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PubMed2002

Stimulation of both humoral and cellular immune responses to HIV-1 gp120 by interleukin-12 in Rhesus macaques.

The adjuvant effect of recombinant Rhesus macaque interleukin-12 (RhIL-12) on the induction of cellular and humoral immune responses elicited by the HIV-1 subunit vaccine protein gp120 in Rhesus macaques was examined. RhIL-12 in conjunction with gp120 was given at day 0, 28 and 84 intramuscularly. Coadministration resulted in an approximate 10-fold increase in plasma anti-gp120 antibody levels as compared to levels generated in control monkeys receiving gp120 alone. Potentiation of the humoral arm of the immune response was evident by both ELISA and an antiviral bioassay. In addition, RhIL-12 was found to produce a significant increase in gp120-specific proliferative responses and in the frequency of antigen-specific IFN-gamma and IL-2 producing T cells after restimulation of PBMC with gp120 in vitro indicating that RhIL-12 potentiates cell-mediated immune responses as well. A critical finding was that during the course of the study, RhIL-12 did not induce a neutralizing antibody response to the administered cytokine. The doses of RhIL-12 were well tolerated and no detectable adverse side-effects on hematopoietic and hepatic parameters were noted. The data revealed that IL-12, when coadministered intramuscularly, acts as a potent adjuvant which is able to enhance not only cellular but also humoral immune responses to gp120 in non-human primates and may have to be considered in future HIV vaccine strategies.

Animals↗

PubMed2001

Differential evolutionary MHC class II strategies in humans and rhesus macaques: relevance for biomedical studies.

The rhesus macaque is an important preclinical model in transplantation research and in investigations of chronic and infectious diseases that need a well-characterised major histocompatibility complex (MHC-Mamu). In a large population of pedigreed rhesus macaques, 70 Mamu-DRB, 18 -DQA1, 24 -DQB1, and 14 -DPB1 alleles were detected. In humans, five HLA-DRB region configurations are present, displaying diversity with regard to number and combinations of loci. The HLA-DRB1 gene of each of these configurations is highly polymorphic. For rhesus monkeys, at least 31 Mamu-DRB region configurations have been determined. In contrast to humans, most Mamu-DRB region configurations display no or only limited allelic polymorphism. Segregation analyses revealed 28 Mamu-DQA1/DQB1 pairs, each pair linked to a limited number of Mamu-DRB region configurations and vice versa. In comparison with humans, the degree of freedom of recombination between Mamu-DQA1 and -DQB1 is extremely low and equivalents of HLA-DQA2/DQB2 are absent. The Mamu-DPA1 gene is invariant and -DPB1 manifests only moderate allelic variation, whereas the HLA-DPA1 gene is oligomorphic and HLA-DPB1 highly polymorphic. Thus, both species used different evolutionary strategies to create polymorphism and diversity at the MHC class II loci in order to cope with pathogens.

Animals↗

PubMed2002

Assessment of the nasopharyngeal bacterial flora of rhesus macaques: moraxella, Neisseria, haemophilus, and other genera.

The nasopharyngeal bacterial flora of healthy rhesus macaques was surveyed for the presence of Neisseria and Haemophilus species, as well as Moraxella catarrhalis. M. catarrhalis was found both in healthy rhesus macaques and in possibly immunocompromised rhesus macaques. Several Haemophilus spp. that are part of the normal nasopharyngeal bacterial flora of humans were found in many animals; these Haemophilus species included H. parahaemolyticus, H. segnis, and H. parainfluenzae. While Haemophilus influenzae was not identified, it is possible that the identification of H. influenzae types may have been thwarted by the growth of less fastidious species. A number of animals harbored Neisseria spp. such as N. sicca. However, Neisseria meningitidis was not found. In summary, it appears as though the rhesus macaque may be used as a model for M. catarrhalis infections. Moreover, in view of the susceptibility of macaques to organisms of the Haemophilus and Neisseria genera, it is possible that these animals may also accurately model nontypeable H. influenzae and N. meningitidis infections.

Animals↗

PubMed1978

Genetic variation in transferrin alleles of rhesus macaques, Macaca mulatta.

