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PubMed1996

PCR Identification and Differentiation of Baboon Cytomegalovirus From Other Human and Nonhuman Primate Cytomegalovirus.

Background: Differential identification of baboon alpha, beta, and gamma herpesviruses is an essential technology in order to monitor xenozoonotic transmission of baboon viruses to foreign species organ and/or cell recipients. We present polymerase chain reaction techniques that will differentiate known baboon cytomegaloviruses (CMV) from their closely related counterparts found in humans. Methods and Results: Polymerase chain reaction techniques for identification of the known beta herpesviruses commonly present in the baboon are reported. The techniques described also permit the unequivocal differentiation of these virus types from closely related human as well as other nonhuman primate viruses in the family herpesviridae. Methods are based upon sequence analysis of specifically selected genes of baboon CMV. Primer pairs from sequence analyses were selected based upon nonhomologous sequences in gene homologues of human CMV. Unique, baboon species specific amplimers were identified both with ethidium bromide staining and with radiolabeled probe analyses. Conclusions: With the described techniques, it is possible to monitor organ/cell recipients of xenograft transplantation for the establishment of baboon CMV in the foreign human host. Monitoring can be performed throughout the life of the recipient in effort to rule out host susceptibility to baboon CMV, as well as to rule out potential host:donor recombinant viruses formed between the closely related members of herpesvirus family.

Journal Article↗
PubMed1990

Carcinogenicity of 2-amino-3-methylimidazo[4,5-f]quinoline in nonhuman primates: induction of tumors in three macaques.

The carcinogenic potential of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) was evaluated in cynomolgus monkeys. Monkeys received IQ, beginning at the age of one year, at doses of 10 or 20 mg/kg by gavage. Thus far, IQ has induced hepatocellular carcinoma in three monkeys with a latent period of 27 to 37 months. Metastases to the lung occurred in two of the three monkeys. Microscopically, the hepatocellular carcinoma in all three cases demonstrated a trabecular pattern. These data demonstrate that IQ is a potent carcinogen in nonhuman primates and support the idea that it is a potential carcinogen for humans.

Animals↗
PubMed1989

Effect of treatment with aromatase inhibitor 4-hydroxandrostenedione on the nonhuman primate menstrual cycle.

4-Hydroxyandrostenedione (4-OHA) is a potent inhibitor of rat ovarian and human placental aromatase activity as assessed in vitro and has been shown to suppress ovarian estrogen secretion in vivo in rats. The compound inhibited extragonadal aromatization in male rhesus monkeys and reduced plasma levels of estradiol in postmenopausal women with advanced, metastatic breast cancer. Furthermore, 4-OHA caused disease remission in these patients. Prior to using this compound in premenopausal patients, the present study was carried out to determine whether 4-OHA affects the menstrual cycle by inhibiting ovarian estrogen production in nonhuman primate species. Four baboons (Papio anabis) exhibiting regular menstrual cycles were studied. Blood samples were collected daily throughout a control menstrual cycle and during treatment with daily s.c. injections of 4-OHA. Menstruation was not observed in three of four animals during treatment and did not resume until cessation of 4-OHA administration. The midcycle surge of estradiol which averaged 411 pg/ml in the control menstrual cycle was reduced during 4-OHA treatment by a mean of 49% of control. Thereafter, with continued 4-OHA treatment, serum concentrations of estradiol were significantly reduced below the basal control level [75.3 +/- 5.6 (SE) pg/ml] and were very low or undetectable. Perineal turgescence, an index of estrogenicity, was inhibited by 4-OHA administration. The preovulatory surge of serum luteinizing hormone, which averaged 114 ng/ml during the control cycle, appeared normal in three of four animals following 12 to 14 days of 4-OHA administration, but no luteinizing hormone surge occurred with continued 4-OHA administration. The results indicate that, although 4-OHA reduces ovarian estrogen formation during the first cycle, treatment for a second consecutive cycle appears to be necessary for maximal suppression.

Androstenedione↗
PubMed2000

Mu-class GSTs are responsible for aflatoxin B(1)-8, 9-epoxide-conjugating activity in the nonhuman primate macaca fascicularis liver.

