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Beginning in November 1989, a number of cynomolgus monkeys (Macaca fascicularis) imported into the United States were found to have been infected with a previously unrecognized Ebola-like filovirus. This report summarizes findings of surveillance and serologic testing of nonhuman primates imported under special permits from June 1990 through September 1991.
Lipoprotein oxidation is believed to play an important role in atherogenesis. To investigate whether inhibition of oxidation of low density lipoprotein (LDL) would alter atherogenesis in the nonhuman primate, we administered probucol, a potent antioxidant, to Macaca nemestrina fed a high-fat, high-cholesterol diet. Probucol was administered to half of the 16 monkeys 14 wk after starting the hypercholesterolemic diet, and was given daily until they were sacrificed after 11 mos. To evaluate the antioxidant effect of probucol, the resistance of isolated plasma LDL to in vitro oxidation was evaluated. Probucol significantly increased the resistance of LDL to oxidative modification, as shown by an increase in the lag time required for conjugated diene formation. Lesions in the probucol-treated animals appeared less mature, and increased accumulation of lipid was observed in smooth muscle cells. Comparison of all control and probucol-treated monkeys demonstrated that intimal lesion areas in the thoracic aortas of the probucol-treated monkeys were reduced by 43% (P < 0.0001), but no significant difference in lesion area was found in the abdominal aortas or in the iliac arteries. However, the lag phase of conjugated diene formation was not prolonged in 2 of the 8 probucol-treated animals. A plot of intimal lesion size versus lag phase of all 16 animals showed a trend that lesion size was inversely related to oxidation resistance for all anatomic sites. The strong inverse relationship between intimal lesion size and resistance of LDL to oxidation supports a role for lipoprotein oxidation in the development and progression of lesions of atherosclerosis. The possibility that some of the effect is due to other biological properties of probucol cannot be ruled out.
The in vivo imaging of a novel iodinated phenylpiperazine derivative for 5-HT1A receptors, [123I]p-MPPI (4-(2'-methoxy-)phenyl-1-[2'-(n-2"-pyridinyl)-p-iodobenzamido-] ethyl-piperazine), using single photon emission computed tomography (SPECT), was evaluated in nonhuman primates. After an i.v. injection, [123I]p-MPPI penetrated the blood-brain barrier quickly and localized in brain regions where 5-HT1A receptor density is high (hippocampus, frontal cortex, cingulate gyrus, entorhinal cortex). Maximum ratio of hippocampus to cerebellum was 3 to 1 at 50 min postinjection. The specific binding of the radioligand in the hippocampal region, an area rich in 5-HT1A receptor density, was blocked by a chasing dose of (+/-) 8-OH-DPAT (2 mg/kg, i.v.) or non-radioactive p-MPPI (1 mg/kg, i.v.), whereas the regional distribution of [123I]p-MPPI was unaffected by treatment with non 5-HT1A agents, such as ketanserin. Ex vivo and in vitro autoradiographic studies using monkey brain further confirmed that the specific binding of [123I]p-MPPI is associated with 5-HT1A receptor sites. However, the initial attempt at [123I]p-MPPI human imaging studies did not display specific localization of 5-HT1A receptors. This discrepancy observed for [123I]p-MPPI may be due to a dramatic difference in metabolic pathways between humans and monkeys.
Evidence of amodal completion exists for both visual and auditory stimuli in humans. The importance of this mechanism in forming stable representations of sensory information suggests that it may be common among multiple modalities and species. Here we show that a species of nonhuman primate amodally completes biologically meaningful acoustic stimuli, which provides evidence that the neural mechanism mediating this aspect of auditory perception is shared among primates, and perhaps other taxonomic groups as well.
Autoantibody production increases with ageing. However, the pathological significance of this increase as well as the corresponding underlying mechanisms are poorly understood. To further our understanding of the role that ageing plays in the development of autoantibody responses, we used a novel nonhuman primate model consisting of healthy baboons of ages representing the entire lifespan of this animal species. Results from this study indicate that production of antinuclear antibodies, anticell extract antibodies and natural autoantibodies gradually and significantly increases from young age to old age without a corresponding increase in neither serum immunoglobulin concentration nor in levels of selected markers of immune dysregulation (sTNF-RI, sTNF-RII, IL-2 sR alpha and IFN-gamma). Therefore, in the baboon model, autoantibodies may be produced in absence of recognizable pathological conditions of the ageing immune system.
