenetetrazol-induced paroxysmal activity than the full benzodiazepine agonist diazepam. Interestingly, the simultaneous use of positron emission tomography and EEG recording allowed us to show that triazolam-positive intrinsic efficacy is slightly higher (20%) than that of diazepam. An attractive hypothesis proposes that the severity of side effects of BZR ligands is proportional to their intrinsic efficacy. Therefore, our study shows that triazolam side effects, as for other benzodiazepines, may be related to its high intrinsic efficacy in vivo.

Animals↗
PubMed2005

Electroconvulsive shock decreases binding to 5-HT2 receptors in nonhuman primates: an in vivo positron emission tomography study with [18F]setoperone.

BACKGROUND: Dysfunction within the serotonin (5-HT) system plays a major role in the etiology of human depression, and treatment with antidepressant drugs downregulates 5-HT(2) receptors in rodents and humans. The consequences of another effective antidepressant treatment, electroconvulsive therapy (ECT), on 5-HT(2) receptors are less established. METHODS: We studied the effects of a course of electroconvulsive shock (ECS) on 5-HT(2) receptor binding in nonhuman primates in vivo using positron emission tomography (PET) and the radiotracer [(18)F]setoperone. Seven adult male rhesus monkeys received two bilateral ECS treatments per week for 3 weeks; PET scans were performed before treatment, and 24 hours, 1 week, and 4-6 weeks after completion of the course of ECS. Regions of interest were placed throughout the cortex, and the data analyzed as the ratio of specific:nonspecific radioactivity accumulation, with the cerebellum used as a measure of nonspecific binding. RESULTS: Serotonin 5-HT(2) binding was significantly decreased at 24 hours and 1 week post-ECS, but returned to baseline 4-6 weeks posttreatment. CONCLUSIONS: These results show for the first time in a primate species that chronic ECS decreases binding to 5-HT(2) receptors and indicate that 5-HT(2) receptor downregulation may be a common effect of both pharmacologic and nonpharmacologic antidepressant treatments.

Analysis of Variance↗
PubMed2005

Human and nonhuman primate lentiviral infection and autoimmunity.

The goal of this communication is to summarize the following-the types of autoimmune responses that have been characterized in human HIV-1 infection; the potential mechanisms that were initially thought to be the basis for such autoimmune responses; the prevalence and incidence of conventional autoimmune diseases with HIV-1 infection; the spectrum of autoimmune disorders following the institution of HAART and its associated mechanisms; the role of such autoimmunity in SIV-infected nonhuman primates; and the molecular basis for autoimmune responses, such as the role of exosomes in lentiviral disease.

Animals↗
PubMed1986

Coxsackie virus B4 produces transient diabetes in nonhuman primates.

Cynomolgus, rhesus, and Cebus monkeys failed to show glucose tolerance or insulin secretion abnormalities after infection with encephalomyocarditis virus or Coxsackie virus B4. Patas monkeys also showed no abnormalities after infection with encephalomyocarditis virus. However, patas monkeys infected with Coxsackie virus B4 or treated first with a subdiabetogenic dose of streptozocin and then infected sequentially with Coxsackie viruses B4 and B3 showed transient elevation of glucose tolerance tests, depressed insulin secretion, and glucose in the urine. Our experiments in nonhuman primates support earlier studies in mice and humans that under certain circumstances, Coxsackie viruses can cause abnormalities in glucose homeostasis.

Animals↗
PubMed2005

High levels of persistent expression of alpha1-antitrypsin mediated by the nonhuman primate serotype rh.10 adeno-associated virus despite preexisting immunity to common human adeno-associated viruses.

Alpha1-antitrypsin (alpha1AT) deficiency is a genetic disorder causing emphysema if serum alpha1AT levels are <570 microg/ml. We have shown that intrapleural administration of an AAV5alpha1AT vector yielded persistent therapeutic alpha1AT serum levels. Since anti-AAV2 and -AAV5 antibodies prevalent in humans may limit the use of these common serotypes in gene therapy, we screened 25 AAV vectors derived from humans and nonhuman primates for alpha1AT expression following intrapleural administration to mice. The rhesus AAVrh.10 serotype yielded the highest levels and was chosen for further study. Following intrapleural administration, 77% of total body transgene expression was in the chest wall, diaphragm, lung, and heart. Intrapleural administration of AAVrh.10alpha1AT provided long-term, therapeutic alpha1AT expression in mice, although higher doses were required to achieve therapeutic levels in female mice than in male mice. Intrapleural administration of AAVrh.10alpha1AT produced the same levels in AAV2/AAV5-preimmune and naive mice. In mice administered with AAV5alpha1AT and subsequently "boosted" with the AAVrh.10alpha1AT vector, serum levels were increased by 300%. These data indicate that AAVrh.10 is the most effective known AAV vector for intrapleural gene delivery and has the advantage of circumventing human immunity to AAV.

Animals↗
PubMed2001

Endogenous release of tissue factor pathway inhibitor by topical application of an ointment containing mucopolysaccharide polysulfate to nonhuman primates.

