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PubMed1995

Initial studies on the effects of combined 60 Hz electric and magnetic field exposure on the immune system of nonhuman primates.

In a pilot immunology experiment, peripheral blood samples from six baboons (Papio cynocephalus) housed as a social group were collected during week 5 of preexposure, exposure, and postexposure periods that were each 6 weeks in duration. The subjects were exposed to vertical 6 kV/m and horizontal 50 microT (0.5 G) fields for 12 h per day. Lymphocytes collected during the exposure period displayed statistically significant (p < .05) reductions in CD3+ and CD4+ counts, interleukin 2 receptor expression, and proliferative response to pokeweed mitogen. A second experiment was conducted using samples from seven subjects exposed to 30 kV/m and 100 microT (1.0 G) and eight sham-exposed subjects. Statistically significant Period x Group interactions occurred for total white blood cell count and CD4+ to CD8+ ratio, but the pattern of results was not suggestive of an exposure-related effect. Although components of the nonhuman primate immune system appear to be affected by 60 Hz electric and magnetic field exposure in one of two experiments, additional experiments are required to evaluate this possibility.

Animals↗
PubMed1980

Myxoma of bone in a nonhuman primate.

A myxoma of the mandibles in an adult female Macaca mulatta is described. The left mandible was markedly enlarged by the tumor, which extended from the symphysis to the temporomandibular joint. The tumor had extended a short distance across the symphysis into the right mandible. It was composed of a glistening mucinous material. Radiographs of the tumor showed a large expansile radiolucent lesion of the left mandible without soft tissue involvement. Light microscopy demonstrated capillaries, stellate shaped cells with processes up to 15 mu long, very few other cell types, and an amorphous ground substance. Electron microscopic examination revealed similarity to the myxoma of bone of man. The oxytalan fibers discovered in this myxoma have not been found in myxomas before and suggest the tumor is odontogenic in origin. The incidence of spontaneous neoplasia in general and that of spontaneous oral tumors in particular in nonhuman primates are reviewed.

Animals↗
PubMed2001

Potent and selective inhibition of human cathepsin K leads to inhibition of bone resorption in vivo in a nonhuman primate.

Cathepsin K is a cysteine protease that plays an essential role in osteoclast-mediated degradation of the organic matrix of bone. Knockout of the enzyme in mice, as well as lack of functional enzyme in the human condition pycnodysostosis, results in osteopetrosis. These results suggests that inhibition of the human enzyme may provide protection from bone loss in states of elevated bone turnover, such as postmenopausal osteoporosis. To test this theory, we have produced a small molecule inhibitor of human cathepsin K, SB-357114, that potently and selectively inhibits this enzyme (Ki = 0.16 nM). This compound potently inhibited cathepsin activity in situ, in human osteoclasts (inhibitor concentration [IC]50 = 70 nM) as well as bone resorption mediated by human osteoclasts in vitro (IC50 = 29 nM). Using SB-357114, we evaluated the effect of inhibition of cathepsin K on bone resorption in vivo using a nonhuman primate model of postmenopausal bone loss in which the active form of cathepsin K is identical to the human orthologue. A gonadotropin-releasing hormone agonist (GnRHa) was used to render cynomolgus monkeys estrogen deficient, which led to an increase in bone turnover. Treatment with SB-357114 (12 mg/kg subcutaneously) resulted in a significant reduction in serum markers of bone resorption relative to untreated controls. The effect was observed 1.5 h after the first dose and was maintained for 24 h. After 5 days of dosing, the reductions in N-terminal telopeptides (NTx) and C-terminal telopeptides (CTx) of type I collagen were 61% and 67%, respectively. A decrease in serum osteocalcin of 22% was also observed. These data show that inhibition of cathepsin K results in a significant reduction of bone resorption in vivo and provide further evidence that this may be a viable approach to the treatment of postmenopausal osteoporosis.

Animals↗
PubMedDate not supplied

Retinal vasculitis in ocular toxoplasmosis in nonhuman primates.

