The transduction of rat submandibular glands by an adenoviral vector carrying the human growth hormone gene is associated with limited and reversible changes at the infusion site.
Adenoviral vectors have been shown to efficiently deliver exogenous genes to salivary glands and have therefore been investigated as tools for the treatment of human disease. The purpose of this study was to evaluate the response of F344 rats to intraductal infusion of the right submandibular salivary gland with an adenoviral vector encoding the gene for human growth hormone (AdCMVhGH). Co-administration of hydroxychloroquine (HCQ) was used to redirect the secretion of human growth hormone (hGH) from saliva into serum. This paper documents the findings of the pathology evaluation of this National Toxicology Program study. The right submandibular salivary gland (infusion site) was the primary target organ, with microscopic lesions characteristic of a mild to moderate insult observed at 3 days post infusion in vector exposed animals. These lesions were characterized by variable degrees of acute glandular inflammation, degeneration and necrosis, with more severe lesions in the higher dose groups. Rats at 28 days post infusion had milder inflammation, degeneration and necrosis compared to day 3 rats, with variable degrees of regeneration. In conclusion, the effects on the salivary glands are reversible as indicated by the milder inflammation and degeneration in the day 28 rats concomitant with mild to moderate regeneration. Therefore, the vector appears relatively innocuous with limited tissue toxicity. [The supplemental data referenced in this paper is not printed in this issue of Toxicologic Pathology. It is available as a downloadable file in the online edition of Toxicologic Pathology, 34(4). In order to access the full article online, you must have either an individual subscription or a member subscription accessed through www.toxpath.org.].
Elmore
S
S
Otsuka Maryland Research Institute, Rockville, Maryland, 20850, USA. elmore@niehs.nih.gov
Lanning
L
L
Allison
N
N
Vallant
M
M
Nyska
A
A
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D019382:Human Growth Hormone / Q000235:genetics*; D006801:Humans; D006886:Hydroxychloroquine / Q000008:administration & dosage / Q000494:pharmacology; D015994:Incidence; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D007274:Injections, Intraperitoneal; D008297:Male; D009336:Necrosis / Q000139:chemically induced / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D013363:Submandibular Gland / Q000187:drug effects / Q000378:metabolism*; D013364:Submandibular Gland Diseases / Q000139:chemically induced / Q000453:epidemiology / Q000473:pathology; D013997:Time Factors; D014161:Transduction, Genetic
D018501:Antirheumatic Agents; D019382:Human Growth Hormone; D006886:Hydroxychloroquine