The rhesus macaque displays an extensive polymorphism at the transferrin locus. A principal components analysis describes the variance and covariance of alleles at the transferrin locus in eight widely dispersed sample populations. Using an eigenvectorial representation of the covariance matrix and systematically approximated geographical locations the distribution of populations and transferrin alleles is compared. Alleles with high variance prove to be the determining factor in the placement of populations in a "genetic map" and provide a means for interpreting the low congruence of genetics and geography found.

Alleles↗

PubMed1990

Antibody-dependent enhancement of simian immunodeficiency virus (SIV) infection in vitro by plasma from SIV-infected rhesus macaques.

Plasma from two rhesus macaques (Macaca mulatta) experimentally infected with the simian immunodeficiency virus (SIV; isolate SIVmac251) enhanced SIVmac infection of a human CD4+ lymphoblastoid cell line, MT-2. Prechallenge plasma samples from these animals and serum from SIV-negative macaques did not enhance infection. Compared with controls, infection enhancement was characterized by the rapid appearance of syncytium formation (3 to 4 days sooner), reverse transcriptase release (10-fold increase), and cytopathic effect (60% cell killing). Enhancement of activity was dependent on the presence of diluted, fresh SIV-negative macaque serum as a source of complement. A requirement for complement was shown by the absence of enhancement in heat-inactivated serum and by dose-dependent inhibition of enhancement in the presence of polyclonal antibody to monkey complement component C3. Monoclonal antibody to CD4 (OKT4a) blocked enhancement completely, while monoclonal antibody to the human complement component C3d receptor CR2 (OKB7) reduced enhancement by greater than 50%, indicating a requirement for CD4 and CR2 in mediating this phenomenon. SIV infection-enhancing activity appeared in macaques soon after experimental inoculation (28 days). The titer increased over time and peaked just prior to the death of both macaques from opportunistic infections and lymphoma. In vitro SIV infection enhancement is nearly identical to the in vitro complement-mediated, antibody-dependent enhancing (C'-ADE) activity observed in human immunodeficiency virus-positive human sera (Robinson et al., Lancet i:790-794, 1988; Robinson et al., J. Acq. Immun. Def. Synd. 2:33-42, 1989). These observations validate the macaque-SIV model for studies of C'-ADE.

Animals↗

PubMed1985

Toxicity and fetotoxicity of TCDD, TCDF and PCB isomers in rhesus macaques (Macaca mulatta).

In rhesus macaques (Macaca mulatta), consumption of food containing commercial polychlorinated biphenyl (PCB) mixtures, some pure polychlorobiphenyl congeners, 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD), and 2,3,7,8-tetrachlorodibenzofuran (TCDF) caused the same clinical toxic manifestations and histopathologic lesions, although the potencies of the toxicants covered a range of five orders of magnitude. Recovery from poisoning by 3,4,3',4'-tetrachlorobiphenyl (34TCB) or TCDF was rapid, whereas recovery from poisoning by Aroclor 1242, 3,4,5,3', 4', 5'-hexachlorobiphenyl (345HCB) or TCDD was protracted, if it occurred at all. 34TCB did not appreciably accumulate in body fat, but the level of 345HCB in fat rose steadily during ingestion. In one monkey, 25% of TCDD stored in fat after a single dose was still present after 2 years. Among the symmetrical tetra-and hexachlorobiphenyl isomers tested, subacute oral toxicity could be demonstrated only for those without ortho chlorine substitutions. 34TCB and 345HCB were toxic at dietary levels of less than 1 ppm, but ingestion of food containing 2,5,2',5'- tetrachlorobiphenyl at 5 ppm, or 2,4,5,2',4',5'-, 2,4,6,2',4',6'-, or 2,3,6,2',3',6'-hexachlorobiphenyl at 15 or 65 ppm, caused no discernible deleterious effects. The principal demonstrable histopathological lesions, bone marrow excepted, were metaplasias in some specialized epithelial structures, such as sebaceous glands, nail beds, gastric mucosa, ameloblast, and thymic corpuscles. These changes were interpreted as toxicant-induced, reversible redirection of differentiation. This aberration was wholly reversible. TCDD and 34TCB caused abortions when given in one or a few oral doses early in pregnancy. At the total doses used (1 or 5 micrograms/kg of body weight for TCDD, 3 or 0.6 mg/kg of body weight for 34TCB), maternal toxicity was frequently apparent subsequent to the abortion.