Infections with human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2, respectively) are zoonotic infections. In Africa, the potential exists for additional cross-species transmissions from at least 33 different species of simian immunodeficiency virus (SIV)-infected nonhuman primates (NHPs) through hunting and butchering of these animals for food. Here we describe a highly sensitive and specific enzyme immunoassay (EIA) with chemically modified, multiple antigenic peptides (MAPs) developed for the detection and discrimination of antibodies to SIV genetic lineages. The SIV EIA was developed by using a comprehensive array of MAPs covering two envelope gene regions from all of the SIV lineages for which env sequences were available. Assay sensitivity was evaluated by using 63 plasma or serum samples obtained from primates naturally or experimentally infected with SIVs from 10 genetic lineages. Assay specificity was determined by using 97 known SIV-negative plasma specimens from these same species. Also used in the evaluations were 369 human samples: 198 HIV seronegative, 170 HIV-1 and/or HIV-2 seropositive, and 1 from a human SIVsm infection. Overall assay sensitivity and specificity were 100% with both immunodominant region (IDR) and V3 region MAPs. Although SIV env sequences from talapoin monkeys were not available for specific MAP inclusion, 5 (100%) of 5 SIVtal-infected samples were detected through cross-reactivity with other SIV IDR MAPs used in the assay. The one human SIVsm infection was identified. In conclusion, our SIV MAP EIA proved to be highly sensitive and specific for detecting SIV infections in NHPs and humans. As shown with SIV-infected talapoin monkeys, this assay has the potential to detect previously unidentified SIV strains and should be suitable for sentinel surveillance for potential new cross-species transmissions of SIVs to humans.
The major cause of xenograft loss beyond hyperacute rejection is a form of injury, traditionally termed delayed xenograft rejection (DXR), whose pathogenesis is unknown. Here we analyze the immunologic and morphologic features of DXR that develops in pig kidney xenografts transplanted into nonhuman primates. Kidneys from miniature swine were transplanted into cynomolgus monkeys (n = 14) or baboons (n = 11) that received regimens aimed to induce mixed chimerism and tolerance. No kidney was rejected hyperacutely. Morphologic and immunohistochemical studies were performed on serial biopsies, and an effort was made to quantify the pathologic features seen. The early phase of DXR (Days 0-12) was characterized by focal deposition of IgM, IgG, C3, and scanty neutrophil and macrophage infiltrates. The first abnormality recognized was glomerular and peritubular capillary endothelial cell death as defined by in situ DNA nick-end labeling (TUNEL). Damaged endothelial cells underwent apoptosis and, later, frank necrosis. The progressive phase developed around Day 6 and was characterized by progressive deposition of IgM, IgG, C3, and prominent infiltration of cytotoxic T cells and macrophages, with a small number of NK cells. Thrombotic microangiopathy developed in the glomeruli and peritubular capillaries with TUNEL+ endothelial cells, platelet aggregation, and destruction of the capillary network. Only rare damaged arterial endothelial cells and tubular epithelial cells were observed, with rare endothelialitis and tubulitis. In the advanced phase of DXR, interstitial hemorrhage and infarction occurred. During the development of DXR, the number of TUNEL+ cells increased, and this correlated with progressive deposition of antibody. The degree of platelet aggregation correlated with the number of TUNEL+ damaged endothelial cells. We conclude that peritubular and glomerular capillary endothelia are the primary targets of renal DXR rather than tubular epithelial cells or arterial endothelium and that the earliest detectable change is endothelial cell death. DXR was characterized by progressive destruction of the microvasculature (glomeruli and peritubular capillaries) and formation of fibrin-platelet thrombi. Both cytotoxic cells and antibodies potentially mediate the endothelial damage in DXR; however, in this model, DXR is largely humorally mediated and is better termed "acute humoral xenograft rejection."
