Neutrophil chemotaxis in rhesus macaques (Macaca mulatta).

Chemotactic responses of isolated peripheral blood neutrophils from rhesus macaques (Macaca mulatta) were studied, using a micropore filter method. Cell migration toward zymosan-activated serum was similar to that of human cells, whereas the response to N-formyl methionyl leucyl phenylalanine (FMLP) was weaker than was that in human cells, requiring higher concentrations of FMLP for maximal migration. Optimal FMLP concentrations for attraction of rhesus neutrophils and human neutrophils were 5.0 X 10(-7)M and 1.0 X 10(-8)M, respectively. The chemotactic responses of the 2 neutrophils to complement (zymosan-activated serum) were similar. However, rhesus neutrophils required a higher concentration of the formyl peptide, FMLP, for maximal migratory response.

Genetic differences in oxygen toxicity are correlated with cytochrome P-450 inducibility.

Susceptibility to oxygen toxicity was studied in three inbred and two hybrid strains of mice. Because in vitro studies have shown that the cytochrome P-450 enzymes can produce oxygen radicals and H2O2, we tested the hypothesis that inducibility of these enzymes might play a role in oxygen toxicity. Mice responsive to hepatic microsomal enzyme induction by aromatic hydrocarbons [C3H/HeJ, C3H/HeN, C3H/HeJ X DBA/2J (designated C3D2F1/J), C3H/HeN X DBA/2J (designated C3D2F1/N)] were more sensitive to the toxic effects of 100% oxygen exposure than were genetically unresponsive mice (DBA/2J). DBA/2J mice survived significantly longer exposure periods with less lung damage. Lung and liver cytochrome P-450 levels increased 2-to 3-fold in C3H and F1 mice during 100% oxygen exposure (maximum levels at 72-96 hr) and subsequently fell prior to death. No increases were seen in cytochrome P-450 levels in DBA/2J mice. Metabolic pathways involving cytochrome P-450 enzymes may initiate or modulate oxidative damage due to oxygen radicals. The difference in responsiveness of mice to microsomal enzyme induction may imply genetic differences in susceptibility to oxidative stress, may help to explain species differences in susceptibility, and may have long-term implications in therapeutics and patient care if similar inherited differences exist in humans.

Animal chamber for in vivo testing of toxic gases.

A closed-circuit chamber system for exposing animals to toxic concentrations of oxygen or nitrogen was designed and built. The facility was equipped with systems for the removal of carbon dioxide, ammonia, methane, water vapor, and particulates from the gas stream. Integral systems were built to monitor and control temperature (+/- 1 degree C), relative humidity (+/- 2%), oxygen concentration (10 to 100% +/- 0.5%), and methane concentration (below 2%). Operation was set at standard pressure (1.0 X 10(5) Newtons/m2). Hyperoxic studies have been performed on six species of rodents, as well as sheep, and have lasted from 1 to 28 days.

Effects of synthetic ovine CRF on ACTH, cortisol and blood pressure in sheep.

Intravenously administered synthetic ovine CRF at doses of 0.1, 1.0 and 10.0 micrograms/kg increased plasma ACTH and cortisol concentrations in a dose-dependent fashion in unanesthetized sheep. In two unanesthetized sheep, aortic blood pressure remained relatively unaffected after the intravenous administration of CRF at 5 and 20 micrograms/kg. These results suggest that peripherally administered ovine synthetic CRF specifically stimulates the sheep pituitary-adrenal axis. Unlike other species receiving intravenous synthetic ovine CRF, sheep did not show hypotensive effects.

Evaluation of a killed phase I Coxiella burnetii vaccine in cynomolgus monkeys (Macaca fascicularis).

