PRO 2000 elicits a decline in genital tract immune mediators without compromising intrinsic antimicrobial activity

Keller, Marla J.; Guzman, Esmeralda; Hazrati, Ehsan; Kasowitz, Andrea; Cheshenko, Natalia; Wallenstein, Sylvan; Cole, Amy L.; Cole, Alexander M.; Profy, Albert T.; Wira, Charles R.; Hogarty, Kathleen; Herold, Betsy C.

doi:10.1097/qad.0b013e328013d9b5

Cited by 120 publications

(153 citation statements)

References 31 publications

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“…That uterine hormone-induced protection is crucial to reproductive health is further supported by the findings at midcycle, when E 2 levels are elevated, that cervical-vaginal concentrations of antimicrobials as well as cytokines/ chemokines decline by 10-to 100-fold. 31 In addition to preparing the upper FRT for implantation, our findings of enhanced antimicrobial production in the uterus further suggest that midcycle secretions from the Fallopian tubes and uterus, by draining into the cervix and vagina, provide innate protection to the lower FRT when local immune protection is suppressed.…”

Section: Discussionmentioning

confidence: 70%

“…[27][28][29][30] We and others have found that a number of cytokines, chemokines, and antimicrobials in cervical-vaginal lavage vary with stage of the menstrual cycle. 31,32 Relative to that measured during the early proliferative and late secretory phases of the menstrual cycle, concentrations of SLPI, defensins, IL-8, and so on are lowest at midcycle when ovulation occurs and estradiol levels are known to be elevated. In studies with isolated polarized epithelial cells, we previously demonstrated that apical secretions from polarized human UECs from the premenopausal women, but not from postmenopausal women, were antibacterial against both Gram-positive and Gram-negative bacteria; antibacterial activity was partially neutralized with antibody to SLPI.…”

Section: Introductionmentioning

confidence: 98%

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Estradiol selectively regulates innate immune function by polarized human uterine epithelial cells in culture

et al. 2008

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The goal of this study was to examine the role of E 2 in regulating innate immune protection by human uterine epithelial cells (UECs). Recognizing that UECs produce cytokines and chemokines to recruit and activate immune cells as well as viral and bacterial antimicrobials, we sought to examine the effect of E 2 on constitutive and Toll-like receptor (TLR) agonist (lipopolysaccharide (LPS) and poly (I:C))-induced immune responses. The secretion by polarized UECs in culture of interleukin (IL)-6, macrophage inhibitory factor (MIF), and secretory leukocyte protease inhibitor (SLPI) was examined as well as the mRNA expression of human β-defensin-2 (HBD2), tumor necrosis factor (TNF)-α, IL-8, and nuclear factor (NF)-kB. When incubated with E 2 for 24-48 h, we found that E 2 stimulated UEC secretion of SLPI (fourfold) and mRNA expression of HBD2 (fivefold). Moreover, when antibacterial activity in UEC secretions was measured using Staphylococcus aureus, E 2 increased the secretion of soluble factor(s) with antibacterial activity. In contrast, E 2 had no effect on constitutive secretion of proinflammatory cytokines and chemokines by UECs but completely inhibited LPS-and poly (I:C)-induced secretion of MIF, IL-6, and IL-8. Estradiol also reversed the stimulatory effects of IL-1β on mRNA expression of TNF-α, IL-8, and NF-kB by 85, 95, and 70%, respectively. As SLPI is known to inhibit NF-kB expression, these findings suggest that E 2 inhibition of proinflammatory cytokines may be mediated through SLPI regulation of NF-kB. Overall, these findings indicate that the production of cytokines, chemokines, and antimicrobials by UECs are differentially regulated by E 2 . Further, it suggests that with E 2 regulation, epithelial cells that line the uterine cavity have evolved immunologically to be sensitive to viral and bacterial infections as well as the constraints of procreation.

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Section: Discussionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 98%

Estradiol selectively regulates innate immune function by polarized human uterine epithelial cells in culture

et al. 2008

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“…35 Administration of PRO 2000 resulted in no loss of anti-HSV, anti-HIV, or antibacterial activity in the CVL. 37 In this study, antiviral testing suggested that CS retained its antiviral activity in the vaginal environment for at least 8-18 h after dosing and had no apparent detrimental effect on endogenous defenses after dosing was discontinued. A limitation of our study is that we did not measure CS levels in the CVLs.…”

Section: Vaginal Safety Of Cs Hec Placebo and N-9mentioning

confidence: 99%

“…A limitation of our study is that we did not measure CS levels in the CVLs. Antiviral activity was seen to persist in the vaginal environment of PRO 2000 37 and tenofovir 40 users; in those studies, levels of drug in the CVL were measured.…”

