A comprehensive murine model to evaluate topical vaginal microbicides: mucosal inflammation and susceptibility to genital herpes as surrogate markers of safety.
A critical gap in microbicide development is the absence of surrogate safety markers. The objective of the present study was to develop a murine model to examine the mucosal response to microbicides and to assess the functional implication of observed changes. Mice received 14 daily intravaginal doses of nonoxynol-9, PRO 2000, or placebo gel. Nonoxynol-9 induced an inflammatory response characterized by increases in levels of cytokines and chemokines, recruitment of neutrophils and monocytes into the genital tract, and activation of the transcription factors NF- kappa B and activator protein-1. Minimal inflammation was observed in response to 2% PRO 2000. Nonoxynol-9-treated mice were significantly more susceptible to challenge with a low dose of herpes simplex virus type 2; the response of PRO 2000-treated mice was similar to the response to placebo. These findings suggest that PRO 2000 has little deleterious effect on mucosal immunity and, if validated by clinical experiences, support the inclusion of this model in the preclinical evaluation of future candidate microbicides.
Galen
Benjamin T
BT
Department of Pediatrics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Martin
Andrea P
AP
Hazrati
Ehsan
E
Garin
Alexandre
A
Guzman
Esmeralda
E
Wilson
Sarah S
SS
Porter
David D
DD
Lira
Sergio A
SA
Keller
Marla J
MJ
Herold
Betsy C
BC
D000282:Administration, Intravaginal; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000009:adverse effects; D004198:Disease Susceptibility; D005260:Female; D006558:Herpes Genitalis / Q000517:prevention & control* / Q000635:transmission / Q000821:virology; D051379:Mice; D023421:Models, Animal; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D017137:Nonoxynol / Q000008:administration & dosage* / Q000009:adverse effects; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015229:Sexually Transmitted Diseases, Viral / Q000517:prevention & control / Q000635:transmission / Q000821:virology; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000235:genetics; D014621:Vagina / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D014622:Vaginal Creams, Foams, and Jellies / Q000008:administration & dosage / Q000009:adverse effects; D014627:Vaginitis / Q000139:chemically induced / Q000473:pathology
D000890:Anti-Infective Agents; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014622:Vaginal Creams, Foams, and Jellies; D017137:Nonoxynol