Semen: A modulator of female genital tract inflammation and a vector for HIV-1 transmission.

In order to establish productive infection in women, HIV must transverse the vaginal epithelium and gain access to local target cells. Genital inflammation contributes to the availability of HIV susceptible cells at the female genital mucosa and is associated with higher HIV transmission rates in women. Factors that contribute to genital inflammation may subsequently increase the risk of HIV infection in women. Semen is a highly immunomodulatory fluid containing several bioactive molecules with the potential to influence inflammation and immune activation at the female genital tract. In addition to its role as a vector for HIV transmission, semen induces profound mucosal changes to prime the female reproductive tract for conception. Still, most studies of mucosal immunity are conducted in the absence of semen or without considering its immune impact on the female genital tract. This review discusses the various mechanisms by which semen exposure may influence female genital inflammation and highlights the importance of routine screening for semen biomarkers in vaginal specimens to account for its impact on genital inflammation.

The antiviral activity of arbidol hydrochloride against herpes simplex virus type II (HSV-2) in a mouse model of vaginitis.

OBJECTIVE: HSV-2 infection has increased significantly in recent years, which is closely associated with cervical cancer and HIV infection. The lack of success in vaccine development and the emergence of drug resistance to commonly used drugs emphasize the urgent need for alternative antivirals against HSV-2 infection. Arbidol (ARB) has been demonstrated to be a broad spectrum antiviral drug that exhibits immunomodulatory properties that affect the HSV-2 life cycle. This study investigated the efficacy and mechanism of ARB against HSV-2 in vivo and in vitro to further explore the clinical application of ARB. METHODS: The efficacy of ARB on HSV-2 infection in vitro was examined by CPE and MTT assays. A vaginitis model was established to monitor changes in histopathology and inflammatory cytokine (IL-2, IL-4, TNF-α and TGF-ß) expression by H&E staining and ELISA, respectively, and the efficacy of ARB was evaluated accordingly. Furthermore, flow cytometry was used to determine the ratio of CD4+/CD8+ T cells in the peripheral blood of the vaginitis animals. Considering the balance of efficacy and pharmacokinetics, ARB ointment was strictly prepared to observe formulation efficacy differences compared to the oral dosing form. RESULTS: The results showed that, in vitro, the TC50 and IC50 of ARB were 32.32 µg/mL and 4.77 µg/mL (SI = 6.82), respectively, indicating that ARB presents effective activity against HSV-2 in a dose-dependent manner. The results of the time-course assay suggested that 25 µg/mL ARB affected the late stage of HSV-2 replication. However, ARB did not inhibit viral attachment or cell penetration. The in vivo results showed that ARB ointment can improve the survival rate, prolong the survival time and reduce the reproductive tract injury in mice infected with HSV-2, regulate cytokine expression; and balance the CD4+ and CD8+ T lymphocyte ratio in the peripheral blood to participate in the regulation of immune response. CONCLUSION: ARB showed anti-HSV-2 activity in vitro in a dose-dependent manner and played a role in inhibiting the late replication cycle of the virus. The vaginitis model was successfully established, according to immunomodulation outcomes, responded better to ARB in ointment form than in oral form.

Effects of Bone Marrow Multipotent Mesenchymal Stromal Cells and Their Secretion Products on the Cellular Composition of the Thymus and Spleen of Female Wistar Rats with Experimental Chronic Inflammation of the Internal Genitals.

The effects of bone marrow multipotent mesenchymal stromal cells and their secretion products on the subpopulation composition of thymic and splenic lymphocytes were studied in female Wistar rats with experimental chronic inflammatory process in the internal genitals. Stromal cells and medium conditioned by these cells in different administration routes (intravenous or lymphotropic injection) produces different modulating effect on blood leukocyte count and on subpopulation composition of the splenic and thymic lymphocytes. The most manifest anti-inflammatory effect was observed after lymphotropic injection of multipotent mesenchymal stromal cells creating a high concentration and long persistence of the factors produced by these cells in the focus of inflammation.

Evaluation of immunological markers of ovine vaginal irritation: Implications for preclinical assessment of non-vaccine HIV preventive agents.

