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PubMed1997

Formation and persistence of DNA adducts of 2-amino-3-methylimidazo[4,5-f]quinoline in the rat and nonhuman primates.

The formation and persistence of the two principal DNA adducts of the food derived carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) have been investigated in rats and nonhuman primates. DNA adduct formation in the liver of male Fischer-344 rats occurred in a dose-dependent manner (0.01-20 mg/kg) where N-(deoxyguanosin-8-yl)-2-amino-3-methylimidazo[4,5-f]quinoline (dG-C8-IQ) and 5-(deoxyguanosin-N2-yl)-2-amino-3-methylimidazo[4,5-f] quinoline (dG-N2-IQ) accounted for approximately 60-80% and 20-40%, respectively, of the total adducts observed by 32P postlabeling. Similar DNA adduct profiles were observed in kidney and colorectal tissue of rats given a single oral dose of IQ (20 mg/kg) which, when given chronically to this species, results in tumorigenesis in liver and colorectum, but not in kidney. dG-C8-IQ was removed more rapidly than dG-N2-IQ from liver and kidney, but removal of both adducts from the colorectum closely followed cell replication. Similar DNA adduct profiles were observed in liver and extrahepatic tissues of nonhuman primates following a single dose of IQ (20 mg/kg). In chronically treated monkeys undergoing carcinogen bioassay, there was a sharp increase in the contribution of dG-N2-IQ to total DNA adducts in all slowly dividing tissues. There was no preferential accumulation of dG-N2-IQ in the colon, a tissue with a high rate of cell division, and dG-C8-IQ remained the predominant lesion. These findings point to a preferential removal of the dG-C8-IQ adduct by enzyme repair system(s) in slowly dividing tissues in both rats and nonhuman primates.

Animals↗
PubMed1999

Management of a measles outbreak among Old World nonhuman primates.

BACKGROUND AND PURPOSE: A measles outbreak in a facility housing Old World nonhuman primates developed over a 2-month period in 1996, providing an opportunity to study the epidemiology of this highly infectious disease in an animal-handling setting. METHODS: Serum and urine specimens were collected from monkeys housed in the room where the initial measles cases were identified, other monkeys with suspicious measles-like signs, and employees working in the affected areas. Serum specimens were tested for measles virus-specific IgG and IgM antibodies, and urine specimens were tested for measles virus by virus isolation or reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: A total of 94 monkeys in two separate facilities had evidence of an acute measles infection. The outbreak was caused by a wild-type virus that had been associated with recent human cases of acute measles in the United States; however, an investigation was unable to identify the original source of the outbreak. Quarantine and massive vaccination helped to control further spread of infection. CONCLUSIONS: Results emphasize the value of having a measles control plan in place that includes a preventive measles vaccination program involving human and nonhuman primates to decrease the likelihood of a facility outbreak.

Animals↗
PubMed1991

Recombinant human interleukin 6 is a potent inducer of the acute phase response and elevates the blood platelets in nonhuman primates.

Human interleukin 6 (IL-6) produced by molecular cloning was administered to nonhuman primates to assess its biological activities in vivo. Rhesus monkeys were treated s.c. with recombinant human (rh) IL-6 at 3 and 30 micrograms/kg body weight/day for 11 days, followed by the administration of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) at 5.5 micrograms/kg/day for 5 days. Serum levels of positively regulated acute phase proteins (APP) (C-reactive protein, alpha 1-antitrypsin, haptoglobin, and ceruloplasmin) increased, whereas negatively regulated APP (prealbumin) decreased in response to rhIL-6 treatment in a dose-dependent manner. Platelet counts rose after a latent period of 4-5 days following the start of rhIL-6 treatment, resulting in a maximum twofold increase above normal levels 2-3 days after the termination of the rhIL-6 treatment. Recombinant human IL-6 treatment induced a two to threefold rise in myeloid progenitor blood cell levels. The subsequent administration of rhGM-CSF to rhIL-6-pretreated animals did not increase the progenitor cell levels in blood above those found with rhGM-CSF treatment alone, indicating that rhIL-6 compared to recombinant human interleukin 3 (rhIL-3) has a minor proliferative effect on hematopoietic precursors in vivo. In conclusion, rhIL-6 was shown to be a potent stimulator of APP and was able to increase the number of platelets in circulation in nonhuman primates.

Acute-Phase Reaction↗
PubMedDate not supplied

Oral administration of 3,4-methylenedioxymethamphetamine (MDMA) produces selective serotonergic depletion in the nonhuman primate.

