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PubMed2000

Differences among nonhuman primates in susceptibility to bone marrow progenitor transduction with retrovirus vectors.

Nonhuman primates are increasingly being used as models for pre-clinical assessment of retrovirus vector expression and function following stem and progenitor cell transduction. We compared the relative susceptibility of CD34+ marrow progenitors from four nonhuman primate species and humans to transduction with amphotropic pseudotyped retrovirus vectors containing the Neo gene. The rate of functional gene transfer was measured by colony formation under G418 selection. Marrow progenitors from pigtail macaques (Macaca nemestrina) were transduced at about twice the rate (19.1 +/- 4.3%) as those from rhesus (11.2 +/- 3.7%) and cynomolgus (7.6 +/- 1.9%) macaques, baboons (7.8 +/- 1.8%), and humans (9.6 +/- 1.7%). Semiquantitative RT/PCR analysis suggests this difference may be due to elevated expression of the amphotropic receptor Pit2 in pigtailed macaque CD34+ cells. Further, transduction rates increased an average 1.6 +/- 0.4-fold when the culture temperature was lowered to 33 degrees C, and 2.1 +/- 0.3-fold when the culture dishes were coated with the fibronectin fragment CH-296. The data presented here point to important differences among nonhuman primate models as well as transduction culture conditions, and suggest that pigtailed macaques may be particularly useful for assessing expression and function of therapeutic retrovirus vectors. Gene Therapy (2000) 7, 359-367.

Animals↗
PubMed2003

Varicosities of intraretinal ganglion cell axons in human and nonhuman primates.

PURPOSE: To describe varicosities of intraretinal ganglion cell axons in the nerve fiber layer of human and nonhuman primate retinas. METHODS: Intraretinal ganglion cell axons of seven human donors (1-85 years old) and two nonhuman primates (Macaca mulatta, 15 and 17 years old) were immunohistochemically stained with an antibody of neurofilament on flatmounted retinas and examined with light microscopy. In addition, the axons within the retinal nerve fiber layer were examined with transmission electron microscopy in one human and one nonhuman retina. The variations of diameters of single axons were measured on transverse- and parallel-cut sections, and the frequency distributions of the diameters were statistically evaluated. RESULTS: Varicosities of the intraretinal ganglion cell axons were found throughout the retinas in both nonhuman primate and human eyes of all ages examined. The varicosities were rich in mitochondria and had desmosome- and hemidesmosome-like junctions with other axons and retinal glial cells. Measured on parallel-cut axons, the mean diameter (+/-SD) of varicosities was 2.7 +/- 0.9 micro m, whereas the mean diameter of intervaricosity regions was 0.7 +/- 0.3 micro m. The diameter distribution for transverse-cut axons was also bimodal, but the two peaks were much closer because the peak of the larger-diameter group decreased. CONCLUSIONS: The results demonstrated that intraretinal ganglion cell axons are predominantly varicose fibers in both human and nonhuman primates. Size variations exist within a single axon's diameter and thereby affect the patterns of diameter distribution seen in transverse-cut preparations. The mitochondria-rich varicosities and the presence of intercellular junctions suggest that the varicosities may be functional sites that serve local high-energy demands of unmyelinated fibers and signal transmission.

Adolescent↗
PubMed1986

Mast cell heterogeneity in higher animals: a comparison of the properties of autologous lung and intestinal mast cells from nonhuman primates.