The presence of genital inflammatory responses and a compromised vaginal epithelial barrier have been linked to an increased risk of HIV acquisition. It is important to assure that application of candidate microbicides designed to limit HIV transmission will not cause these adverse events. We previously developed high resolution in vivo imaging methodologies in sheep to assess epithelial integrity following vaginal application of a model microbicide, however characterization of genital inflammation in sheep has not been previously possible. In this study, we significantly advanced the sheep model by developing approaches to detect and quantify inflammatory responses resulting from application of a nonoxynol-9-containing gel known to elicit vaginal irritation. Vaginal application of this model microbicide resulted in foci of disrupted epithelium detectable by confocal endomicroscopy. Leukocytes also infiltrated the treated mucosa and the number and composition of leukocytes obtained by cervicovaginal lavage (CVL) were determined by differential staining and flow cytometry. By 18h post-treatment, a population comprised predominantly of granulocytes and monocytes infiltrated the vagina and persisted through 44h post-treatment. The concentration of proinflammatory cytokines and chemokines in CVL was determined by quantitative ELISA. Concentrations of IL-8 and IL-1ß were consistently significantly increased after microbicide application suggesting these cytokines are useful biomarkers for epithelial injury in the sheep model. Together, the results of these immunological assessments mirror those obtained in previous animal models and human trials with the same compound and greatly extend the utility of the sheep vaginal model in assessing the vaginal barrier and immune microenvironment.

Peculiarities of the Inflammatory Process in the Reproductive Organs of C57Bl/6 Female Mice with Experimental Tuberculosis.

Intravenous infection of C57Bl/6 female mice with M. tuberculosis H37Rv led to involvement of the lungs and dissemination of the tuberculous infection to the abdominal and pelvic organs. M. tuberculosis were detected in the lungs and spleen in 14, 35, and 90 days and in the uterine horns in 90 days after infection. Morphological analysis of organs showed successive development of exudative necrotic tuberculosis of the lungs, acute and chronic nonspecific inflammation in the reproductive organs (vagina, uterus, and uterine horns). The inflammatory process in the reproductive organs was associated with the development of anaerobic dysbiosis, that was most pronounced in 35 days after infection. Antituberculous therapy was followed by reduction of M. tuberculosis count in the lungs and spleen in 60 and 90 days after infection, eliminatation of M. tuberculosis in the uterine horns, arrest of nonspecific inflammation in female reproductive organs, recovery of the balance between aerobic and anaerobic microflora, and development of candidiasis of the urogenital mucosa.

Inhalant allergy compounding the chronic vaginitis syndrome: characterization of sensitization patterns, comorbidities and responses to sublingual immunotherapy.

OBJECTIVE: To characterize sensitization patterns, diagnoses and comorbidities, and to assess the response of lower genital tract symptoms to sublingual immunotherapy for airborne allergens in a select population of patients with chronic vaginitis. METHODS: Fifty-two patients referred for allergy evaluation over a 44 month period were studied. Charts were retrospectively reviewed to establish: (1) gynecological diagnoses, (2) allergic-immunological diagnoses, and (3) IgE-mediated sensitivity to airborne allergens on presentation. Patients were contacted at 9-50 months of treatment to assess response to sublingual immunotherapy based on a questionnaire addressing frequency and severity of symptoms and use of medication to control symptoms. RESULTS: Recurrent vulvovaginal candidiasis was identified in 34 (65 %); vulvar vestibulitis syndrome in 12 (23 %); and contact dermatitis in 10 (19 %) patients. Comorbidities included: non-reflux gastrointestinal complaints in 11 (21 %), gastroesophageal reflux in 5 (9 %), migraines in 9 (17 %), chronic non-migrainous headaches in 8 (17 %), and chronic sinusitis in 6 patients (11 %). Asthma was diagnosed in 8 patients (15 %). Oral allergy syndrome was present in 6 (11 %). Most frequent sensitivities were to: ragweed in 33 (63 %), molds in 26 (50 %), dust mites in 23 (44 %), and grass in 12 (23 %) patients. Mono-sensitization was demonstrated for ragweed in 7 (13 %), and for molds, dust mites and grass for 3 (5 %) patients each. Candida sensitization was identified in 15 patients with chronic vaginitis (28 %). Eleven patients with recurrent vulvovaginal diagnosis (32 %) showed Candida sensitization. Response to immunotherapy was generally favorable with pruritus/irritation being more responsive than visceral pain. CONCLUSIONS: In a Midwestern referral population, chronic vaginitis compounded by inhalant allergy showed: (1) high incidence rate of recurrent vulvo-vaginal candidiasis, (2) Candida IgE-mediated sensitization in less than one-third of patients with recurrent vulvovaginal candidiasis, (3) comorbid conditions not dissimilar to those of other allergic patients, and (4) allergen sensitization pattern typical for the Midwest.

Vaginal Inflammation: Association between Leukocyte Concentration and Levels of Immune Mediators.