Abortion, Spontaneous↗

PubMed2004

Effect of 17beta-estradiol on hypothalamic GnRH-II gene expression in the female rhesus macaque.

The hypothalamus of rhesus macaques expresses two molecular forms of gonadotropin-releasing hormone (GnRH-I and GnRH-II). However, it is unclear whether these two neuropeptides play similar roles in the control of reproductive neuroendocrine function, especially in the context of positive and negative estrogen feedback. To address this issue, in situ hybridization histochemistry was used to compare the effect of 17beta-estradiol (E) on the expression of GnRH-I and GnRH-II mRNA in the medial basal hypothalamus (MBH) of adult female macaques. GnRH-I mRNA expression was found to be significantly (P<0.01) more abundant in ovariectomized (ovx) animals compared with ovariectomized E-treated (ovx+E) animals. In marked contrast, GnRH-II mRNA expression was found to be significantly (P<0.05) more abundant in ovx+E animals than in the ovx animals. To help elucidate how E exerts this stimulatory action on GnRH-II gene expression, hypothalamic sections were subsequently double labeled using a combination of immunohistochemisty for estrogen receptor (ER) -alpha or -beta and in situ hybridization histochemistry for GnRH-II. Approximately 50% of the GnRH-II positive cells in the MBH were found to express ERbeta, but none expressed ERalpha. Taken together, these data give credence to a novel pathway by which E may control the primate neuroendocrine reproductive axis, one that involves stimulation of GnRH-II release via an ERbeta-mediated mechanism.

Animals↗

PubMed2000

One-round determination of seven leukocyte subsets in rhesus macaque blood by flow cytometry.

BACKGROUND: Rhesus macaques are frequently used in biomedical research as experimental models for studying infectious diseases and for preclinical vaccination trials. The infection of these monkeys with simian immunodeficiency viruses (SIV) or simian-human immunodeficiency viruses (SHIV) reproduces the clinical and immunological characteristics of human infection by human immunodeficiency virus (HIV). Evolution of the immune response in the infected animals is generally analyzed by determining the lymphocyte subsets on blood samples using flow cytometry but requiring multiple, blood consuming, determinations. METHODS: Cell subsets present in whole-blood samples were labeled with a combination of anti-human monoclonal antibodies to CD2, CD20, CD4, CD8, and CD14 coupled to FITC or PE and analyzed by flow cytometry. RESULTS: In one round, we obtained the precise determination of macaque blood cell composition by flow cytometry. Monocytes, granulocytes, eosinophils, B lymphocytes, helper, and cytotoxic T lymphocytes were distinguished. Results obtained correlated strongly with those obtained with conventional blood cell differential systems and with separate staining of lymphocytes. The analysis of blood from healthy rhesus macaques and SHIV-infected animals demonstrated the accuracy of the determination even in very pathological situations such as macaques with simian AIDS. CONCLUSIONS: Our method allows fast determination of the blood cell composition and will be particularly useful to evaluate the cell subset evolution of macaques involved in large-scale experimental trials.

Animals↗

PubMed1980

Thoracic radiography of the normal rhesus macaque (Macaca mulatta).

Thoracic radiographs of rhesus macaques should be performed with short exposure times (1/60 s or faster) and the patient in the erect position. The patient's neck should be extended dorsally, and the arms extended above and behind the head. The tracheobronchial and lobar pulmonary anatomic features of the rhesus macaque are similar to those of the dog. The pulmonary parenchymal pattern also is similar; however, the interstitial markings are somewhat more prominent in the macaque. This may be due to lung mite infestation. The macaque does not appear from a radiologic standpoint to be superior as an animal model to dogs or cats unless there is something specific about the response or susceptibility to a disease being studied.

Animals↗

PubMed2006

Coat condition, housing condition and measurement of faecal cortisol metabolites--a non-invasive study about alopecia in captive rhesus macaques (Macaca mulatta).