Several studies have shown that tissue factor pathway inhibitor (TFPI) is released after the intravenous and subcutaneous administration of heparin and heparin-related drugs. Mucopolysaccharide polysulfate (MPS) is a preparation of glycosaminoglycans (GAGS) derived from mammalian cartilage, which has several structural and functional properties similar to heparin. Previous reports have shown that MPS is capable of releasing TFPI after intravenous administration. Therefore, this investigation was performed to determine the ability of topically administered MPS to release TFPI in a nonhuman primate model. A group of four monkeys were administered 3% MPS ointment in a dosage of 0.5 g/kg corresponding to 15 mg MPS/kg; another four monkeys were administered placebo ointment at a dosage of 0.5 g/kg once a day for 5 days in a period of 10 days. No effect of MPS was observed on the coagulation assays activated partial thromboplastin time (APTT), thrombin time (TT) and Heptest or on the platelet count. However, both the total and free TFPI levels were significantly and progressively elevated over the 10-day period in comparison to the placebo control group (P<.05). It is proposed that the ability of the topically administered MPS to increase the free and total TFPI levels may be one of the modes of action that contributes to the anticoagulant and anti-inflammatory actions of this agent.

Administration, Cutaneous↗
PubMed1999

A method to determine when active translocation of nonhuman primates is justified.

This article addresses translocation, or artificial dispersal, the movement of one or more organisms from one location to another, and focuses on the decisions to be made before translocation begins. Scientific, economic, or pragmatic reasons such as pest removal or conservation of biodiversity may account for undertaking translocation. When is translocation ethical, and how can that decision be determined? This article provides one quantitative and utilitarian method for evaluating these questions. Although this analysis may apply to any nonhuman species for which costs and benefits can be assessed, the examples in this article derive from the nonhuman primate literature.

Journal Article↗
PubMed1998

Molecular cloning and sequence analysis of interleukin 16 from nonhuman primates and from the mouse.

Interleukin 16 (IL-16) is synthesized as a 67 000 Mr precursor (pro-IL-16), but only a carboxy terminal part of 12 000-14 000 Mr is secreted by CD8(+) lymphocytes. This lymphokine binds to CD4 and has been shown to induce migration, affect the activation state of T cells, and inhibit immunodeficiency virus replication. It has been suggested that CD8(+) cell-derived soluble factors play a pivotal role in protecting natural-host nonhuman primates from developing immunodeficiency following SIV infection. In a first attempt to address this question, we cloned and sequenced the IL-16 cDNA from different primates. Here we report the pro-IL-16 sequence from chimpanzees, African green monkeys (AGM), rhesus macaques, and cynomolgus macaques. In order to compare and analyze structural motifs possibly involved in processing, intracellular targeting, or secretion, we extended our study to the New World monkeys saimiri and aotus and to the mouse. Alignments of deduced amino acids reveal that the human protein shares 99% similarity to that of chimpanzees, approximately 95% to rhesus, cynomolgus and AGM, about 90% to aotus and saimiri, and 77.5% to the mouse. Phylogenetic analyses revealed the expected evolutionary groupings.

Amino Acid Sequence↗
PubMed1999

Plasma and CSF pharmacokinetics of ganciclovir in nonhuman primates.

PURPOSE: The antiviral nucleoside analogue ganciclovir is a potent inhibitor of replication in herpes viruses and is effective against cytomegalovirus infections in immunocompromised patients. Ganciclovir is also used in cancer gene therapy studies that utilize the herpes simplex virus thymidine kinase gene (HSV-TK). The pharmacokinetics of ganciclovir in adults and children have been described previously but there are no detailed studies of the CNS pharmacology of ganciclovir. We studied the pharmacokinetics of ganciclovir in plasma and CSF in a nonhuman primate model that is highly predictive of the CSF penetration of drugs in humans. METHODS: Ganciclovir, 10 mg/kg i.v., was administered over 30 min to three animals. Ganciclovir concentrations in plasma and CSF were measured using reverse-phase HPLC. RESULTS: Peak plasma ganciclovir concentrations ranged from 18.3 to 20.0 microg/ml and the mean plasma AUC was 1075+/-202 microg/ml x min. Disappearance of ganciclovir from the plasma was biexponential with a distribution half-life (t(1/2)alpha) of 18+/-7 min and an elimination half-life (t(1/2)beta) of 109+/-7 min. Total body clearance (ClTB) was 9.4+/-1.6 ml/min/kg. The mean CSF ganciclovir AUC was 168+/-83 microg/ml x min and the mean peak CSF concentration was 0.7+/-0.3 microg/ml. The ratio of the AUCs in CSF and plasma was 15.5+/-7.1%. CONCLUSIONS: Ganciclovir penetrates into the CSF following i.v. administration. This finding will be useful in the design of gene therapy trials involving the HSV-TK gene followed by treatment with ganciclovir in CNS or leptomeningeal tumors.

Animals↗