Assessment of cervicovaginal cytokine levels following exposure to microbicide Nisin gel in rabbits

Topical microbicides is an emerging female controlled strategy for preventing the acquisition and transmission of STIs/HIV infections. Since they are intended for repeated vaginal and/or rectal use it is essential to validate their safety. Nisin, a naturally occurring contraceptive antimicrobial pep...

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Published in:Cytokine (Philadelphia, Pa.) Pa.), 2008-07, Vol.43 (1), p.63-70
Main Authors: Aranha, C.C., Gupta, S.M., Reddy, K.V.R.
Format: Article
Language:English
Subjects:
Animals
Anti-Infective Agents - toxicity
Biomarkers - metabolism
Cervicovaginal epithelium
Cervix Uteri - cytology
Cervix Uteri - drug effects
Cervix Uteri - metabolism
Cytokines
Cytokines - biosynthesis
Cytokines - genetics
Cytokines - metabolism
Female
Gels
Human immunodeficiency virus
Humans
Nisin
Nisin - toxicity
Rabbits
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - biosynthesis
Tissue Culture Techniques
Vagina - cytology
Vagina - drug effects
Vagina - metabolism
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Summary:Topical microbicides is an emerging female controlled strategy for preventing the acquisition and transmission of STIs/HIV infections. Since they are intended for repeated vaginal and/or rectal use it is essential to validate their safety. Nisin, a naturally occurring contraceptive antimicrobial peptide (AMP) is currently the focus of clinical trials. The present in vitro vaginal tissue explants culture studies revealed that Nisin did not effect vaginal cell viability analyzed at 15, 30, 45 and 60 min following treatment with different concentrations of Nisin gel prepared in 1% polycarbophil gel (30.3, 60.6, 121.2, 242.4 and 484.8 μM/g tissue) and SDS (0.35, 0.70, 1.4, 2.8 and 5.6 μM/g tissue) gels compared to placebo gel treated groups. The levels of various pro-inflammatory (IL-6, IL-8 and TNF-α,) and immuno-regulatory cytokines (IL-10 and GM-CSF) in the explant culture supernatants of the Nisin treated cells were unaffected. Repeated intravaginal application of high dose of Nisin gel (15,150 μM/day/14 days) on cervicovaginal epithelium was evaluated in rabbits and the results were compared with SDS treated (56 μM) and 1% polycarbophil gel (placebo) groups. We examined vaginal cell morphology, structural integrity of vaginal epithelium and local production of cytokines (PICs) in the cervicovaginal lavage (CVL) of Nisin treated animals and compared with placebo and SDS treated groups. The results demonstrated no treatment related abnormalities either in the vaginal cell morphology or structural abnormalities in the mucosal epithelium. There was no change in the cytokine levels in cervicovaginal lavage (CVL) compared to SDS gel treated animals indicating Nisin gel did not induce irritation and/or inflammation in the vaginal epithelium. CVL cytokine levels were in accordance with immunohistochemical (IHC) localization of cytokines and flow cytometric evaluation of CD45 immune cell population in cervicovaginal epithelium. The levels of cytokines in the CVLs appear to be sensitive indicators in identifying and/or screening out suitable candidate microbicides before they enter phase-1 trials. In conclusion, the lack of vaginal toxicity of Nisin gel means that it has clinical potential as a safe, prophylactic contraceptive in addition to its antimicrobial activities to curb sexual transmission of HIV in human.
ISSN:1043-4666
1096-0023
DOI:10.1016/j.cyto.2008.04.005