Mice are resistant to the carcinogenic effects of the mycotoxin aflatoxin B(1) (AFB(1)) because they constitutively express an alpha-class glutathione S-transferase (mGSTA3-3) that has high (approximately 200,000 pmol/min/mg) activity toward aflatoxin B(1)-8, 9-epoxide (AFBO). Rats do not constitutively express a GST with high AFBO-conjugating activity and are sensitive to AFB(1)-induced hepatocarcinogenesis. Constitutively expressed human hepatic alpha-class GSTs (hGSTA1-1 and hGSTA2-2) possess little or no AFBO-detoxifying activity (<2 pmol/min/mg). Recently, we found that the nonhuman primate, Macaca fascicularis (Mf), exhibits significant (approximately 300 pmol/min/mg) constitutive hepatic GST activity towards AFBO. To determine which specific GST isoenzyme(s) is (are) responsible for this activity, MF: GSTs were purified from liver tissue and characterized and, Mf mu-class GST cDNAs were cloned by reverse transcriptase-coupled polymerase chain reaction (RT-PCR). Purification by glutathione agarose (GSHA) affinity chromatography yielded a protein, GSHA-GST, that exhibited relatively high AFBO-conjugating activity (239 pmol/min/mg) compared to other GST-containing peaks. Western blotting and enzymatic activity analyses revealed that GSHA-GST belongs to the mu class. Two distinct mu-class GST cDNAs, mfaGSTM1 (GenBank accession # AF200709) and mfaGSTM2 (GenBank accession # AF200710), were generated by RT-PCR. CDNA-derived amino acid sequence analysis revealed that mfaGSTM1 and mfaGSTM2 share 97% and 96% homology with the human mu-class GSTs hGSTM4 and hGSTM2, respectively. In contrast to recombinant mfaGSTM1-1, which had no detectable AFBO-conjugating activity, mfaGSTM2-2 exhibited this activity at 333 pmol/min/mg. Activity profiles for the stereoisomers exo- and endo-AFBO, and of 1-chloro-2,4-dinitrobenzene of the purified protein GSHA-GST and recombinant mfaGSTM2-2, suggested that they are two distinct enzymes. Our results indicate that, in contrast to rodents, mu-class GSTs are responsible for the majority of AFBO-conjugating activity in the liver of Macaca fascicularis.

Aflatoxin B1↗
PubMed1992

Monoclonal antibodies against human T cell adhesion molecules--modulation of immune function in nonhuman primates.

The cytotoxic T cell is thought to be a primary effector of allograft rejection. In vitro studies have demonstrated that the interaction between cytotoxic T cells and target cells involves cell surface adhesion molecules that result in conjugate formation, with subsequent antigen recognition, T cell activation, and target cell lysis. Experiments have also demonstrated the ability of monoclonal antibodies with specificity for two human T cell adhesion molecules, lymphocyte function associated (LFA) antigen-1 (LFA-1, CD11a, alpha-chain/CD18, beta-chain) and LFA-2 (CD2), to inhibit conjugate formation in vitro. Studies in a nonhuman primate model were undertaken to determine whether the in vivo administration of monoclonal antibodies with specificity for the alpha chain of LFA-1 (CD11a) or with specificity for CD2 could modulate in vivo T cell function. Cynomolgus monkeys (Macaca fascicularis) received 10 daily intravenous infusions of either anti-CD11a, anti-CD2 or both anti-CD11a and anti-CD2 monoclonal antibodies. Antibody administration was well tolerated and resulted in high levels of circulating murine monoclonal antibody in the peripheral circulation. Nearly all the animals generated antimurine antibodies that were specific for both idiotypic and nonidiotypic determinants of the infused mouse protein. Circulating lymphocytes and T cells were not depleted by treatment with anti-CD11a or anti-CD2 mAbs; in fact, treatment with the combination of anti-CD11a plus anti-CD2 or anti-CD11a alone led to increased numbers of circulating lymphocytes and T cells. Modulation of the LFA-1 molecule on circulating T cells occurred as a result of treatment with anti-CD11a (or the combination of anti-CD11a plus anti-CD2), whereas treatment with anti-CD2 (or anti-CD11a plus anti-CD2) did not result in modulation of the CD2 antigen despite detectable levels of circulating anti-CD2 mAb. In vivo T cell function was assessed by placement of skin allografts. As compared with treatment with saline or a control mAb, allograft survival was significantly prolonged in animals treated with anti-CD11a or combination treatment but not in animals receiving anti-CD2 alone. We conclude that the in vivo administration of anti-LFA-1 mAb may be useful for the blockade of effector T cell activity during allograft rejection, that saturation of antigen and antigen modulation may be important for efficacy of such antibody effects in vivo, and that monoclonal antibodies with specificity for functionally important T cell surface molecules may alter T cell function in vivo without lymphocyte depletion.