The issue of mast cell heterogeneity has been investigated in nonhuman primates by a comparative examination of lung and intestinal mast cells. These cells were obtained in parallel from the respective tissues of individual monkeys by an identical enzymatic dispersion technique. Mast cells derived from the lungs differed from those derived from the intestine in that the majority of the former cell type could be stained with toluidine blue at pH 4 to 5, whereas the intestinal mast cells in the dispersed preparations required a more acidic pH (less than 1) to display metachromasia. In addition, the lung cells exhibited an increased content of the mast cell mediator histamine. Nonhuman primate lung mast cells were also quantitatively more responsive to an immunologic challenge than their intestinal counterparts in that they released a higher percentage of cellular histamine and generated more leukotriene C4 on stimulation. Considerable inter-animal variation was observed between the magnitude of mediator release from both mast cell types after anaphylactic activation, but evidence for the presence in nonhuman primates of the phenomenon of releasability was not obtained. The responsiveness of both cell types to a range of potential nonimmunologic secretagogues and anti-allergic agents, including compound 48/80, substance P, theophylline, and isoprenaline, was essentially similar. We conclude that mast cell heterogeneity in higher animals may be reflected more by cytochemical rather than by functional differences between mast cell classes.

Animals↗
PubMed2004

Role of the nonhuman primate for research related to women's health.

This overview of the current status of medical problems that affect women is related to current studies on pathophysiology and therapeutic interventions using nonhuman primates to demonstrate the utility of the primate model for the study of disease processes in women. The current medical literature on women's health is compared with the literature on nonhuman primate research. The findings reviewed in the articles of ILAR Journal Volume 45 Issue 2 of 2004 are evaluated in the context of the scope and problems associated with disease entities in women. Nonhuman primate research with known information regarding women's disease is discussed, and the utility of the animal model for the study of human disease is highlighted, based on its significant relevance due to similarities of nonhuman primate and human subjects' physiology, metabolism, and responses to therapeutic interventions. Additional advantages of the animal model include the ability to control the experimental environment and the capacity to perform chronic study procedures. These findings allow us to utilize the nonhuman primate as the most relevant model in the animal world for the study of human disease processes.

Animals↗
PubMedDate not supplied

Experience with renal transplantation in the nonhuman primate: a modified ureteroneocystostomy to prevent urologic complications.

Nonhuman primates provide an optimal model for the evaluation of tolerance in the preclinical setting. Transplantation and management of nonhuman primates are technically demanding, and the purpose of this article is to review our extensive experience in renal transplantation in non-human primates, with particular emphasis on modifications of surgical techniques on urologic complications. We retrospectively reviewed our results with 329 renal transplants in rhesus monkeys over an 18-year period. The surgical technique and, in particular, the ureteroneocystostomy have evolved over this period of time. This review extensively details our current technique, the surgical and urologic complications, and their management. There were 329 renal transplants performed. There were 85 early deaths, or animals euthanized, within 30 days of the transplant operation. In the first 15 years, there were 27 (10.68%) surgical complications that required euthanasia, and in the last 3 years the complication rate has been reduced to 5 (7.3%, p < .05). The routine use of microsurgical techniques has reduced the incidence of arterial thrombosis (6.2% vs. 2.9%, p < .05). The incidence of ureteral strictures (15 vs. 0, p < .005) has been reduced by a modification of the ureteroneocystostomy technique detailed in the text. Renal transplantation in small rhesus monkeys is technically demanding. The routine use of microsurgical techniques and a modified ureteroneocystostomy has reduced the incidence of surgical complications.

Animals↗
PubMed1991

Social interaction in nonhuman primates: an underlying theme for primate research.

Social living is assumed to be a critical feature of nonhuman primate existence inasmuch as most primate species live in social groups in nature. Recent USDA legislation emphasizes the importance of social contact in promoting psychological well-being and recommends that laboratory primates be housed with companions when consistent with research protocols. Our goals were to examine the link between social housing and psychological well-being and to explore the idea that research may be compromised when primates are studied in environments that vary too greatly from their natural ecological setting (individual cage housing versus group housing). Three general points emerge from these examinations. First, providing companionship may be a very potent way in which to promote psychological well-being in nonhuman primates; however, social living is not synonymous with well-being. The extent to which social housing promotes psychological well-being can vary across species and among individual members of the same species (for example, high- and low-ranking monkeys). Secondly, housing conditions can affect research outcomes in that group-housed animals may differ from individually housed animals in response to some manipulation. Social interaction may be a significant variable in regulating the biobehavioral responses of nonhuman primates to experimental manipulations. Finally, a larger number of socially housed subjects than individually housed subjects may be necessary for some biomedical research projects to yield adequate data analysis. Thus, social living has significant benefits and some potential costs not only for the animals themselves, but for the research enterprise.