PROBLEM: A wide variety of mediators are involved in inflammatory processes. However, the identity of those participating in vaginal immune responses has not been established. We correlated extracellular matrix metalloproteinase inducer (EMMPRIN), matrix metalloproteinase-8 (MMP-8), hyaluronan (HA), hyaluronidase-1 (Hyal-1), human ß-defensin-2 (hBD2), and neutrophil gelatinase-associated lipocalin (NGAL) concentrations with the extent of leukocyte infiltration into the vagina and suggest their participation in vaginal inflammation. METHODS OF STUDY: Vaginal fluid was obtained from 233 women seen at the outpatient clinic in the Department of Obstetrics and Gynecology at Campinas University, Brazil. The magnitude of vaginal inflammation was determined by the leukocyte count on vaginal smears and categorized as no inflammation (0 leukocytes/field), moderate inflammation (1-4 leukocytes/field), and intense inflammation (>4 leukocytes/field). Concentrations of EMMPRIN, MMP-8, HA, Hyal-1, hBD2, and NGAL were determined in vaginal fluid by ELISA. RESULTS: EMMPRIN, MMP-8, HA, hBD2, and NGAL concentration increased with elevated leukocyte numbers (P < 0.05), while Hyal-1 did not. EMMPRIN concentrations were correlated with HA and MMP-8 levels. CONCLUSION: EMMPRIN, MMP-8, HA, ß-defensin, and NGAL are elevated in women with vaginal inflammation.

Papanicolaou smear findings in solid-organ transplant recipients compared with normal subjects according to the Bethesda 2001 system.

OBJECTIVES: Solid-organ transplant recipients are at increased risk of developing cancer including cervical cancer compared with woman in the general population, mostly due to long-term immunosuppressive therapy. The Papanicolaou smear remains the primary method of screening cervical pathology including preinvasive and invasive lesions. The objective of this study was to evaluate Pap smear findings in solid-organ transplant recipients, determine the prevalence of abnormal smears, and compare these patients with the general population. MATERIALS AND METHODS: We retrospectively examined 111 women patients who received liver or kidney transplant between January 1990 to December 2012 at Baskent University Ankara Hospital. Pap smear findings were compared with normal control patients matched for same age and technical procedure of cervical cytology. To selection of control patients, propensity score matching program was performed. All Pap smears were re-examined according to Bethesda 2001 criteria. RESULTS: In 111 transplant patients, 2 patients (1.8%) had atypical squamous cells of undetermined significance, 8 patients (7.2%) had low-grade squamous intraepithelial lesion, 15 patients (13.5%) had Candida infection, 2 patients (1.8%) had Trichomonas vaginalis, 1 patient (0.9%) had herpes simplex infection, 13 patients (11.7%) had bacterial vaginosis, 15 patients (13.5%) had reactive changes due to inflammation, and 18 patients (16.2%) had atrophy. When we compared our results with the control group, there were statistically significant differences (P ≤ .05) between the 2 groups in epithelial cell abnormalities (low-grade squamous intraepithelial lesion), Candida infection, bacterial vaginosis, and atrophy. CONCLUSIONS: Pap smear screening potentially may help recognize cervical preinvasive and invasive lesions. The risk of developing cervical intraepithelial neoplasia is greater in transplant recipients because of immunosuppressive therapy. The incidence of low-grade squamous intraepithelial lesion was significantly greater in transplant recipients than the general population. Intensive follow-up with Pap smear in transplant recipients is important in the early detection of these lesions.

In vivo evaluation of safety and toxicity of a Lactobacillus jensenii producing modified cyanovirin-N in a rhesus macaque vaginal challenge model.

Sexual transmission of human immunodeficiency virus type 1 (HIV-1) across the cervicovaginal mucosa in women is influenced by many factors including the microbiota and the presence of underlying inflammation. It is important that potential HIV preventative agents do not alter the mucosal environment in a way that enhances HIV acquisition. We examined the impact of a "live" microbicide on the vaginal mucosal environment in a rhesus macaque repeated vaginal simian-HIV (SHIVSF162P3) challenge model. The microbicide contained a human vaginal Lactobacillus jensenii expressing the HIV-1 entry inhibitor, modified Cyanovirin-N (mCV-N), and henceforth called LB-mCV-N. Macaques were colonized vaginally each week with LB-mCV-N and sampled six days after colonization for culturable bacteria, pH and cervical-vaginal cytokines during the duration of the six-week study. We show that macaques that retained the engineered LB-mCV-N strain in their vaginal microbiota, during SHIV challenge, had lower pH, when colonization levels were higher, and had no evidence of inflammatory cytokines. Indeed, Interleukin-13, a mediator of inflammation, was detected less often in LB-mCV-N colonized macaques than in controls and we found higher levels of Interleukin 1 receptor antagonist (IL-1RA) in LB-mCV-N colonized macaques during the SHIV challenge period. We noted an inverse correlation between levels of mucosal IL-1RA and peak plasma viral load, thus higher IL-1RA correlated with lower viral load in LB-mCV-N treated macaques. These data support the use of LB-mCV-N as a safe "live" microbicide and suggest that lactobacilli themselves may positively impact the mucosal environment.