Animals↗
PubMed1999

Odor structure-activity relationships compared in human and nonhuman primates.

The ability of 4 squirrel monkeys to distinguish between members of 3 homologous series of substances (aliphatic alcohols, aldehydes, and ketones) was investigated, and their performance was compared with that of a group of 10 human participants. With all 3 substance classes, and in both species, a significant negative correlation was found between discrimination performance and structural similarity of odorants in terms of differences in carbon chain length. These findings suggest carbon chain length of aliphatic odorants to be one of presumably several determinants of the interaction between stimulus molecule and olfactory receptor and support the assumption that human and nonhuman primates may share common mechanisms of odor quality perception.

Adult↗
PubMed2006

Preclinical evaluation of the neuroprotective effect of soluble complement receptor type 1 in a nonhuman primate model of reperfused stroke.

OBJECT: Postischemic cerebral inflammatory injury has been extensively investigated in an effort to develop effective neuroprotective agents. The complement cascade has emerged as an important contributor to postischemic neuronal injury. Soluble complement receptor Type 1 (sCR1), a potent inhibitor of complement activation, has been shown to reduce infarct volume and improve functional outcome after murine stroke. Given numerous high-profile failures to translate promising antiinflammatory strategies from the laboratory to the clinic and given the known species-specificity of the complement cascade, the authors sought to evaluate the neuroprotective effect of sCR1 in a nonhuman primate model of stroke. METHODS: A total of 48 adult male baboons (Papio anubis) were randomly assigned to receive 15 mg/kg of sCR1 or vehicle. The animals were subjected to 75 minutes of middle cerebral artery occlusion/reperfusion. Perioperative blood samples were analyzed for total complement activity by using a CH50 assay. Infarct volume and neurological scores were assessed at the time the animals were killed, and immunohistochemistry was used to determine cerebral drug penetration and C1q deposition. An interim futility analysis led to termination of the trial after study of 12 animals. Total serum complement activity was significantly depressed in the sCR1-treated animals compared with the controls. Immunostaining also demonstrated sCR1 deposition in the ischemic hemispheres of treated animals. Despite these findings, there were no significant differences in infarct volume or neurological score between the sCR1--and vehicle-treated cohorts. CONCLUSIONS: A preischemic bolus infusion of sCR1, the most effective means of administration in mice, was not neuroprotective in a primate model. This study illustrates the utility of a translational primate model of stroke in the assessment of promising antiischemic agents prior to implementation of large-scale clinical trials.

Animals↗
PubMed1998

Polynucleotide immunization of nonhuman primates against carcinoembryonic antigen.

In preparation for a Phase I trial of DNA immunization against carcinoembryonic antigen (CEA) in patients with colorectal carcinoma, we have produced a single plasmid DNA encoding CEA and hepatitis B surface antigen (HBsAg) under transcriptional regulatory control of two separate cytomegalovirus promoters within separate eukaryotic expression cassettes, designated pCEA/HBsAg. Hepatitis B surface antigen was included to provide an internal positive control for the efficacy of this immunization strategy without regard to the issue of breaking tolerance to a self-antigen. In the present work, we sought to examine the immunogenicity of this plasmid in a nonhuman primate model with close phylogenetic relationship to humans. Groups of pig-tailed macaques were immunized with pCEA/ HBsAg by i.m. injection or particle bombardment of the skin according to a dose and schedule thought to be optimal for the respective technique of DNA immunization. Both administration techniques produced humoral and lympho-proliferative responses of comparable magnitude. However, delayed type hypersensitivity to CEA and CEA-specific interleukin-2 release were observed only in the i.m. group, suggesting a qualitative difference in the character of the immune response elicited by the two techniques of DNA immunization. The antibody responses to CEA and HBsAg were surprisingly persistent in that all immunized animals maintained moderate antibody titers against both antigens for more than 15 months after the last boost. No toxicity was observed during 2 years of follow-up, including no measurable levels of anti-DNA antibody. This antitumor immunization strategy is presently being examined in patients with metastatic colorectal carcinoma using pCEA/HBsAg administered by i.m. injection.