Animals↗
PubMed2001

A nonhuman primate aerosol deposition model for toxicological and pharmaceutical studies.

Nonhuman primates may be used as human surrogates in inhalation exposure studies to assess either the (1) adverse health effects of airborne particulate matter or (2) therapeutic effects of aerosolized drugs and proteins. Mathematical models describing the behavior and fate of inhaled aerosols may be used to complement such laboratory investigations. For example, the optimal conditions, in terms of ventilatory parameters (e.g., breathing frequency and tidal volume) and aerosol characteristics (e.g., geometric size and density), necessary to target drug delivery to specific sites within the respiratory tract may be estimated a priori with models. In this work a mathematical description of the rhesus monkey (Macaca mulatta) lung is presented for use with an aerosol deposition model. Deposition patterns of 0.01- to 5-microm-diameter monodisperse aerosols within lungs were calculated for 3 monkey lung models (using different descriptions of alveolated regions) and compared to human lung results obtained using a previously validated mathematical model of deposition physics. Our findings suggest that there are significant differences between deposition patterns in monkeys and humans. The nonhuman primates had greater exposures to inhaled substances, particularly on the basis of deposition per unit airway surface area. However, the different alveolar volumes in the rhesus monkey models had only minor effects on aerosol dosimetry within those lungs. By being aware of such quantitative differences, investigators can employ the respective primate models (human and nonhuman) to more effectively design and interpret the results of future inhalation exposure experiments.

Aerosols↗
PubMed1996

Thrombopoietic activity of recombinant human interleukin 11 (rHuIL-11) in normal and myelosuppressed nonhuman primates.

We have extensively characterized the hematological response of normal and myelosuppressed nonhuman primates to treatment with recombinant human interleukin 11 (rHuIL-11) in vivo. In normal cynomolgus monkeys, rHuIL-11 significantly increased peripheral platelet counts when administered at doses of 10 micrograms/kg/day to 100 micrograms/kg/day either by constant i.v. infusion or s.c. injection. As few as four days of rHuIL-11 treatment were sufficient to increase peripheral platelet counts significantly. In addition, extending the treatment period enhanced both the magnitude and the duration of the response. Bone marrow megakaryocytes from animals treated with 100 micrograms/kg/day of rHuIL-11 were increased in size compared to controls and were ultrastructurally normal. A nonhuman primate myelosuppression model using carboplatin, which causes severe thrombocytopenia with platelet counts of < or = 20 x 10(3) platelets/microliters, was developed. This novel model was used to evaluate the effectiveness of rHuIL-11 in platelet restoration. rHuIL-11, administered s.c. at a dose of 125 micrograms/kg/day either concurrently or following chemotherapy, prevented severe thrombocytopenia in addition to accelerating platelet recovery compared to control animals receiving no rHuIL-11. These data demonstrate that rHuIL-11 has potent in vivo thrombopoietic effects when administered to normal and myelosuppressed nonhuman primates, and that rHuIL-11 can be an important therapy to reduce the severity and duration of thrombocytopenia following chemotherapy.

Animals↗
PubMed1998

HIV-1/simian immunodeficiency virus infection of human and nonhuman primate lymphocytes results in the migration of CD2+ T cells into the intestine of engrafted SCID mice.