HIV-1 vaccine candidates are designed to elicit Type 1 immune responses, including cytotoxic T cells and neutralizing antibodies. The type of immune response is influenced by many factors, including the levels of antigen expression and production of cytokines or chemokines; we designed a nonhuman primate study to evaluate the influence of these factors on protective immunity. Recombinant SHIV were engineered to express macrophage inflammatory protein-1 alpha (MIP-1alpha), regulated upon activation, normal T-cell expressed and secreted (RANTES), or Lymphotactin (Ltn) in place of nef in SHIV(89.6) (SHIV(89.6-MIP-1), SHIV(89.6-RANTES), SHIV(89.6-Ltn)). The parental virus SHIV(89.6) was included because it replicates to higher titer while still not causing disease. Control groups included animals that received a recombinant SHIV with a truncated chemokine construct (SHIV(89.6-dLtn)) and unvaccinated macaques. After pathogenic challenge with SHIV(89.6pd), animals from groups that received recombinant (nef-deleted) viruses had peak viremia levels three orders of magnitude lower than unvaccinated controls and increased survival times. Animals that received the original SHIV(89.6) (nef+) were highly resistant to both intrarectal and intravenous challenge with SHIV(89.6PD), and showed no signs of disease. There were no differences in survival times comparing unvaccinated and SHIV(89.6-dLtn) (control) groups, indicating that nef deleted viruses did not provide durable protection in this model. Strongest protection was seen in animals with the highest replicating virus (SHIV(89.6)), and the lower effect on survival after SHIV(89.6) nef-deleted vaccination, likely reflects differences in replication capacity. The protective effect of nef-deleted virus was partly restored by expressing Type 1 chemokines to augment viral immunity.
A 5-year review (March 1974-March 1979) of bacteriological findings in Old and New World Primates is discussed. Emphasis is on clinical findings in "sick" animals; the primary clinical problems being pneumonia, tuberculosis, intestinal disorders, and trauma infection. The isolation of infrequently encountered pathogenic organisms is discussed. Nonhuman primtes included in this study are baboons (Papio cynocephalus), chimpanzees (Pan sp.), capuchins (Cebus sp.), rhesus (Macaca mulatta), marmoset (Saguinus sp.), squirrel monkey (Saimiri sciureus), and grivet (Ceropithecus aethiops). We believe, from the clinical isolations presented, that this report may serve as a guideline in determining the causative bacterial species of infection and illness in nonhuman primates and served as a basis for standardizing primate colonies.
Mild, transient proteinuria and azotemia were produced in three cynomolgus monkeys (Macaca fascicularis) and a chimpanzee (Pan troglodytes) following intravenous inoculation with Prospect Hill virus, a hantavirus isolated from meadow voles in the United States. This is the first demonstration of an acute nephropathy in nonhuman primates with the viruses causing hemorrhagic fever with renal syndrome.
One of the major unanswered questions regarding the presence of Listeria monocytogenes in foods is how many cells must be ingested in order to cause illness. To answer this question, studies were undertaken by using Macaca fascicularis (cynomolgus monkey) as an animal model. Healthy nonhuman primates were dosed with various concentrations of L. monocytogenes suspended in sterile whole milk. Final concentrations of 10(5), 10(7), and 10(9) total cells of the organism were used; a control was also included. Blood samples, as well as fecal and nasal specimens, were taken at various time intervals. Only animals that received 10(9) cells of L. monocytogenes became noticeably ill, with symptoms of septicemia, irritability, loss of appetite, and occasional diarrhea. Monkeys that received 10(7) and 10(9) cells shed L. monocytogenes in the feces for approximately 21 days. In monkeys that received the dose of 10(9) cells, severe lymphopenia and neutrophilia occurred within 48 h. In a separate trial, monkeys received Maalox to reduce the gastric acidity of the stomach. However, no substantial differences were observed between Maalox-treated and control monkeys.
Cytotoxic T-lymphocyte (CTL) responses have been implicated as playing an important role in control of human immunodeficiency virus (HIV) infection. However, it is technically difficult to demonstrate CTL responses consistently in nonhuman primate and human subjects using traditional cytotoxicity assay methods. In this study, we systematically evaluated culture conditions that may affect the proliferation and expansion of CTL effector cells and presented a sensitive method for detection of cytotoxicity responses with bulk CTL cultures. We confirmed the sensitivity and specificity of this method by demonstration of vigorous CTL responses in a simian-HIV (SHIV)-infected rhesus macaque. The expansion of epitope-specific CTL effector cells was also measured quantitatively by CTL epitope-major histocompatibility complex tetramer complex staining. In addition, two new T-cell determinants in the SIV gag region are identified. Last, we showed the utility of this method for studying CTL responses in chimpanzee and human subjects.