MDMA (3,4-methylenedioxymethamphetamine) has been reported to produce serotonergic depletion in nonhuman primates at doses as low as 2.5 mg/kg (1-2 times the typical human dose). The current study evaluated the dose-response relationships of MDMA (1.25-20.0 mg/kg) using regional concentrations of serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and home cage behavior as endpoints. Adult female rhesus monkeys (n = 16) were treated orally with 0, 1.25, 2.5, or 20.0 mg/kg MDMA twice daily for 4 consecutive days. Eighteen behaviors were measured in the home cage prior to, during, and after MDMA treatment. One month after the last dose, the animals were sacrificed and brains dissected into several regions for neurochemical analyses. 5-HT and 5-HIAA were analyzed via HPLC/EC. The lower doses of MDMA (1.25 and 2.5 mg/kg) did not significantly alter 5-HT or 5-HIAA concentrations in any brain region except hippocampus in which 5-HT concentrations were decreased after 2.5 mg/kg. MDMA at 20.0 mg/kg significantly decreased 5-HT and 5-HIAA concentrations in several cortical and midbrain structures. However, 5-HT and 5-HIAA concentrations in brain stem and hypothalamus were not significantly altered after any dose of MDMA. Combined with previous data from this laboratory, these results indicate that the decreased concentrations of 5-HT and 5-HIAA in selected brain regions show a selective dose-response relationship for MDMA-induced neurotoxicity as measured by serotonergic depletion in the nonhuman primate.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Species-specific TT viruses and cross-species infection in nonhuman primates.

Viruses resembling human TT virus (TTV) were searched for in sera from nonhuman primates by PCR with primers deduced from well-conserved areas in the untranslated region. TTV DNA was detected in 102 (98%) of 104 chimpanzees, 9 (90%) of 10 Japanese macaques, 4 (100%) of 4 red-bellied tamarins, 5 (83%) of 6 cotton-top tamarins, and 5 (100%) of 5 douroucoulis tested. Analysis of the amplification products of 90 to 106 nucleotides revealed TTV DNA sequences specific for each species, with a decreasing similarity to human TTV in the order of chimpanzee, Japanese macaque, and tamarin/douroucouli TTVs. Full-length viral sequences were amplified by PCR with inverted nested primers deduced from the untranslated region of TTV DNA from each species. All animal TTVs were found to be circular with a genomic length at 3.5 to 3.8 kb, which was comparable to or slightly shorter than human TTV. Sequences closely similar to human TTV were determined by PCR with primers deduced from a coding region (N22 region) and were detected in 49 (47%) of the 104 chimpanzees; they were not found in any animals of the other species. Sequence analysis of the N22 region (222 to 225 nucleotides) of chimpanzee TTV DNAs disclosed four genetic groups that differed by 36.1 to 50.2% from one another; they were 35.0 to 52.8% divergent from any of the 16 genotypes of human TTV. Of the 104 chimpanzees, only 1 was viremic with human TTV of genotype 1a. It was among the 53 chimpanzees which had been used in transmission experiments with human hepatitis viruses. Antibody to TTV of genotype 1a was detected significantly more frequently in the chimpanzees that had been used in transmission experiments than in those that had not (8 of 28 [29%] and 3 of 35 [9%], respectively; P = 0.038). These results indicate that species-specific TTVs are prevalent in nonhuman primates and that human TTV can cross-infect chimpanzees.

Animals↗
PubMed2002

Displacement activities as a behavioral measure of stress in nonhuman primates and human subjects.

Traditionally, research on human stress has relied mostly on physiological and psychological measures with a relatively minor emphasis on the behavioral aspects of the phenomenon. Such an approach makes it difficult to develop valid animal models of the human stress syndrome. A promising approach to the study of the behavioral correlates of stress is to analyze those behavior patterns that ethologists have named displacement activities and that, in primates, consist mostly of self-directed behaviors. In both nonhuman primates and human subjects, displacement behavior appears in situations characterized by social tension and is likely to reflect increased autonomic arousal. Pharmacological studies of nonhuman primates have shown that the frequency of occurrence of displacement behavior is increased by anxiogenic compounds and decreased by anxiolytic drugs. Ethological studies of healthy persons and psychiatric patients during interviews have found that increased displacement behavior not only correlates with a subjective feeling state of anxiety and negative affect but also gives more veridical information about the subject's emotional state than verbal statements and facial expression. The measurement of displacement activities may be a useful complement to the physiological and psychological studies aimed at analyzing the correlates and consequences of stress.