Animals↗
PubMed2005

The physiology and neurochemistry of self-injurious behavior: a nonhuman primate model.

Self-injurious behavior (SIB) is a serious behavioral condition that afflicts millions of individuals in the United States alone. The underlying factors contributing to the development of self-injury in people are poorly understood, and existing treatment strategies for this condition are limited. A low but persistent percentage of socially reared individually housed rhesus monkeys also spontaneously develop SIB. Data obtained from colony records suggest that the risk of developing SIB in socially reared rhesus monkeys is heightened by adverse early experience and subsequent stress exposure. The present review summarizes the physiological and neurochemical findings obtained in this nonhuman primate model of SIB, focusing on monoamine neurotransmitters, neuropeptides, and neuroendocrine systems. The results indicate that monkeys with SIB exhibit long-lasting disturbances in central and peripheral opioid and stress response systems, which lead to increased levels of anxiety. Based on these findings, we propose an integrated developmental-neurochemical hypothesis in which SIB arises from adverse life events in a subset of vulnerable monkeys, is maintained by a persisting dysregulation of several neurochemical and physiological systems, and functions to periodically reduce anxiety when the levels of anxiety become excessive. Implications of this hypothesis for understanding self-injury in patients with borderline personality disorder and members of the general population are discussed.

Animals↗
PubMed2004

A fully synthetic therapeutic vaccine candidate targeting carcinoma-associated Tn carbohydrate antigen induces tumor-specific antibodies in nonhuman primates.

We recently developed an efficient strategy based on a fully synthetic dendrimeric carbohydrate display (multiple antigenic glycopeptide; MAG) to induce anticarbohydrate antibody responses for therapeutic vaccination against cancer. Here, we show the superior efficacy of the MAG strategy over the traditional keyhole limpet hemocyanin glycoconjugate to elicit an anticarbohydrate IgG response against the tumor-associated Tn antigen. We highlight the influence of the aglyconic carrier elements of such a tumor antigen for their recognition by the immune system. Finally, we additionally developed the MAG system by introducing promiscuous HLA-restricted T-helper epitopes and performed its immunological evaluation in nonhuman primates. MAG:Tn vaccines induced in all of the animals strong tumor-specific anti-Tn antibodies that can mediate antibody-dependent cell cytotoxicity against human tumor. Therefore, the preclinical evaluation of the MAG:Tn vaccine demonstrates that it represents a safe and highly promising immunotherapeutic molecularly defined tool for targeting breast, colon, and prostate cancers that express the carbohydrate Tn antigen.

Animals↗
PubMed1982

Use of genetic markers in the colony management of nonhuman primates: a review.

Genetic markers in blood were used to identify paternity and reconstruct genealogical relationships in six captive breeding groups of rhesus monkeys (Macaca mulatta) using paternity exclusion analysis. The theoretical and observed incidence of inbreeding and its deleterious effects were discussed and colony management alternatives proposed for minimizing these effects. Genetic markers for disorders and both desirable and undesirable phenotypic characteristics have been sought so as to maximize the reproductive success and vitality of the colony by selective breeding. A sound genetic component such as that described here is a necessary adjunct to any successful long-term program for breeding nonhuman primates.

Animals↗
PubMed2005

Long-term inducible gene expression in the eye via adeno-associated virus gene transfer in nonhuman primates.