Six monkeys had prior systemic immunization followed by intraretinal challenge to each eye with Toxoplasma antigens. All eyes developed iridocyclitis, vitritis, and retinal edema, but no necrotizing retinochoroiditis. One-half of the eyes were then challenged with living organisms and the other one-half with Toxoplasma antigens. All eyes developed iridocyclitis, vitritis, and retinal edema, but no necrotizing retinochoroiditis. Four months later, the right eye of each monkey was challenged with living Toxoplasma organisms injected intraretinally. Each injected eye developed iridocyclitis, vitritis, and retinal edema 24 hours after injection, and all developed a retinal vasculitis 6 days after injection. One injected eye developed a papillitis. A subcutaneous booster of living Toxoplasma organisms in four of the monkeys failed to produce a reactivation of the iridocyclitis, vitritis, and vasculitis. These findings suggest that hyperimmunization provides protection against the development of a necrotizing toxoplasmic retinochoroiditis in nonhuman primates and that it may lead to retinal vasculitis and iridocyclitis. This study also serves as an animal model of retinal vasculitis in ocular toxoplasmosis.

Animals↗
PubMed2005

Symmetry activates extrastriate visual cortex in human and nonhuman primates.

Humans often create and appreciate visual symmetry in their environment, and the underlying brain mechanisms have been a topic of increasing interest. Here, symmetric versus random dot stimuli produced robust functional MRI (fMRI) activity in higher-order regions of human visual cortex (especially areas V3A, V4, V7, and LO) but little activity elsewhere in brain. This fMRI response was found both with and without attention controls. Moreover, it was highly correlated with the psychophysical perception of symmetry. Similar symmetry responses were found by using line-based and dot stimuli and were found at a wide range of stimulus sizes and geometric configurations. Weaker symmetry responses were found in analogous regions of macaque visual cortex by using fMRI techniques with higher sensitivity. This evidence suggests that visual symmetry is specifically enhanced in the human brain, but that the underlying neural mechanisms may nevertheless be resolvable in nonhuman primates.

Adult↗
PubMed1998

Adenoviral gene transfer in arteries of hypercholesterolemic nonhuman primates.

Arterial gene transfer with adenoviral vectors is a promising approach for the treatment and prevention of vascular disorders. However, in small animals such as rats and rabbits adenoviral vectors can have deleterious effects on the artery wall. The effects of adenovirus in primate arteries have not been studied. AdRSVn-LacZ, a replication-defective adenoviral vector, was delivered to the left brachial arteries of six hypercholesterolemic cynomolgus monkeys; right brachial arteries received vehicle only. Serum was collected before gene transfer and at vessel harvest 9 or 10 days later. Recombinant gene expression was present in occasional endothelial cells of transduced arteries, and all animals generated neutralizing antibodies. In transduced arteries, immunostaining revealed a fourfold increase in intimal and medial macrophage accumulation (p < 0.05); intimal cellularity was also significantly increased (twofold; p < 0.05). T cell density and total cellular proliferation (determined by bromodeoxyuridine labeling) were unaffected. In hypercholesterolemic nonhuman primates, adenoviral vectors increase vessel wall inflammation and promote the progression of early atherosclerotic lesions. The long-term consequences of these observations remain unclear; however, a better understanding of host responses to specific vector systems appears necessary for the development of safe and effective approaches to human vascular gene therapy.

Adenoviridae↗
PubMed1977

Human Pb, human post-Pb, and nonhuman primate Pb proteins: immunological and biochemical relationships.

The isolation and characterization of a protein from human parotid saliva termed the "post-Pb protein" is described. By several criteria, this protein is closely related to the human Pb proteins. When reacted against antisera to human Pb protein in double diffusion, the post-Pb protein is found to be related to the Pb proteins by lines of identity. However, when the partial N-terminal amino acid sequences of the post-Pb protein and Pb proteins are compare, the sequences are not identical. Because of the similarity in size of the Pb and post-Pb proteins and because of the observed sequence differences, any product-precursor relationship between the Pb and post-Pb proteins is unlikely. The post-Pb protein probably is the product of a genetic locus different from the Pb locus. Two additional species of nonhuman primates (Papio papio and P. sphinx) have been found to have Pb proteins electrophoretically similar to these found in the rhesus monkey and differing from those in the human. The isolated Pb proteins of the rhesus monkey have been found to have close biochemical and immunological relationships to the human Pb proteins.

Amino Acid Sequence↗
PubMed1980

Initial renal responses of nonhuman primate to immersion and intravascular volume expansion.