Animals↗
PubMed1999

Posterolateral intertransverse process spinal arthrodesis with rhBMP-2 in a nonhuman primate: important lessons learned regarding dose, carrier, and safety.

Recombinant osteoinductive proteins have been used successfully in canine and rabbit models of posterolateral intertransverse process arthrodesis, but little is known about the ability of these compounds to achieve fusion in nonhuman primates. The goals of this investigation were to compare different combinations of recombinant human bone morphogenetic protein-2 (rhBMP-2) dosages and carriers in a nonhuman primate model of posterolateral intertransverse process spinal fusion and to determine the feasibility of using rhBMP-2 in the presence of exposed dura in a laminectomy model. Posterolateral intertransverse process arthrodeses were performed at L4-5 in 29 rhesus monkeys. The most striking findings were as follows: rhBMP-2 could induce bone in a nonhuman primate spine; the presence of a laminectomy defect with exposed dura did not preclude the safe use of rhBMP-2 for posterolateral fusion; soft tissue compression of the collagen sponge carrier prevented bone induction at standard BMP doses, presumably due to squeezing of the protein out of the sponge; and longer rhBMP-2 loading time into the collagen carrier and mechanical protection from the soft tissue compression both allowed more bone induction at a lower dose of rhBMP-2.

Animals↗
PubMed1999

The role of nonhuman primates in the development of an AIDS vaccine.

Over the past decade, a substantial research investment has generated a vast body of knowledge relevant to the development of an effective AIDS vaccine. Furthermore, studies in nonhuman primates have demonstrated that a number of candidate immunogens can confer a significant degree of protection against a potentially pathogenic SIV or SHIV. Currently, there exists a robust program that supports discovery of new HIV immunogens and a proven successful program for collaborative human trials of promising vaccine candidates. However, we believe that there is a gap between discovery and clinical trials. An orderly process for screening of candidate immunogens prior to human trials would facilitate the vaccine development program. We suggest that nonhuman primates can fill this strategic gap and could accelerate vaccine development. Recognizing that there is considerable controversy about the potential usefulness of the primate models, we have attempted to set forth the relevant practical and biological issues as a series of questions for discussion. The most important biological problem is the absence of a single immune response correlate that will predict vaccine efficacy. Data from primate models indicate that such a single predictive correlate may not exist. In turn, this argues for a vaccine screening protocol that includes a pathogenic virus challenge, an approach only available in the nonhuman primate model. The further assumption is that nonprimate models can be used to predict the relative protective efficacy of diverse immunization protocols, a hypothesis that can only be tested by comparative studies yet to be conducted. A 'standard' set of virus challenges must be selected for comparison of different immunization protocols, and this effort has been initiated. At the practical level, it appears that the large number of candidate immunogens now being developed requires a screening process of the kind proposed, since it would not be practical to test all new immunogens and protocols in humans. In conclusion, it appears timely to crystallize an orderly process for the discovery, screening, and human testing of candidate AIDS vaccines, understanding that a vaccine development program should not be conducted at the expense of investigator-initiated research in the diverse disciplines that support rational vaccine design and development. The components of a rational process of vaccine development are well established and only remain to be welded into one coherent program.

AIDS Vaccines↗
PubMed1978

Implantation of cranial base metallic markers in nonhuman primates.

Cranial base metallic markers are useful in growth and developmental research on the nonhuman primate model. Metallic implants aid in superimposing serial cephalometric roentgenograms in the study of craniofacial changes. They also enable measurement of linear and angular changes in the cranial base. The design of a special implant gun is described in detail. A suggested technique for placement of tantalum markers in the cranial base of nonhuman primates is discussed.

Animals↗
PubMed2000

Inverse correlation of telomerase activity/proliferation of CD4+ T lymphocytes and disease progression in simian immunodeficiency virus-infected nonhuman primates.

Both increased lymphocyte renewal with subsequent exhaustion of the immune system and impaired T-cell renewal have been put forth to account for CD4+ T-cell depletion and development of AIDS in HIV-1-infected humans and SIV-infected nonhuman primates. In the present study, telomeric terminal restriction fragment length and telomerase activity were used as measures of proliferative activity of T lymphocytes from three nonhuman primate species before and after being infected with SIV. In peripheral blood T cells, our data show both species and T-cell-subset-specific differences in proliferative activity accompanied by different patterns of disease progression. A significant postinfection increase in telomerase/proliferative activity in CD4+ T cells from seropositive sooty mangabeys and from normal progressor rhesus macaques was associated with asymptomatic infection or delayed disease progression, respectively, whereas a decrease in telomerase/proliferative activity detected in CD4+ T cells postinfection from SIVsmmPBj14-infected pigtailed macaques was associated with rapid CD4+ T-cell depletion and disease progression. The levels of telomerase activity observed in CD4+ T cells from peripheral blood closely parallelled those seen in CD4+ T cells in lymph node samples from selected animals. Our data suggest that an increase in proliferative activity of T lymphocytes in vivo may be associated with a favorable course of SIV infection in nonhuman primates.