Section: Vaginal Safety Of Cs Hec Placebo and N-9mentioning

confidence: 99%

“…36 Other nonspecific broad-spectrum anti-HIV microbicide candidates including PRO 2000, BufferGel, and Carraguard, which were not effective at preventing HIV infection in clinical trials, also showed decreases in SLPI. [37][38][39] Of note, in a 14-day study of the TFV vaginal gel, no significant effect was seen for a group of soluble mediators, including SLPI, although for statistical reasons a threshold p-value of < 0.01 rather than < 0.05 was used. 40 We have recently reported that a decrease in SLPI in cervical secretions was associated with subsequent HIV infection in a cohort of HIV-seronegative women at risk of acquiring the infection through heterosexual intercourse (unpublished data presented by Morrison et al at CROI 2012 as Paper #1052, ''Biomarkers of cervical inflammation and immunity associated with hormonal contraception, pregnancy and HIV-1 seroconversion'').…”

Section: Vaginal Safety Of Cs Hec Placebo and N-9mentioning

confidence: 99%

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Toward Early Safety Alert Endpoints: Exploring Biomarkers Suggestive of Microbicide Failure

Mauck

Lai

Weiner

et al. 2013

AIDS Research and Human Retroviruses

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TitleToward early safety alert endpoints: exploring biomarkers suggestive of microbicide failure. Several microbicides, including nonoxynol-9 (N-9) and cellulose sulfate (CS), looked promising during early trials but failed in efficacy trials. We aimed to identify Phase I mucosal safety endpoints that might explain that failure. In a blinded, randomized, parallel trial, 60 healthy premenopausal sexually abstinent women applied Universal HEC placebo, 6% CS or 4% N-9 gel twice daily for 13½ days. Endpoints included immune biomarkers in cervicovaginal lavage (CVL) and endocervical cytobrushes, inflammatory infiltrates in vaginal biopsies, epithelial integrity by naked eye, colposcopy, and histology, CVL anti-HIV activity, vaginal microflora, pH, and adverse events. Twenty women enrolled per group. Soluble/cellular markers were similar with CS and placebo, except secretory leukocyte protease inhibitor (SLPI) levels decreased in CVL, and CD3 + and CD45 + cells increased in biopsies after CS use. Increases in interleukin (IL)-8, IL-1, IL-1RA, and myeloperoxidase (MPO) and decreases in SLPI were significant with N-9. CVL anti-HIV activity was significantly higher during CS use compared to N-9 or placebo. CS users tended to have a higher prevalence of intermediate Nugent score, Escherichia coli, and Enterococcus and fewer gram-negative rods. Most Nugent scores diagnostic for bacterial vaginosis were in N-9 users. All cases of histological inflammation or deep epithelial disruption occurred in N-9 users. While the surfactant N-9 showed obvious biochemical and histological signs of inflammation, more subtle changes, including depression of SLPI, tissue influx of CD45 + and CD3 + cells, and subclinical microflora shifts were associated with CS use and may help to explain the clinical failure of nonsurfactant microbicides.

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Clinical Safety and Pharmacology Trial

Mauck

Thurman

Schwartz

2013

Current Topics in Microbiology and Immunology

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Guidelines for establishing clinical safety of microbicides in early clinical studies have evolved significantly since the first trials. In addition, because of the difficulty of establishing efficacy of a microbicide prior to Phase III testing, there has been an increasing emphasis on establishing pharmacokinetic (PK)/pharmacodynamic (PD) relationships using genital samples collected in vivo in Phase I studies. A healthy pipeline is critical to success; however, it is unlikely that the majority of microbicide candidates will progress to clinical testing. Those that do enter clinical testing may have different mechanisms of action than early candidates. Given this, drug-specific modifications for early clinical assessment will need to be considered. These emerging issues associated with early clinical trials of microbicides will be reviewed, along with recommendations for future clinical safety and PK/PD evaluation.

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PRO 2000 elicits a decline in genital tract immune mediators without compromising intrinsic antimicrobial activity

Abstract: In contrast to experience with nonoxynol-9, PRO 2000 did not trigger an inflammatory response in cervicovaginal secretions. There was a modest reduction in mucosal immune mediators, but this loss was not associated with a reduction in intrinsic antimicrobial activity.

Cited by 120 publications

References 31 publications

Estradiol selectively regulates innate immune function by polarized human uterine epithelial cells in culture

Estradiol selectively regulates innate immune function by polarized human uterine epithelial cells in culture

Toward Early Safety Alert Endpoints: Exploring Biomarkers Suggestive of Microbicide Failure

Clinical Safety and Pharmacology Trial

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