The protective efficacy of a killed, purified, phase I Coxiella burnetii vaccine was tested in cynomolgus monkeys. Monkeys vaccinated once with 30 micrograms of the antigen were challenged 6 or 12 months later with virulent phase I rickettsiae administered in small-particle aerosols. The vaccine provided only partial protection, since some of the challenged monkeys developed clinical signs of illness. However, the vaccinated animals did not develop pneumonia as determined by radiographic evaluation nor any hematologic or chemical changes except for an increase in fibrinogen. Although rickettsiae were isolated from peripheral blood in vaccinated monkeys, the rickettsemia persisted for only 1-2 days; whereas, organisms were recovered from unvaccinated animals for 6-7 days. All vaccinated animals had circulating microagglutinating antibodies to phase I and phase II antigens 6 and 12 months after vaccination.

Prevalence of rickettsial antibody and cell-mediated reaction in cynomolgus monkeys (Macaca fascicularis).

Serologic studies on feral, colony-held cynomolgus monkeys indicated that 61% reacted to Coxiella burnetii antigens, and 36% reacted to Rickettsia conorii antigens. The results suggest that a high percentage of cynomolgus monkeys have been exposed to these organisms.

Epidemic typhus infection in cynomolgus monkeys (Macaca fascicularis).

A nonhuman primate model of clinical Rickettsia prowazekii infections was developed in cynomolgus monkeys (Macaca fascicularis). Monkeys infected intravenously with 10(7) plaque-forming units developed clinical signs of illness and pathological changes characteristic of epidemic typhus infection in humans. Increases in total leukocyte counts, serum alkaline phosphatase, blood urea nitrogen, and serum glutamic pyruvate transaminase values were observed. Microscopic examination revealed typical typhus nodules in the brains of two monkeys that died. These data indicated that the cynomolgus monkey is a suitable model for study of the pathogenesis of epidemic typhus infection and may prove valuable in the evaluation of candidate R. prowazekii vaccines.

Electrocardiograms of nine species of nonhuman primates sedated with ketamine.

Electrocardiograms were studied in nine species of nonhuman primates sedated with ketamine hydrochloride. Electrocardiographic values were similar in all species although heart rate and other rate-related values (QT and PR intervals) were species-dependent. Arrhythmias were infrequent. Ketamine hydrochloride did not appear to induce marked alterations in the ECG of primates.

Evaluation of a killed Rocky Mountain spotted fever vaccine in cynomolgus monkeys.

A nonhuman primate model of Rocky Mountain spotted fever infection was developed in cynomolgus monkeys (Macaca fascicularis) infected by the subcutaneous route or by aerosol. Clinical responses, hematology and serum chemistry values, and pathological findings were similar to those found in humans ill with Rocky Mountain spotted fever. The clinical model was then used to test the efficacy of a killed Rocky Mountain spotted fever vaccine grown in chicken embryo cells. Monkeys were immunized with varying dilutions of the vaccine with a two-dose schedule and then challenged at 2 months with virulent Rickettsia rickettsii by the subcutaneous route or by aerosol. The undiluted vaccine totally protected monkeys against both challenges, even at extremely high doses.

Suppression of PHA-stimulated lymphocyte transformation in cynomolgus monkeys following infection with Coxiella burnetii.

Phytohemagglutin (PHA) induced blastogenesis of peripheral blood lymphocytes from cynomolgus monkeys infected with C. burnetii was suppressed between 14 and 28 days after infection. Lymphocytes became responsive to PHA again on day 35 with an increase in stimulation index when cultured with specific antigens. In contrast, production of specific humoral antibodies was not diminished during the acute and early convalescent stages of infection.

Cynomolgus monkey model for experimental Q fever infection.

A subhuman primate model was developed for study of the pathogenesis of infection with Coxiella burnetii. Cynomolgus monkeys (Macaca fascicularis) that were exposed to 10(5) mouse median infectious intraperitoneal doses of C. burnetii in a small-particle aerosol developed clinical signs of illness and pathologic changes characteristic of Q fever infection in humans. All monkeys had radiologic evidence of pneumonia by day 9. Antibodies to C. burnetii were detectable by the indirect fluorescent antibody test by day 7. These data indicate that the cynomolgus monkey is a suitable model for study of the pathogenesis of Q fever infection and may prove valuable in the evaluation of C. burnetii vaccines.