Increased lymphocytic infiltration of intestinal tissues has been observed in patients infected with HIV-1 and in SIV-infected rhesus macaques. To determine whether HIV-1 and SIV infections influence the homing of human and nonhuman primate PBMC to intestinal tissues, we engrafted SCID mice with human or nonhuman primate PBMC and infected them with either cell-free or cell-associated HIV-1 or SIV. In mice that received both PBMC and virus, human or nonhuman primate CD2+ T cells were found in intestinal tissues, primarily in the intraepithelial lymphocyte compartment and lamina propria. Immunomagnetic sorting revealed that these cells were derived from the CD4+ population. Using gag-specific primers, PCR analysis of these tissues detected the presence of HIV-1 proviral DNA. However, in SCID mice that were engrafted with either human or nonhuman primate PBMC and no HIV-1 or SIV, CD2+ T cells were not detected in intestinal tissues. These results indicate that HIV-1 and SIV can modulate the migratory properties of human and nonhuman primate T cells in the SCID mouse model.

Animals↗
PubMed1985

Nonhuman primate models of atherosclerosis: potential for the study of diabetes mellitus and hyperinsulinemia.

Nonhuman primates have been used for many years to investigate the pathogenesis and progression of atherosclerosis. The use of these animal models has resulted in a better understanding of the risk factors associated with atherosclerosis. Nonhuman primates that have consumed an atherogenic diet for several years develop lesions that are comparable to those found in human beings. Diabetes, both spontaneous and chemically induced, has been described in a number of nonhuman primate species. These diabetic models may be used to understand the accelerated progression and vascular complications of atherosclerosis in diabetic human beings.

Animals↗
PubMed2006

IgG Fc receptor III homologues in nonhuman primate species: genetic characterization and ligand interactions.

Ig Fc receptors bind to immune complexes through interactions with the Fc regions of specific Ab subclasses to initiate or inhibit the defense mechanisms of the leukocytes on which they are expressed. The mechanism of action of IgG-based therapeutic molecules, which are routinely evaluated in nonhuman primate models, involves binding to the low-affinity FcRIII (CD16). The premise that IgG/CD16 interactions in nonhuman primates mimic those present in humans has not been evaluated. Therefore, we have identified and characterized CD16 and associated TCR zeta-chain homologues in rhesus macaques, cynomolgus macaques, baboons, and sooty mangabeys. Similar to humans, CD16 expression was detected on a lymphocyte subpopulation, on monocytes, and on neutrophils of sooty mangabeys. However, CD16 was detected only on a lymphocyte subpopulation and on monocytes in macaques and baboons. A nonhuman primate rCD16 generated in HeLa cells interacted with human IgG1 and IgG2. By contrast, human CD16 binds to IgG1 and IgG3. As shown for humans, the mAb 3G8 was able to block IgG binding to nonhuman primate CD16 and inhibition of nonhuman primate CD16 N-glycosylation enhanced IgG binding. Clearly, differences in interaction with IgG subclasses and in cell-type expression should be considered when using these models for in vivo evaluation of therapeutic Abs.

Amino Acid Sequence↗
PubMed2000

Applications of microdialysis methodology in nonhuman primates: practice and rationale.

This review provides a comprehensive summary of the use of microdialysis procedures in nonhuman primates. Using these methods in primates is feasible, including both the anesthetized and awake preparations. The latter permit neurochemical sampling during complex information processing and behavioral performance. The close homology in structure and function between human and nonhuman primate brain makes using nonhuman primates particularly appealing, and the literature suggests that their use has provided instances of unique insight into brain structure and function. The continued use of these methods in areas such as the neurobiology of addiction, affective disorders, and psychosis will help in our ever-increasing understanding of the complex pathophysiologies of these disorders.

Animals↗
PubMedDate not supplied

TH1/TH2 subset analysis. I. Establishment of criteria for subset identification in PBMC samples from nonhuman primates.