BACKGROUND: Previous studies have characterized alopecia in captive rhesus macaques (Macaca mulatta) by a mixed partial to complete alopecia in a bilateral symmetric pattern. METHODS: In this study, coat condition assessments were related to exogenous and endogenous factors in captive rhesus macaques under different housing conditions in order to identify disturbances in environmental factors controlling or influencing hair growth. Additionally, the degree of alopecia was investigated in relation to adrenal endocrine function as an indicator of social stress using faecal glucocorticoid measurements. RESULTS: Hair loss was found to vary with season and sex, was most pronounced in adult females during the winter and spring months. Generally, infants were not affected, but alopecia developed during adolescence. However, the housing system, available enclosure space and variations in group size and composition also appeared to influence coat condition. Levels of immunoreactive cortisol metabolites (11-oxoetiocholanolone) in faeces were significantly negatively correlated with alopecia, suggesting a relationship between hypothalamic-pituitary-adrenal (HPA) axis activity and hair loss in captive rhesus macaques. CONCLUSIONS: Although the present study demonstrates the influence of the HPA axis on coat condition, it is not known if hair loss is caused by abnormal behaviour or hormonal imbalances of the HPA axis itself. Our data suggest that alopecia in rhesus macaques is a highly complex multicausal disorder.

Aging↗

PubMed2003

The CD1d natural killer T-cell antigen presentation pathway is highly conserved between humans and rhesus macaques.

Natural killer T (NKT) cells play an important role in controlling cancers, infectious diseases and autoimmune diseases. Although the rhesus macaque is a useful primate model for many human diseases such as infectious and autoimmune diseases, little is known about their NKT cells. We analyzed V alpha 24TCR+ T cells from rhesus macaque peripheral blood mononuclear cells stimulated with alpha-galactosylceramide (alpha-GalCer) and interleukin-2. We found that rhesus macaques possess V alpha 24TCR+ T cells, suggesting that recognition of alpha-GalCer is highly conserved between rhesus macaques and humans. The amino acid sequences of the V-J junction for the V alpha 24TCR of rhesus macaque and human NKT cells are highly conserved (93% similarity), and the CD1d alpha1-alpha2 domains of both species are highly homologous (95.6%). These findings indicate that the rhesus macaque is a useful primate model for understanding the contribution of NKT cells to the control of human diseases.

Amino Acid Sequence↗

PubMed2004

Rhesus macaque antibody molecules: sequences and heterogeneity of alpha and gamma constant regions.

Rhesus macaques (Macaca mulatta) are extensively used in vaccine development. Macaques infected with simian immunodeficiency viruses (SIV) or simian-human immunodeficiency viruses (SHIV) are the best animal model currently available for acquired-immune-deficiency-syndrome-related studies. Recent results emphasize the importance of antibody responses in controlling HIV and SIV infection. Despite the increasing attention placed on humoral immunity in these models, very limited information is available on rhesus macaque antibody molecules. Therefore, we sequenced, cloned and characterized immunoglobulin gamma (IGHG) and alpha (IGHA) chain constant region genes from rhesus macaques of Indian and Chinese origin. Although it is currently thought that rhesus macaques express three IgG subclasses, we identified four IGHG genes, which were designated IGHG1, IGHG2, IGHG3 and IGHG4 on the basis of sequence similarities with the four human genes encoding the IgG1, IgG2, IgG3 and IgG4 subclasses. The four genes were expressed at least at the messenger RNA level, as demonstrated by real-time reverse transcription polymerase chain reaction (RT-PCR). The level of intraspecies heterogeneity was very high for IGHA genes, whereas IGHG genes were remarkably similar in all animals examined. However, single amino acid substitutions were present in IGHG2 and IGHG4 genes, indicating the presence of IgG polymorphism possibly resulting in the expression of different allotypes. Two IgA alleles were identified in several animals and RT-PCR showed that both alleles may be expressed. Presence of immunoglobulin gene polymorphism appears to reflect the unusually high levels of intraspecies heterogeneity already demonstrated for major histocompatibility complex genes in this non-human primate species.

Amino Acid Sequence↗

PubMed1994

Expansion and contraction of rhesus macaque DRB regions by duplication and deletion.

