Non-human primates: a model for tuberculosis research.

A variety of animals have been used for tuberculosis research, and each animal model has its strengths and weaknesses. We sought to develop a non-human primate model of tuberculosis to model aspects of human tuberculosis that are difficult to model in other animals, including the pathology in the lungs, various progression to disease, and immunologic correlates of infection or disease that are likely to be similar in humans. To date, we have infected 17 cynomolgus macaques (Macaca fasicularis) with a low dose (15-25CFU) of Mycobacterium tuberculosis strain Erdman. The monkeys were grouped into three categories on the basis of disease progression: rapid progression (advanced disease by 3 months post-infection), active/chronic infection (signs of disease but a slower progression), and latent infection (no signs of clinical disease). Animals were followed clinically post-infection, including blood work, physical examinations, serial bronchoalveolar lavage (BAL) and gastric aspirates for M. tuberculosis culture, chest radiographs, and tuberculin reactivity. Immunologic assays on cells from blood, BAL fluid, and tissue, have been performed, including proliferation, flow cytometry, ELIspot assays, cytotoxic T lymphocyte (CTL) assays, and ELISAs. The spectrum of disease observed in these monkeys is similar to humans, and this model may be very useful for studying pathogenesis and immunology of tuberculosis, as well as testing vaccines, diagnostic reagents, and drugs prior to use in human populations.

Herpesvirus-mediated systemic delivery of nerve growth factor.

Sustained systemic dissemination of therapeutic proteins from peripheral sites is an attractive prospect for gene therapy applications. Replication-defective genomic herpes simplex virus type 1 (HSV-1) vectors were evaluated for their ability to express nerve growth factor (NGF) as a model gene product both locally and systemically. Intra-articular inoculation of NGF expression vectors in rabbits resulted in significant increases in joint lavage and blood plasma NGF that persisted for 1 year. A rhesus macaque injected intra-articularly displayed a comparable increase in plasma NGF for at least 6 months, at which time the serum NGF levels of this animal were sufficient to cause differentiation of PC12 cells in culture, but not to increase footpad epidermis innervation. Long-term reporter transgene expression was observed primarily in ligaments, a finding confirmed by direct inoculation of patellar ligament. Patellar ligament inoculation with a NGF vector resulted in elevated levels of circulating NGF similar to those observed following intra-articular vector delivery. These results represent the first demonstration of sustained systemic release of a transgene product using HSV vectors, raising the prospect of new applications for HSV-1 vectors in the treatment of systemic disease.

Cardiovascular, respiratory, thermoregulatory, sedative, and analgesic effects of intravenous administration of medetomidine in rhesus macaques (Macaca mulatta).

BACKGROUND AND PURPOSE: Medetomidine is a selective, specific, and potent alpha2-adrenergic receptor agonist that has been utilized successfully as a sedative/analgesic agent in a variety of domestic and nondomestic animals. The objective of this study was to document the physiological effects of the intravenous administration of medetomidine in rhesus macaques (Macaca mulatta). METHODS: Fifteen healthy rhesus macaques (Macaca mulatta), 5 to 15 years old and weighing 5.5 to 11.8 kg, were given four dosages of medetomidine (50, 100, 150, and 200 microg/kg of body weight) intravenously, and cardiovascular, respiratory, thermoregulatory, sedative, and analgesic effects were determined. RESULTS: All four doses of medetomidine induced a similar and significant decrease in mean arterial pressure, as well as a transient but significant increase in respiratory rate followed by a longer-lasting significant decrease. Bradycardia, hypotension, and loss of thermoregulatory ability accompanied by a biphasic respiratory response and inconsistent sedation, analgesia, and muscular relaxation were observed. Heart rate decrease was rapid for all doses, but was significantly lower and of shorter duration after administration of the 50 microg/kg dosage. CONCLUSION: The inconsistency of the anesthetic plane induced by intravenous administration of medetomidine precludes it from being used alone to sedate rhesus macaques.