Animals↗
PubMed1990

In vitro fertilization in nonhuman primates.

Ovulation induction, sperm capacitation, and fertilization have been studied for over 50 years in nonhuman primates but it has only been in the past 20 years that extensive studies on sizeable numbers of embryos have been carried out. Of over 200 species of nonhuman primates only a few have been studied and the majority of the findings come from studies of the squirrel monkey, baboon, rhesus, and cynomolgus macaque. Nevertheless, the fertilization process appears to be similar to that identified in other mammals and in man.

Animals↗
PubMed2004

CD154 blockade for induction of mixed chimerism and prolonged renal allograft survival in nonhuman primates.

Costimulatory blockade with anti-CD154 monoclonal antibody (aCD154) prolongs allograft survival in nonhuman primates, but has not reliably induced tolerance when used alone. In the current studies, we evaluated the effect of adding CD154 blockade to a chimerism inducing nonmyeloablative regimen in primates. We observed a significant improvement of donor bone marrow (DBM) engraftment, which has been associated with a lower incidence of acute rejection and long-term survival of renal allografts without the need for previously required splenectomy. Among the long-term survivors, four never showed evidence of rejection, with the longest survival exceeding 1700 days following discontinuation of immunosuppression. Nevertheless, late chronic rejection was observed in three of eight recipients, indicating the necessity of further modifications of the regimen. Control recipients receiving no DBM or donor splenocytes in place of DBM rejected their allografts. Thus, DBM engraftment with, at least, transient mixed chimerism appears essential for induction of allograft tolerance using this conditioning regimen. Modification of the original mixed chimerism approach, by the addition of costimulatory blockade, has been shown to enhance mixed chimerism and induce renal allograft tolerance with less morbidity in nonhuman primates.

Animals↗
PubMed2003

Characterization of monkey enteropathogenic Escherichia coli (EPEC) and human typical and atypical EPEC serotype isolates from neotropical nonhuman primates.

Enteropathogenic Escherichia coli (EPEC) has been associated with infantile diarrhea and mortality in humans in developing countries. While diarrhea is also a major problem among primates kept in captivity, the role of E. coli is unclear. This study was designed to characterize diarrheagenic E. coli recovered from the feces of 56 New World nonhuman primates, primarily marmosets (Callithrix spp.). Seventeen of the 56 primates had signs of diarrhea and/or enteritis. E. coli recovered from feces from these animals was tested by PCR for genes encoding virulence factors of diarrheagenic E. coli and for patterns of adherence to HeLa cells. In addition, isolates were characterized by the fluorescence actin staining test and by their ability to induce attaching and effacing lesions. PCR for the eae gene was positive in 10 of the 39 (27%) apparently healthy animals and in 8 of the 17 (47%) animals with diarrhea and/or enteritis. Colonies of eae(+) E. coli were serotyped and examined by PCR for genes encoding EPEC virulence markers. The eae(+) E. coli isolates recovered from both healthy and sick nonhuman primates demonstrated virulence-associated attributes similar to those of EPEC strains implicated in human disease and are designated monkey EPEC. The results presented here indicate that EPEC may be a significant pathogen for nonhuman primates, deserving further investigation. The similarities between the affected animals investigated in this study and human EPEC infections suggest that marmosets may represent an important model for EPEC in humans.

Actins↗
PubMed2005

Strategies for tolerance induction in nonhuman primates.

Recent advances in the field of reconstructive surgery and immunology resulted in increased interest in composite tissue allograft (CTA) transplantation. Up to date, more than 50 CTA transplants have been reported in humans. A significant number of experimental studies on CTA transplants under different protocols of tolerance-inducting strategies have been reported in small-animal models. There is however, a limited number of CTA transplants performed in nonhuman primates. To reach the ultimate clinical success in CTA transplantation, more experimental studies on tolerance induction in nonhuman primates are needed to apply these immunomodulatory protocols to CTA transplants in humans. In this review, strategies for tolerance induction in the nonhuman primate model in solid organ and CTA transplants are presented in 3 major categories: chimerism induction, T-cell depletion, and costimulatory receptor blockade.