Effectiveness of an optimized benzalkonium chloride gel as vaginal contraceptive: a randomized controlled trial among Chinese women.

BACKGROUND: This study was conducted to evaluate the efficacy, safety and acceptability of a newly developed benzalkonium chloride (BZK) contraceptive gel which was compared to nonoxynol-9 (N-9) gel. STUDY DESIGN: A Phase II, multicenter, randomized, controlled study at three Chinese centers was conducted to compare 120 women who used BZK gel with 120 women who used N-9 gel for 6 months. Contraceptive efficacy was assessed by pregnancy rate, and safety was evaluated by adverse events report, gynecologic examination, Papanicolaou smears, leukorrhea test, and blood and urine tests. The acceptability was assessed through follow-up visit forms and a questionnaire at the 6-month visit. RESULTS: Net cumulative rates in the BZK group at 6 months were as follows: follow-up 100%, terminations 5.1%, pregnancy 1.7%, medical reasons 0% and fear of failure 3.4%. At 6 months, the rates in the N-9 group were as follows: follow-up 99.2%, terminations 9.4%, pregnancy 0.9%, medical reasons 2.5%, fear of failure 3.4% and other personal reasons 2.6%. No significant difference in pregnancy rate and termination rate between the two groups was found (p>.05). Seven cases in the BZK group (5.8%) complained about leukorrhagia and vaginal irritation symptoms (itching and burning) at 6 months, while 16 cases in the N-9 group (13.3%) had similar complaints (p<.05). This significant difference continued to exist until the 6-month visit. The general satisfaction rate for BZK gel use (72.8%) is significantly higher than that for N-9 gel (42.5%). CONCLUSION: The optimized BZK gel is comparable to N-9 gel in terms of contraceptive efficacy and safety, and may be more acceptable to Chinese users.

[Detection of the interferon deficiency in inflammatory gynecological diseases and its correction with interferon inducers].

Interferons deficiency has a negative influence on the development of infection and inflammation in general. The use in the complex of anti-inflammatory therapy of interferon inducers (Meglumine acridоnacetate, Tilorone), combining antiviral, immunomodulatory, interferon correction effects with etiopathogenic action leads to the correction of the interferon system defects and eliminate etiological infectious agents, that is confirmed by laboratory data and clinical efficacy.

Antibacterial activity of selected standard strains of lactic acid bacteria producing bacteriocins--pilot study.

INTRODUCTION: In this paper, an attempt was made to evaluate the antibacterial potential of standard strains of lactic acid bacteria (LAB) producing bacteriocins of various classes, thus demonstrating various mechanisms of cell membrane damages against the Streptococcus agalactiae strains (Group B Streptococcus, GBS), depending on surface polysaccharides and surface alpha-like protein genes. MATERIALS/METHODS: Antimicrobial property of the strains of L. plantarum C 11, L. sakei DSMZ 6333, and L. lactis ATCC 11454 producing bacteriocins: JK and EF plantaricins, sakacin and nisin, respectively, against the GBS strains was evaluated. The chosen to the study GBS strains were represented by serotypes Ia, Ib, II, III, V and they had bca, epsilon, rib, alp2 or alp3 alpha-like protein genes. The experiment was conducted by means of suspension culture and the bacteria count was determined using the serial dilution method. RESULTS: A great ability of L. plantarum C 11 strain was proven to inhibit the GBS growth. The strain of L. sakei DSMZ 6333 did not demonstrate any ability to inhibit the growth of GBS, whereas L. lactis ATCC 11454 inhibited the growth of S. agalactiae indicator strains to a minor extent. Statistically significant differences were demonstrated between the GBS strains representing various serotypes against the antimicrobial activity of model LAB strains. The least sensitive to the activity of bacteriocins were the strains representing serotypes Ib and III, whereas the strains representing serotype II were the most sensitive. The sensitivity of the GBS strains to the antimicrobial activity of LAB was not dependent on alpha-like protein genes. DISCUSSION: Among the LAB standard strains producing bacteriocins, the strongest antimicrobial property was observed in the strain of L. plantarum C 11. Because of the generally known and verified strong antagonistic property of the strains of L. plantarum species against indicator bacteria, it is necessary to further pursue the research presented in this paper.