UNLABELLED: The regional distribution, kinetics and pharmacological specificity of a new radioiodinated cocaine analog, N-((E)-3-iodopropen-2-yl)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl) tropane ([123I]IPT) were examined in brain SPECT studies (n = 20) of nonhuman primates. METHODS: Radiolabeling and purification of the iododestannylated trialkyltin percursor yielded the tracer at greater than 90% radiochemical purity and high (> 20,000 Ci/mmole) specific activity. Cynomologous monkeys were injected with 7.2 +/- 1.3 mCi (mean +/- s.d.) of the tracer, and serial 10-min images were acquired (total scan time = 177 +/- 22 min). Images were reconstructed as transaxial slices (2 mm) using restorative techniques (Wiener prefiltering). RESULTS: Radioactivity concentrated quickly in striatal regions (time of peak = 25 +/- 13 min) and cleared gradually thereafter (8.8 +/- 4.6% hr). Striatal-to-cerebellar ratios of 2.6 +/- 1.5 (n = 19), 6.7 +/- 3.2 (n = 20), 15.1 +/- 10.7 (n = 10) and 22.8 +/- 11.0 (n = 9) were observed at the time of peak and at 1, 2 and 3 hr p.i., respectively. In contrast, extrastriatal activity peaked earlier and at lower levels, cleared more rapidly and resembled cerebellar time-activity curves. Displacing doses of nonspecific antagonists of monoamine transporters (mazindol and beta-CIT) showed that 95% of specific [123I]IPT binding was reversible, while selective antagonists (e.g., paroxetine, nisoxetine and GBR 12909) demonstrated that striatal activity was specifically associated with dopamine transporters. CONCLUSION: These results indicate that [123I]IPT is a useful radioligand for in vivo SPECT imaging of striatal dopamine transporters.
OBJECTIVE: To define which regions of the type II collagen (CII) molecule result in anticollagen antibody production and the subsequent development of autoantibodies in a collagen-induced arthritis (CIA) nonhuman primate model. METHODS: Male and female cynomolgus monkeys (2-6 of each sex per group) were immunized with either chicken (Ch), human, or monkey (Mk) CII, or with cyanogen bromide (CB)-generated peptide fragments of ChCII emulsified in Freund's complete adjuvant. Monkeys were observed for the development of arthritis, and sera were collected and analyzed for anticollagen antibody specificity by enzyme-linked immunosorbent assay. RESULTS: Overt arthritis developed in all groups of monkeys immunized with intact CII and with all major CB peptide fragments of ChCII except CB8. Onset and severity of arthritis correlated best with serum anti-MkCII antibody levels. The levels of IgG autoantibody to MkCII were a result of the cross-reactivity rate of anti-heterologous CII antibodies with MkCII, which was based on the genetic background of individual monkeys rather than on sex differences. CONCLUSION: CII from several species and disparate regions of the CII molecule were able to induce autoantibody-mediated arthritis in outbred cynomolgus monkeys. The strong anti-MkCII response suggests that epitope spreading or induction of broad-based CII cross-reactivity occurred in these animals. Autoantibody levels to MkCII were higher in CIA-susceptible monkeys than in resistant monkeys, despite comparable antibody levels in response to the various immunizations of CII. These results closely parallel the type of anticollagen responses found in sera from rheumatoid arthritis patients. Perhaps this can be accounted for by similar major histocompatibility complex heterogenicity associated with an outbred population, or maybe this is a primate-specific pattern of reactivity to CII.
The successful engraftment of genetically modified hematopoietic stem cells (HSCs) without toxic conditioning is a desired goal for HSC gene therapy. To this end, we have examined the combination of intrabone marrow transplantation (iBMT) and in vivo expansion by a selective amplifier gene (SAG) in a nonhuman primate model. The SAG is a chimeric gene consisting of the erythropoietin (EPO) receptor gene (as a molecular switch) and c-Mpl gene (as a signal generator). Cynomolgus CD34+ cells were retrovirally transduced with or without SAG and returned into the femur and humerus following irrigation with saline without prior conditioning. After iBMT without SAG, 2-30% of colony-forming cells were gene marked over 1 year. The marking levels in the peripheral blood, however, remained low (<0.1%). These results indicate that transplanted cells can engraft without conditioning after iBMT, but in vivo expansion is limited. On the other hand, after iBMT with SAG, the peripheral marking levels increased more than 20-fold (up to 8-9%) in response to EPO even at 1 year posttransplant. The increase was EPO-dependent, multilineage, polyclonal, and repeatable. Our results suggest that the combination of iBMT and SAG allows efficient in vivo gene transduction without marrow conditioning.