Previous sequence analysis of the rhesus macaque MHC (MhcMamu) class II DRB region has allowed the detection of at least 34 alleles belonging to different lineages. In this communication, 36 new Mamu-DRB alleles are reported. The gene content of the DRB region has been determined for several homozygous animals of consanguineous origin. As in other primates, the number of DRB genes present per haplotype is not constant, varying from two to six genes in rhesus macaques. Six major groups of DRB haplotypes have been defined in our rhesus macaque colony. Two haplotype groups were found to carry, as well as other Mamu-DRB genes, two genes that cluster into distinct HLA-DRB1 lineages. In one of these two groups, a haplotype harbors another two sets of DRB alleles that belong to the Mhc-DRB6 and -DRB*W6 lineages, respectively. Such a haplotype was probably generated by duplication, and our data suggest that after this particular expansion of the DR region, one of the duplicated Mamu-DRB6 alleles was the target of an Alu insertion. Although certain transspecies allelic lineages are evolutionarily stable, and have been conserved for at least 36 million years, the rhesus macaque class II haplotypes differ significantly from those found in humans, chimpanzees, and gorillas. Mhc-DRB regions are therefore comparatively unstable over longer evolutionary time spans, with regard to both the number of genes and the gene content, and must have been subjected to expansion and contraction.

Alleles↗

PubMed1991

Serum cortisol concentrations of single-housed and isosexually pair-housed adult rhesus macaques.

Possible social distress was evaluated in 20 adult rhesus macaques housed in compatible isosexual pairs (5 female pairs, 5 male pairs) for the purpose of social environmental enrichment. Serum cortisol concentrations of paired animals were compared with serum cortisol concentrations of individually housed adult rhesus macaques of both sexes (5 females, 5 males). In both sexes, cortisol concentrations of paired animals (means 10 females = 19.5 +/- 2.9 micrograms/dl; means 10 males = 17.5 +/- 4.6 micrograms/dl) showed no significant difference (p always greater than 0.1) with those of single animals (means 5 females = 20.5 +/- 2.1 micrograms/dl; means 5 males = 15.9 +/- 2.6 micrograms/dl). Both in male and in female pairs, dominant partners had cortisol concentrations that were equivalent to those of their subordinate counterparts. It was concluded that neither female nor male adult rhesus macaques experience more distress when sharing a cage with a compatible partner of the same sex than when living alone.

Animals↗

PubMed2005

Birth of rhesus macaque (Macaca mulatta) infants after in vitro fertilization and gestation in female rhesus or pigtailed (Macaca nemestrina) macaques.

A study was conducted to assess the possibility of using pigtailed macaques (Macaca nemestrina) as recipients for rhesus macaque (Macaca mulatta) embryos. A total of 250 oocytes were collected from 11 rhesus monkeys during 12 follicular aspirations. We performed 15 embryo transfers with two embryos each into rhesus recipients, which resulted in eight pregnancies, of which two were lost during the second trimester. Among the remaining six pregnant rhesus macaques, two were carrying twins, resulting in the birth of eight infants. Twelve transfers of rhesus embryos into pigtailed macaques resulted in one pregnancy and the birth of one infant. Fetal growth and development were monitored by monthly ultrasound examinations, during which biparietal measurements were taken and compared with those derived from 22 pregnant control monkeys. In vitro fertilization-derived singletons tended to develop faster than did twins and naturally conceived control singletons during the initial months of pregnancy and weighed more at birth than did twins. There were pronounced morphologic changes in the placenta of the rhesus that developed in the female pigtailed macaque. These included an irregular shape, elevated placenta-to-birth-weight ratio, and an abnormal length and diameter of the umbilical cord. Histologic analyses of the rhesus-pigtailed placenta showed evidence of maternal-placental floor infarction and thrombosis of the spiral artery with resulting infarction of the villi. These results demonstrate that pigtailed macaques can carry rhesus fetuses to term, but further studies are necessary to determine the cause of the decreased pregnancy rates and observed placental abnormalities.

Animals↗

PubMed1997

An adenovirus-simian immunodeficiency virus env vaccine elicits humoral, cellular, and mucosal immune responses in rhesus macaques and decreases viral burden following vaginal challenge.