Experiments were performed in anesthetized Macaca fascicularis monkeys to determine if the initial renal responses of these animals to head-out vertical water immersion and isoncotic, isotonic volume expansion are similar, especially with regard to the onset of any changes in solute or water excretion. Significant increases in urine flow, sodium excretion, and osmolar clearance occurred after 10 min of immersion but not until 30 min after volume expansion. Potassium excretion increased during immersion but decreased after volume expansion. Mean arterial blood pressure increased after 30 min of immersion but was unchanged after volume expansion. Indices of vascular filling, central venous pressure in the immersed animals and left ventricular end-diastolic pressure in the volume-expanded animals, increased immediately after the intervention. Effective renal plasma flow increased in both groups but glomerular filtration rate was not consistently elevated. These results suggest that, in the nonhuman primate, immersion and volume expansion exert their renal effects through different afferent and/or efferent mechanisms and should not be considered as similar volume stimuli.

Animals↗
PubMedDate not supplied

Microglial expression of MHC class II increases in normal aging of nonhuman primates.

The search for factors that influence age-related behavioral and cognitive slowing is ongoing. Because microglia are involved in many neurological disorders, they may also contribute to changes in normal aging. To assess increases in microglial activity, we used an antibody against MHC class II to label microglia in three groups of brains from female Macaca nemestrina: juvenile (2-5 years), young adult (5-11 years), and mature (11-19 years). Image analysis was completed on four white matter and three gray matter regions in a single coronal plane. Microglial expression of MHC class II increased with age, and was highest in the white matter regions of the mature, or middle-aged, monkeys. The higher expression of this antigen may indicate that the cells will more easily respond to stimulation. Their location in the white matter suggest that they may influence myelin loss and the eventual cognitive decline in aged human and nonhuman primates.

Aging↗
PubMed1990

Experimental infection with Chlamydia pneumoniae in nonhuman primates.

To serially examine the immunopathogenesis and histopathology of infection with Chlamydia pneumoniae, we inoculated two cynomolgus monkeys in the conjunctival sac, nose, and nasopharynx with C. pneumoniae TWAR. After inoculation, C. pneumoniae was isolated from the inoculation sites and the rectums of both monkeys for a period of 5 weeks. After a second inoculation, C. pneumoniae was recovered from the inoculation sites and the rectums of both monkeys for 20 weeks. A third inoculation with C. pneumoniae caused very little productive infection at any site. Prior C. pneumoniae infection did not prevent subsequent C. trachomatis serovar E (Bour strain) infection. Clinical and histopathologic ocular responses to C. pneumoniae infection were mild compared with those to infection with C. trachomatis serovar E. Rectal infection, demonstrated by culture isolation and immunohistopathology, occurred without direct experimental inoculation. Both immunofluorescent staining of mucosal smears with monoclonal antibodies and tissue culture were able to detect C. pneumoniae infection. Experimental nonhuman primate infection with C. pneumoniae appears to be clinically and histopathologically mild and can occur at extrapulmonary sites.

Animals↗
PubMed1998

Removal of anti-porcine natural antibodies from human and nonhuman primate plasma in vitro and in vivo by a Galalpha1-3Galbeta1-4betaGlc-X immunoaffinity column.

BACKGROUND: Natural antibodies (NAbs) against a terminal alpha1-3 galactosyl (alphaGal) epitope have been identified as the major human anti-pig NAbs. METHODS AND RESULTS: We used two synthetic alphaGal trisaccharides--type 6 (alphaGal6) and type 2(alphaGal2)--linked to an inert matrix to remove NAbs from human plasma in vitro. Flow cytometry indicated that an average of 85% of the NAb binding activity was depleted by adsorption with alphaGal6. By measuring the binding of NAbs to pig peripheral blood mononuclear cells and bone marrow cells, we demonstrated that alphaGal6 was more effective than alphaGal2 in removing NAbs, and the combination of alphaGal6 + alphaGal2 did not further increase removal of NAbs. The specificity of the removal of NAbs (IgM and IgG) reactive with the alphaGal epitope by alphaGal6 matrix was shown by enzyme-linked immunosorbent assay. In vivo studies in nonhuman primates compared plasma perfusion through a alphaGal6 immunoaffinity column with hemoperfusion through a pig liver for changes in blood pressure, hematocrit, platelets, and NAb adsorption. CONCLUSIONS: Both methods reduced the level of anti-pig IgM and IgG xenoreactive antibodies to nearly background, but column perfusion caused less hypotension and reduction in platelets than liver perfusion. Four pig kidneys transplanted into monkeys after column perfusion did not undergo hyperacute rejection, remaining functional for 2-10 days, with a mean functional period of 7 days, demonstrating that a pig kidney can support renal function in a primate.

Animals↗
PubMedDate not supplied

Anti-OX40 (CD134) administration to nonhuman primates: immunostimulatory effects and toxicokinetic study.