Adeno-associated viral gene therapy has shown promise for the treatment of inherited and degenerative diseases in a variety of animal models. Some of the most dramatic results have been obtained in the field of ocular gene therapy, where efficacy has been tremendous in inherited and acquired retinal disorders. For the promise of this approach to be realized it will be necessary to create vectors capable of pharmacologic or physiologic regulation of the transgene. We describe in this paper a dimerizer-inducible viral expression system that is able to reproducibly drive expression of the reporter gene erythropoietin in the eyes of nonhuman primates over a period of 2.5 years. The expression profiles were characterized by minimal basal expression in the absence of inducer and dose-responsive maximal expression in the presence of inducer drug.

Animals↗
PubMed1998

Detection of active infection in nonhuman primates with Lyme neuroborreliosis: comparison of PCR, culture, and a bioassay.

Ideally a diagnosis of infection of the central nervous system (CNS) is made by culture of the etiologic pathogen, but Borrelia burgdorferi, the causative agent of Lyme neuroborreliosis (LNB), is rarely cultured from the cerebrospinal fluid (CSF). PCR and measurement of specific antibody in the CSF also have their limitations. The role of available assays for LNB has not been studied carefully in a comparative investigation. There is a need to assess the reliability of assays and to increase the ability to document active infection in the CNS. The recent development of the nonhuman primate (NHP) model of LNB allowed us to address this need in a faithful model of human LNB. In this study we compared the abilities of PCR and culture to detect the presence of spirochetes in the CSF and brain tissue of infected NHPs and related these measures of infection to the development of anti-B. burgdorferi antibody. We also tested a bioassay, the mouse infectivity test (MIT), in this model. Fourteen of 16 CSFs from four NHPs were positive by at least one of these techniques. Detection of spirochetes in the CSF by PCR, the MIT, and culture was inversely related to the concomitant presence of anti-B. burgdorferi antibody intrathecally. The performance of any particular test was associated with the strength of the host immune response. In early CNS infection, when anti-B. burgdorferi antibody had not yet appeared, or in immunocompromised hosts, the MIT compared favorably to culture and PCR for infected NHPs; antibody in the CSF was the most useful assay for immunocompetent NHPs.

Animals↗
PubMed2000

Plasma and cerebrospinal fluid pharmacokinetics of O6-benzylguanine and analogues in nonhuman primates.

O6-Benzylguanine (BG) is a potent, specific inactivator of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase, that enhances the sensitivity of tumor cell lines and tumor xenografts to chloroethylnitrosoureas. To search for BG analogues with greater penetration into the cerebrospinal fluid (CSF), we evaluated plasma and CSF pharmacokinetics of BG, 8-aza-O6-benzylguanine (8-azaBG), O6-benzyl-8-bromoguanine (8-BrBG), O6-benzyl-8-oxoguanine (8-oxoBG), O6-benzyl-8-trifluoromethylguanine (8-tfmBG), and O6-benzyl-2'-deoxyguanosine (B2dG) after i.v. administration of 200 mg/m2 of drug through an indwelling Ommaya reservoir in a nonhuman primate model. BG and its analogues were quantified in plasma and CSF using reverse-phase high-performance liquid chromatography assays. The plasma clearances of the four 8-substituted BG analogues were similar (0.04-0.06 l/h/kg), but half-lives ranged from <2 to >24 h. BG was converted to 8-oxoBG, an equally potent O6-alkylguanine-DNA alkyltransferase inactivator, and the elimination of 8-oxoBG was much slower than that of BG. As a result, the plasma area under the curve of 8-oxoBG was 3.5-fold greater than that of BG. B2dG was metabolized to BG and 8-oxoBG, but this pathway accounted for only 20% of B2dG elimination. The CSF penetration percentages (based on the ratio of AUC(CSF): AUCplasma) for BG, 8-azaBG, 8-oxoBG, 8-tfmBG, 8-BrBG, and B2dG were 3.2, 0.18, 4.1, 1.4, <0.3, and 2.0%, respectively. The CSF penetration of BG and its active metabolite 8-oxoBG is greater than the penetration of 8-azaBG, 8-BrBG, 8-tfmBG, and B2dG.

Animals↗
PubMed1983

Biochemistry of the nonhuman primate prostate and seminal vesicles. I. Some chemical parameters.