Animals↗
PubMed1987

Use of monoclonal antibodies in genetic research with nonhuman primates.

Monoclonal antibodies, because of their specificity and unlimited availability, have become one of the most powerful experimental tools available to the biological sciences. It is possible to make monoclonal antibodies that bind to determinants that are monomorphic in one or more species or to determinants that are polymorphic within a species. Few monoclonal antibodies have been made using immunogens derived from nonhuman primates. However, some monoclonal antibodies that recognize monotypic markers in humans can be used to detect polymorphic markers in nonhuman primates. Thus, the rapid development of monoclonal antibodies specific for human proteins significantly increases the potential number of immunogenetic markers useful for studying phylogenetic relationships and for identifying genetic polymorphisms among nonhuman primates.

Animals↗
PubMed2003

Understanding xenotransplantation risks from nonhuman primate retroviruses.

Significant progress in making animal-to-human transplantation a viable adjunct to human organ donation will require a greater understanding of the intricacies of immunologic rejection. Recent success in generating cloned knockout piglets increases the possibility that xenotransplantation may find its way into the clinics. Nonhuman primates' organs have been used for human transplants in the past and there is reason to believe that if ethical considerations and inherent problems with supply were overcome, their close genetic proximity to humans would lessen complications of rejection. Unfortunately, nonhuman primates harbor several pathogens known to be infectious in humans and the potential of other viral infections has precluded further use of monkeys in this setting. Baboons are generally considered the nonhuman primate species of choice yet this species carries several retroviruses considered a threat to humans in transplantation. Both known and potentially undiscovered retroviruses pose an important risk that is the focus of this review.

Animals↗
PubMed2004

Efficacy and safety evaluation of human reovirus type 3 in immunocompetent animals: racine and nonhuman primates.

PURPOSE: Human reovirus type 3 has been proposed to kill cancer cells with an activated Ras signaling pathway. The purpose of this study was to investigate the efficacy of reovirus in immunocompetent glioma animal models and safety/toxicity in immunocompetent animals, including nonhuman primates. EXPERIMENTAL DESIGN: Racine glioma cells 9L and RG2 were implanted s.c. or intracranially in Fisher 344 rats with or without reovirus antibodies, followed by treatment of reovirus. To study whether reovirus kills contralateral tumors in the brain and to determine viral distribution, we established an in situ dual tumor model followed by reovirus intratumoral inoculation only into the ipsilateral tumor. To evaluate neurotoxicity/safety of reovirus, Cynomolgus monkeys and immunocompetent rats were given intracranially with reovirus, and pathological examination and/or behavioral studies were done. Viral shedding and clinical biochemistry were systematically studied in monkeys. RESULTS: Intratumorally given reovirus significantly suppressed the growth of both s.c. and intracranially tumors and significantly prolonged survival. The presence of reovirus-neutralizing antibodies did not abort the reovirus' antitumor effect. Reovirus inhibited glioma growth intracranially in the ipsilateral but not the contralateral tumors; viral load in ipsilateral tumors was 15 to 330-fold higher than the contralateral tumors. No encephalitis or behavioral abnormalities were found in monkeys and rats given reovirus intracranially. No treatment-related clinical biochemistry changes or diffuse histopathological abnormality were found in monkeys inoculated intracranially with Good Manufacturing Practice prepared reovirus. Microscopic changes were confined to the region of viral inoculation and were dose related, suggesting reovirus intracranially was well tolerated in nonhuman primates. CONCLUSIONS: These data show the efficacy and safety of reovirus when it is used in the treatment of gliomas in immunocompetent hosts. Inoculation of reovirus into the brain of nonhuman primates did not produce significant toxicities.

Animals↗
PubMed2005

Enrichment and nonhuman primates: "first, do no harm".

Since the 1998 publication of The Psychological Well-Being of Nonhuman Primates by the National Research Council, and the 1991 implementation of the 1985 Animal Welfare Act Amendment, many formal and informal nonhuman primate enrichment programs have been put into practice. Reports of their successes and failures, however, are few. All programs have at least two things in common: (1) They are best when designed and maintained by teams of individuals with species-specific expertise; (2) the members of those teams, the stakeholders, usually include principal investigators, animal care and use committee members, veterinarians, and animal care staff. Discussions in this article address general principles about enrichment, goals of such programs from the perspective of each of the major stakeholders, and recently published sources of related information. These discussions follow the central premise that enrichment should benefit all involved and "First, do no harm."

Animal Care Committees↗