The immune-stimulatory properties of anti-CD134 (OX40) antibodies have been well documented in rodents, including their ability to enhance antitumor immunity. In this study, an anti-OX40 antibody (Ab) known to costimulate monkey T cells in vitro, was infused into rhesus macaque monkeys during immunization with the simian immunodeficiency virus protein, gp130. The draining lymph nodes from immunized monkeys treated with anti-OX40 were enlarged compared with immunized monkeys injected with mouse Ig. Anti-OX40-treated monkeys had increased gp130-specific Ab titers, and increased long-lived T-cell responses, compared with controls. There were no overt signs of toxicity in the anti-OX40-treated monkeys. The encouraging immune-stimulatory effects led to the good manufacturing practice production of an anti-OX40 Ab for clinical trials in cancer patients. A detailed toxicology study was performed with anti-OX40 in nonhuman primates. Three groups of 8 monkeys received anti-OX40 at 1 of 3 dose levels (0.4, 2.0, and 10 mg/kg) and a control group received saline. No clinical toxicity was observed, but acute splenomegaly and enlarged gut-associated lymph nodes were observed in the anti-OX40-treated animals; splenomegaly and lymphadenopathy resolved by day 28. These studies demonstrate the immune-stimulatory properties and safety of anti-OX40 in primates and provide a strong scientific rationale to pursue clinical trials in humans.

Adjuvants, Immunologic↗
PubMed2006

A recombinant fusion protein containing the domain III of the dengue-2 envelope protein is immunogenic and protective in nonhuman primates.

We have previously reported the construction and evaluation in mice of recombinant fusion proteins formed by a fragment (aa 286-426) of the dengue envelope protein and the P64k protein from Neisseria meningitidis. In this work we describe the immunization of Macaca fascicularis monkeys with two variants of these proteins [PD3 (insertion variant) and PD5 (fusion variant)] corresponding to serotype 2. Four doses of the proteins adjuvated in Freund's adjuvant were administered and the kinetics of antibody induction was monitored by ELISA and neutralization tests. Monkeys receiving PD3 or PD5 developed functional antibodies (Abs) in a dose-dependent manner. Following challenge with 5 log PFU of wild type dengue-2 virus (DEN2), animals immunized with PD5 were protected from developing viremia. These results constitute a proof-of-concept demonstrating that a fragment of the dengue envelope protein, containing the domain III and produced as a recombinant fusion protein in Escherichia coli, induces functional and protective immunity in a nonhuman primate model.

Adjuvants, Immunologic↗
PubMed2005

Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver.

Transduction with recombinant adeno-associated virus (AAV) vectors is limited by the need to convert its single-stranded (ss) genome to transcriptionally active double-stranded (ds) forms. For AAV-mediated hemophilia B (HB) gene therapy, we have overcome this obstacle by constructing a liver-restricted mini-human factor IX (hFIX) expression cassette that can be packaged as complementary dimers within individual AAV particles. Molecular analysis of murine liver transduced with these self-complementary (sc) vectors demonstrated rapid formation of active ds-linear genomes that persisted stably as concatamers or monomeric circles. This unique property resulted in a 20-fold improvement in hFIX expression in mice over comparable ssAAV vectors. Administration of only 1 x 10(10) scAAV particles led to expression of hFIX at supraphysiologic levels (8I U/mL) and correction of the bleeding diathesis in FIX knock-out mice. Of importance, therapeutic levels of hFIX (3%-30% of normal) were achieved in nonhuman primates using a significantly lower dose of scAAV than required with ssAAV. Furthermore, AAV5-pseudotyped scAAV vectors mediated successful transduction in macaques with pre-existing immunity to AAV8. Hence, this novel vector represents an important advance for hemophilia B gene therapy.

Animals↗
PubMed2000

MHC diversity in Caucasians, investigated using highly heterogeneous noncoding sequence motifs at the DQB1 locus including a retroviral long terminal repeat element, and its comparison to nonhuman primate homologues.