Cloned T-cell lines from two nonhuman primate species were phenotyped and their mRNA analyzed for cytokine profiles by RT-PCR procedures. PBMC from rhesus macaques showed a relatively high frequency of cloned T-cell lines with a TH1-like profile; PBMC from sooty mangabeys showed a relatively high frequency of TH2-like cloned T-cell lines. In vitro activated macaque PBMC also resulted in a high frequency of CD4+, CD8+ dual marked cells. These findings suggest that cytokine analysis of cloned T-cell lines from nonhuman primates provides a means to distinguish subsets of both CD4+ and CD8+ T cells.

Animals↗
PubMed2001

Gene transfer into nonhuman primate hematopoietic stem cells: implications for gene therapy.

Hematopoietic stem cells (HSCs) are desirable targets for gene therapy because of their self-renewal and multilineage differentiation abilities. Retroviral vectors are extensively used for HSC gene therapy. However, the initial human trials of HSC gene marking and therapy showed that the gene transfer efficiency into human HSCs with retroviral vectors was very low in contrast to the much higher efficiency observed in murine experiments. The more quiescent nature of human HSCs and the lower density of retroviral receptors on them hindered the efficient gene transfer with retroviral vectors. Since nonhuman primates have marked similarity to humans in all aspects including the HSC biology, their models are considered to be important to evaluate and improve gene transfer into human HSCs. Using these models, clinically relevant levels (around 10% or even more) of gene-modified cells in peripheral blood have recently been achieved after gene transfer into HSCs and their autologous transplantation. This has been made possible by improving ex vivo transduction conditions such as introduction of Flt-3 ligand and specific fibronectin fragment (CH-296) into ex vivo culture during transduction, and the use of retroviral vectors pseudotyped with the gibbon ape leukemia virus or feline endogenous retrovirus envelope. Other strategies including the use of lentiviral vectors and in vivo selective expansion of gene-modified cells with the drug resistance gene or selective amplifier gene (also designated the molecular growth switch) are now being tested to further increase the fraction of gene-modified cells using nonhuman primate models. In addition to the high gene transfer efficiency, high-level and long-term expression of transgenes in human HSCs and their progeny is also required for effective HSC gene therapy. For this purpose, other backbones of retroviral vectors such as the murine stem cell virus and cis-DNA elements, such as the ss-globin locus control region and the chromatin insulator, also need to be tested in nonhuman primate models. Nonhuman primate studies will continue to provide an important framework for human HSC gene therapy. Well-designed nonhuman primate studies will also offer unique insights into the HSCs, immune system, and transplantation biology characteristic of large animals.

Animals↗
PubMed2003

Genomic DNA insertions and deletions occur frequently between humans and nonhuman primates.

Comparative DNA sequence studies between humans and nonhuman primates will be important for understanding the genetic basis of the phenotypic differences between these species. Here we compare approximately 27 Mb of human chromosome 21 with chimpanzee DNA sequences identifying 57 genomic rearrangements (deletions and insertions ranging in size from 0.2 to 8.0 kb) between the two species. These rearrangements are distributed along the entire length of chromosome 21, with approximately 35% found in genomic intervals encoding genes (genic intervals), and have occurred in the genomes of both humans and chimpanzees. Comparison of approximately 9 Mb of human chromosome 21 with orangutan, rhesus macaque, and woolly monkey DNA sequences identified a combined total of 114 genomic rearrangements between humans and nonhuman primates. Analysis of these rearrangements revealed that they are randomly distributed with respect to genic and nongenic intervals and identified one deletion that has likely resulted in the inactivation of a gene (beta1,3-galactosyltransferase) in the woolly monkey. Our data show that genomic rearrangements have occurred frequently during primate genome evolution and significantly contribute to the DNA differences between these species. These DNA rearrangements are commonly found in genic intervals, and thus provide natural starting points for focused investigations of qualitative and quantitative gene expression differences between humans and other primates.

Animals↗
PubMed1993

Comparison of spectral and nonspectral frequency difference limens for human and nonhuman primates.