The genetic determinants of bone mineral quantity and body size and their postulated interaction are just beginning to be elucidated. The heritability of bone quantity and its relationship to components of body size were therefore investigated using segregation analysis applied to a large pedigreed nonhuman primate (Macaca nemestrina) breeding colony. The colony consisted of 216 females and 16 males with uniform dietary histories, environmental conditions, and rearing of offspring apart from the mother to minimize familial aggregation. Bone quantity (bone mineral content and spinal areal density) was measured by dual-energy X-ray absorptiometry (DXA). Size included measures of body mass, length, breadth, and a composite index. Body mass was determined from both body weight and lean body mass by DXA. Length was assessed by measuring trunk and thigh lengths, and breadth by measuring chest circumference and bitrochanteric width. A composite index of size was also calculated from a linear function of trunk and thigh lengths, chest circumference and bitrochanteric width, and lean body mass. Traits of bone quantity and size were highly correlated (r = 0.56-0.96, p < 0.001). Significant (p < or = 0.03) univariate heritabilities were found for spine bone mineral density (SPBMD; h(2) = 0.66) and whole body bone mineral content (WBBMC; h(2) = 0.40) and size measures of length (trunk h(2) = 0.71, thigh h(2) = 0.65), breadth (bitrochanteric width h(2) = 0.31), lean body mass (LEAN; h(2) = 0.37), and the composite index of size (SIZE-PC, h(2) = 0.49) adjusted for demographic variables. The data were also subjected to an analysis of bivariate genetic correlations and factor analysis, both of which suggested a robust interaction between body size and bone quantity. Bivariate genetic correlations between body size and the bone quantities WBBMC, SBMD, and spine bone mineral content (SPBMC) were high (e.g., using LEAN as a measure of size, r = 0.57, 0.41, and 0.57, respectively). Factor analysis showed that 80% of the phenotypic and 72% of the genetic variances of all traits were accounted for by a single factor, suggesting common genetic controls operative over bone quantity and size.
E (erythrocyte) and EAC (erythrocytes coated with antibody and complement) rosettes were quantitated in baboons, cebus monkeys and cotton-topped marmosets. There was poor correlation between E rosette levels and other parameter of T-lymphocyte function. In nonhuman primates, E rosettes were increased in the presence of thymosin fraction V, while human E rosettes were not affected.
The performance of twenty children (3-11 years of age) in a complex operant test battery (OTB) was evaluated. The operant schedules, or tasks, used in the OTB were identical to those originally designed and currently used to assess complex brain function in nonhuman primate laboratory animals (monkeys). The OTB consisted of five operant tasks: 1) Progressive-Ratio [PR]; 2) Conditioned-Position Responding [CPR]; 3) Temporal Response Differentiation [TRD]; 4) Delayed Matching-to-Sample [DMTS] and 5) Incremental Repeated Acquisition [IRA]. These operant tasks are thought to engender responding indicative of processes associated with: 1) motivation; 2) color and position discrimination; 3) time-perception; 4) short-term memory and attention; and 5) learning, respectively. The parameters for each of the tasks in the OTB were optimized for use in the clinical setting to assess cognitive function in children. In the small population studied, performance in the IRA, DMB and TRD tasks was age related. Of the four 6-yr-olds studied, only those categorized as having either learning disabilities (LD, n = 1) or attention deficit disorders (ADD, n = 2) did not complete the "learning" task. By comparison of human and monkey performance in the OTB, we also hope to validate the use of laboratory animal models in research efforts designed to yield insight into complex human brain function. It is also hoped that assessment of children's performance in the tasks in the OTB will assist in the diagnosis and treatment of certain childhood disorders such as learning disabilities and/or attention deficit disorders.