Six female rhesus macaques were immunized orally and intranasally at 0 weeks and intratracheally at 12 weeks with an adenovirus type 5 host range mutant (Ad5hr)-simian immunodeficiency virus SIVsm env recombinant and at 24 and 36 weeks with native SIVmac251 gp120 in Syntex adjuvant. Four macaques received the Ad5hr vector and adjuvant alone; two additional controls were naive. In vivo replication of the Ad5hr wild-type and recombinant vectors occurred with detection of Ad5 DNA in stool samples and/or nasal secretions in all macaques and increases in Ad5 neutralizing antibody in 9 of 10 macaques following Ad administrations. SIV-specific neutralizing antibodies appeared after the second recombinant immunization and rose to titers > 10,000 following the second subunit boost. Immunoglobulin G (IgG) and IgA antibodies able to bind gp120 developed in nasal and rectal secretions, and SIV-specific IgGs were also observed in vaginal secretions and saliva. T-cell proliferative responses to SIV gp140 and T-helper epitopes were sporadically detected in all immunized macaques. Following vaginal challenge with SIVmac251, transient or persistent infection resulted in both immunized and control monkeys. The mean viral burden in persistently infected immunized macaques was significantly decreased in the primary infection period compared to that of control macaques. These results establish in vivo use of the Ad5hr vector, which overcomes the host range restriction of human Ads for rhesus macaques, thereby providing a new model for evaluation of Ad-based vaccines. In addition, they show that a vaccine regimen using the Ad5hr-SIV env recombinant and gp120 subunit induces strong humoral, cellular, and mucosal immunity in rhesus macaques. The reduced viral burden achieved solely with an env-based vaccine supports further development of Ad-based vaccines comprising additional viral components for immune therapy and AIDS vaccine development.

Adenoviruses, Human↗

PubMed1998

Localization of persistent Enterocytozoon bieneusi infection in normal rhesus macaques (Macaca mulatta) to the hepatobiliary tree.

Enterocytozoon bieneusi is the most common microsporidian parasite recognized in human patients with AIDS. Recently, we identified a virtually identical organism causing a spontaneous infection associated with hepatobiliary and intestinal disease in simian immunodeficiency virus (SIV)-infected macaques. To examine the natural history of the infection, we examined captive rhesus macaques for E. bieneusi by PCR, in situ hybridization, and cytochemical techniques. PCR performed on fecal DNA detected enterocytozoon infection in 22 (16.7%) of 131 normal rhesus macaques (Macaca mulatta), compared to 18 (33.8%) of 53 rhesus macaques experimentally inoculated with SIV. In normal rhesus macaques, persistence of infection was demonstrated for up to 262 days and was usually not associated with clinical signs. In six of seven normal rhesus animals, E. bieneusi was detected by PCR in bile obtained through percutaneous cholecystocentesis but not by in situ hybridization performed on endoscopic biopsies of duodenum and proximal jejunum.

Animals↗

PubMed2001

Protection from immunodeficiency virus challenges in rhesus macaques by multicomponent DNA immunization.

Multicomponent DNA vaccines were used to elicit immune responses, which can impact viral challenge in three separate rhesus macaque models. Eight rhesus macaques were immunized with DNA vaccines for HIV env/rev and SIV gag/pol and were challenged intravenously with 10 animal infective doses (AID(50)) of cell-free SHIV IIIB. Three of eight immunized rhesus macaques were protected, exhibiting no detectable virus. Animals protected from nonpathogenic SHIVIIIB challenge were rested for extended periods of time and were rechallenged first with pathogenic SIV(mac239) and subsequently with pathogenic SHIV89.6P viruses. Following the pathogenic challenges, all three vaccinated animals were negative for viral coculture and antigenemia and were negative by PCR. In contrast, the control animals exhibited antigenemia by 2 weeks postchallenge and exhibited greater than 10 logs of virus/10(6) cells in limiting dilution coculture. The control animals exhibited CD4 cell loss and developed SIV-related wasting with high viral burden and subsequently failed to thrive. Vaccinated animals remained virus-negative and were protected from the viral load, CD4 loss, disease, and death. We observed strong Th1-type cellular immune responses in the protected macaques throughout the study, suggesting their important roles in protection. These studies support the finding that multicomponent DNA vaccines can directly impact viral replication and disease in a highly pathogenic challenge system, thus potentially broadening our strategies against HIV.

AIDS Vaccines↗