Difference limens for frequency were measured in normal-hearing human and nonhuman-primate (macaque) subjects. Stimuli were 1-kHz pure tones, containing both spectral and temporal cues, and 100-Hz sinusoidally amplitude modulated broadband noise (SAM noise), containing only temporal (nonspectral) cues. Subjects were tested for a minimum of 20 sessions and until difference limens were stable over time for each stimulus at each of several sensation levels. Difference limens for pure-tone stimuli showed almost no overlap between human and nonhuman-primate subjects. Difference limens for SAM-noise stimuli for human and nonhuman-primate subjects overlapped considerably. The correlations between performance for the pure-tone stimuli and performance for the SAM noise stimuli averaged 0.60. These data suggest that at least two factors influence pure-tone frequency discrimination. One factor is dependent on the presence of place mechanisms while the other factor, or group of factors, seems to influence both spectral and nonspectral frequency discrimination.

Acoustic Stimulation↗
PubMed2000

Gingival crevicular fluid inflammatory mediators and bacteriology of gingivitis in nonhuman primates related to susceptibility to periodontitis.

The hypothesis to be tested was that the microbiota and resulting local host inflammatory response characteristics in oral conditions of high levels of chronic gingival inflammation increases susceptibility to progressing periodontitis. This study used cynomolgus monkeys, Macaca fascicularis (nonhuman primates), with high and low levels of long-standing gingival inflammation to define the profiles of gingival crevicular fluid mediators, cytokines and immunoglobulins; describe the subgingival microbiota; and evaluate their susceptibility to ligature-induced periodontitis. Sixteen nonhuman primates were stratified into two groups (HI, LO) based upon Bleeding Index as a measure of the natural level of inflammation (HI = 1.26 +/- 0.45; LO = 0.22 +/- 0.16). The host mediator levels, subgingival microbiota, and clinical characteristics of the LO and HI groups were compared after 30 days of oral hygiene, during a 30 day experimental gingivitis (7, 14, and 30 days), and during periodontitis (30, 60, and 90 days). The results demonstrated that nonhuman primates with high levels of long-standing gingival inflammation when compared to those nonhuman primates with low inflammation show: 1) different inflammatory mediator profiles in gingival crevicular fluid (particularly for immunoglobulin A (IgA) and IgG levels), 2) a different quantitative and qualitative subgingival microbiota; and 3) a similar progression of periodontitis. Thus, while variations in host inflammatory responses to local factors exist in the nonhuman primates, an extensive subgingival challenge (such as ligation) may negate these individual differences.

Animals↗
PubMed2007

Correlates to traumatic brain injury in nonhuman primates.

BACKGROUND: Traumatic brain injury (TBI) is a major health problem, both in terms of the economic cost to society and the survivor's quality of life. The development of devices to protect against TBI requires criteria that relate observed injury to measurements of head kinematics. The objective of this study is to find the best statistical correlates to impact-induced TBI in nonhuman primates using a qualified, self-consistent set of historical kinematic and TBI data from impact tests on nonhuman primates. METHODS: A database was constructed and qualified from historical head impact tests on nonhuman primates. Multivariate logistic regression analysis with backwards stepwise elimination was performed. Variables considered are the peak rotational acceleration (Omegamax), the peak linear acceleration (Amax), and the number of impacts (N). RESULTS: Bivariate combinations of angular acceleration and the number of impacts are the best correlates to all modes of TBI considered, i.e., concussion, subarachnoid hemorrhage, brain contusion, and subdural hematoma. For a nonhuman primate with 100-g brain mass, the criteria that the probability of TBI is less than 10% by injury mode are:Concussion: OmegamaxN(0.84) < 70 krad/s/s SAH: OmegamaxN(0.70) < 160 krad/s/s Contusion: Omegamax N(0.35) < 160 krad/s/s SDH: Omegamax N(0.60) < 280 krad/s/s CONCLUSIONS: Based on this dataset, the best statistically based risk factor for all modes of TBI in nonhuman primates is the bivariate combination of rotational acceleration and number of impacts.

Acceleration↗