Long terminal repeats (LTRs) are common retrovirus-related sequences spread throughout the human genome. We previously reported the human-specific integration of one LTR (DQLTR3) located 15 kb upstream of HLA DQB1. To elucidate the contribution of retroviral sequences to the variability and phylogenetic background of HLA DQB1 we investigated another LTR (DQLTR13), located 1.3 kb upstream of HLA DQB1, in German families, great apes, and Old World monkeys. Within German families, DQLTR13 presence was strongly linked to HLA DQB1*0302, *0303, and *0402 haplotypes. All other haplotypes had a low frequency or were devoid of DQLTR13. Phylogenetic analysis of DQLTR13 and adjacent nucleotide sequences in humans and non-human primates revealed a high degree of similarity and recent origin of HLA DQB1*0302, *0303, and *0402. Nevertheless, two lineages leading to DQB1*0301 and *0302 were generated by an ancient split of a DQB1*0301, *0302 progenitor. A third lineage consisting of DQB1*05/*06-related sequences may have evolved from the DQB1*0302 lineage, and a DQB1*0201-related sequence shared common ancestry with DQB1*0301. Among the human haplotypes, HLA DQB1*0201 and *0301 are linked to two different DQA1 alleles. Based on the small genetic distance of DQLTR13 as well as the adjacent sequences on these haplotypes, we suggest that a recent recombination is responsible for these associations. In the analysis of nonhuman primate species, we detected DQLTR13 in two lowland gorillas, dating the integration at at least 8 million years ago. We therefore conclude that noncoding sequences up to 1.3 kb upstream of DQB1 provide novel insight into the generation of MHC gene diversity.

Animals↗
PubMed2000

Inflammatory cytokine mRNA expression during early and persistent Helicobacter pylori infection in nonhuman primates.

The role of mononuclear phagocytes in orchestrating the host responses to Helicobacter pylori is inadequately understood. Therefore, gene expression for the monocyte/macrophage-derived cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha was determined before and during H. pylori infection of rhesus monkeys by use of a highly sensitive quantitative reverse transcriptase polymerase chain reaction. The numbers of molecules of IL-1beta, IL-6, and TNF-alpha mRNA in gastric tissue during early infection (7 weeks) significantly exceeded the preinfection numbers (P<.03). Moreover, the numbers of IL-1beta, IL-6, and TNF-alpha mRNA molecules in persistently infected animals (6 years) also were elevated compared with preinfection numbers (P<.02, P=.03, P=.16, respectively). Cytokine gene expression coincided with progressive H. pylori gastritis, confirmed by increased gastritis scores over preinfection scores (P<.005). These findings provide quantitative evidence that H. pylori induces local gene expression of monocyte/macrophage-derived inflammatory cytokines and evokes an innate response in gastric tissue of nonhuman primates.

Animals↗
PubMed1975

Experimentally induced infection of dogs, cats, and nonhuman primates with Ehrlichia equi, etiologic agent of equine ehrlichiosis.

Dogs (German Shepherd Dogs and Beagles), cates, rhesus macaques (Macaca mulatta), and baboons (Papio anubis) were inoculated with Whrlichia equi, the etiologic agent of equine ehrlichiosis. Within 3 to 7 days after inoculation, morulae were observed in the eosinophils of cats, neurtrophils of macaques and baboons, and in both neutrophils and eosinophils of dogs. The severe disease produced in horses by this agent was not a feature of E equi infection in dogs, cats, macaques, and baboons. However, a susceptible horse, inoculated with the pooled blood of 2 infected macaques, developed severe clinical signs of equine ehrlichiosis. Infection with E equi did not alter the susceptibiltiy of dogs to infection with Ehrlichia canis and did not prevent development of signs of disease resulting from this infection. The broad experimental host range from this infection. The broad experimental host range of E equi distinguishes it from other ehrlichial agents which are characterized by a rather narrow host range. The susceptibiltiy of nonhuman primates to infection with E equi provides a basis for consideration of the potential transmission of ehrlichial agents to man.

Animals↗
PubMed1995

Detection thresholds for 60 Hz electric fields by nonhuman primates.

Because responses of animals to detection of the presence of an electric field (EF) are a possible mechanism for production of biological effects, it is important to know what EF intensities are detectable. Operant methods were used to train six baboons (Papio cynocephalus) to perform a psychophysical task involving detection of EF presence. During the response phase of a trial, a subject responded on one push button to report the presence of the EF and on a different push button to report the absence of the EF. Correct reports of EF presence of absence produced delivery of food rewards. The subjects became proficient at performing this psychophysical detection task; during 35 days of testing, false alarm rates averaged 9%. The average EF detection threshold was 12 kV/m; the range of means among subjects was 5-15 kV/m. Two special test procedures confirmed that the subjects were responding directly to EF presence of absence and not to artifacts that might be associated with EF generation. The EF detection threshold of nonhuman primates is similar to thresholds reported for rats and humans.

Animals↗