Normative biochemical values for cranial prostate, caudal prostate, and seminal vesicles were obtained in four macaque species and in baboons, with a view to chemical comparison of the cranial lobe with the other two tissues. The cranial prostatic lobe and the seminal vesicles were both significantly different from the caudal prostate in prostatic acid phosphatase activity. However, citric acid and lactate dehydrogenase in the cranial lobe were comparable to concentrations in the caudal lobe and significantly different from the seminal vesicles. Dihydrotestosterone was higher in content than testosterone in all tissues of each species examined. The nonhuman primate cranial lobe seems to be a link between the seminal vesicles and the caudal prostate.

Acid Phosphatase↗
PubMed1995

Polyglyconate fixation successfully stabilizes zygomatic osteotomies in a nonhuman primate.

Investigators have reported problems with metal plates and screws, including restriction of craniofacial growth necessitating secondary removal; bone resorption secondary to stress shielding; increased incidence of infection, extrusion, and palpability, especially in regions with minimal soft-tissue coverage; and interference with radiological studies and postoperative radiation therapy. Biodegradable rigid fixation can easily eliminate a majority of these problems because the material provides adequate fixation for a finite interval corresponding to bony repair. For this reason, there has been increasing interest in developing satisfactory biodegradable plate and screw systems. We tested a commercially developed polyglyconate plate and screw system to stabilize zygomatic osteotomies in a nonhuman primate model before embarking on clinical trials. In this experimental model, the stabilized segments revealed satisfactory alignment; in the control animals, the bony fragments became significantly displaced. This polyglyconate plate and screw system appears to have a promising role in the surgical correction of craniomaxillofacial deformities in humans, and clinical testing should commence.

Animals↗
PubMed1980

Residual effects of polychlorinated biphenyls on adult nonhuman primates and their offspring.

After 18 mo of consuming a diet containing 2.5 and 5.0 ppm PCB (Aroclor 1248), during which they and their offspring experienced marked alterations in physical status, female rhesus monkeys were placed on a control diet for 1 yr. During this year there was a decided improvement in their general body health and reproductive capabilities. Infants born to these animals were small at birth and during their postnatal life developed signs of PCB intoxication similar to those observed in their siblings born during the period of PCB exposure. These data indicate that the residual effects of low-level ingestion of PCBs by nonhuman primates persist for over 1 yr after discontinuation of exposure. There are also indications that the fetal and neonatal monkeys born to PCB-exposed mothers are more severely affected for a longer period than are the adult female monkeys.

Abnormalities, Drug-Induced↗
PubMed2004

Induction of Plasmodium falciparum transmission-blocking antibodies in nonhuman primates by a combination of DNA and protein immunizations.

Malaria transmission-blocking vaccination can effectively reduce and/or eliminate transmission of parasites from the human host to the mosquito vector. The immunity achieved by inducing an antibody response to surface antigens of male and female gametes and parasite stages in the mosquito. Our laboratory has developed DNA vaccine constructs, based on Pfs25 (a Plasmodium falciparum surface protein of 25 kDa), that induce a transmission-blocking immune response in mice (C. A. Lobo, R. Dhar, and N. Kumar, Infect. Immun. 67:1688-1693, 1999). To evaluate the safety, immunogenicity, and efficacy of the Pfs25 DNA vaccine in nonhuman primates, we immunized rhesus macaques (Macaca mulatta) with a DNA vaccine plasmid encoding Pfs25 or a Pfg27-Pfs25 hybrid or with the plasmid (empty plasmid) alone. Immunization with four doses of these DNA vaccine constructs elicited antibody titers that were high but nonetheless unable to reduce the parasite's infectivity in membrane feeding assays. Further boosting of the antibody response with recombinant Pfs25 formulated in Montanide ISA-720 increased antibody titers (30-fold) and significantly blocked transmission of P. falciparum gametocytes to Anopheles mosquitoes (approximately 90% reduction in oocyst numbers in the midgut). Our data show that a DNA prime-protein boost regimen holds promise for achieving transmission-blocking immunity in areas where malaria is endemic and could be effective in eradicating malaria in isolated areas where the level of malaria endemicity is low.

Animals↗