Cervicovaginal inflammatory cytokines and sphingomyelinase in women with and without bacterial vaginosis.

INTRODUCTION: The objective is to analyze proinflammatory cytokines [interleukin-1ß (IL-1ß), interleukin-6 and tumor necrosis factor-α] and sphingomyelinase in women with bacterial vaginosis (BV), cervicitis and vaginitis. METHODS: From January 2009 to June 2010, human immunodeficiency virus (HIV)-negative, nonpregnant, married women, living with husband, aged 20 to 40 years were recruited from a slum at Hyderabad, India, after taking written consent. One hundred forty-six women including 61 women with BV, 47 women with intermediate flora and 38 women with normal vaginal flora were evaluated for local proinflammatory cytokines and sphingomyelinase. Cervicitis and vaginitis were also analyzed by scoring white blood cells in the cervix and vaginal smears, respectively. RESULTS: Of the 146 women, 50.7% had cervicitis and 19.5% had vaginitis. IL-1ß, tumor necrosis factor-α and interleukin-6 levels were significantly high in women with cervicitis (P < 0.001) and vaginitis (P < 0.001) and IL-1ß in BV (P < 0.005), intermediate flora (P < 0.05) when compared with normal women. High vaginal pH was associated with IL-1ß. Neutral sphingomelinase showed an inverse association (P < 0.05) with cervicitis. Acid sphingomelinase directly correlated with IL-1ß although not significantly. CONCLUSIONS: This study shows proinflammatory response not only in BV but also in women with vaginitis and cervicitis. These conditions are likely to be important in promoting the transmission of HIV-1 and should be the focus of HIV prevention strategies.

Biodegradable nanoparticles in the murine vagina: trans-cervical retrograde transport and induction of proinflammatory cytokines.

Biodegradable nanoparticles (NP) of average size 75 nm and composed of poly(lactic acid, PLA) were prepared by single emulsion. Upon instillation into the vagina of mice in estrus, these particles undergo retrograde transport across the cervix to the uterus. Uterus lavage conducted after instillation of NP into the vagina indicated that proinflammatory signals such as RANTES and TNF were induced in the uterine environment, which is inimical to establishment of pregnancy. These NP are under investigation for contraceptive potential.

Persistent antibodies to HPV virus-like particles following natural infection are protective against subsequent cervicovaginal infection with related and unrelated HPV.

Whether persistent human papillomavirus (HPV) IgG antibodies following natural infection are protective against subsequent infection is unknown. In a cohort of 508 college women followed for 3 y, persistent seropositivity was defined as the presence of type-specific HPV virus-like particle (VLP) antibodies at > or = 2 consecutive visits 1 y apart. Protection from incident infection with any HPV was conferred by persistent antibodies to HPV16 (p = 0.02), HPV31 (p < 0.001), HPV33 (p = 0.03), HPV35 (p = 0.002), HPV52 (p = 0.007), HPV45 (p = 0.003), and HPV53 (p = 0.01). The risk of incident infection with species-specific HPV types was also decreased in women with persistent antibodies to any HPV type in that group, suggesting that exposure to HPV with persistent development of antibody response can be protective, and may explain the decreased efficacy of HPV vaccine in women with prior exposure.

[Anti-infectious defense of vagina during use of low-dose monophasic contraceptives].

Increase in incidence of candidal colpitis has been observed during use of contraceptive drugs. Elimination of staphylococci from genital tract after use of contraceptives was detected in 34,7% of patients. Composition of other aerobic microflora did not change. Nonspecific immune reaction was characterized by intensified phagocytosis, increase of results of NBT reduction test and level of proinflammatory cytokines. Conclusion about inappropriateness of using low-dose oral contraceptives in patients with recurrent vulvovaginal candidosis was made. Such contraceptives can be recommended to women with prolonged inflammatory diseases of reproductive system.

Phenotypic and functional characterization of vaginal dendritic cells in a rat model of Candida albicans vaginitis.

This study analyzes the phenotype of vaginal dendritic cells (VDCs), their antigenic presentation and activation of T-cell cytokine secretion, and their protective role in a rat model of Candida vaginitis. Histological observation demonstrated a significant accumulation of OX62(+) VDCs in the mucosal epithelium of Candida albicans-infected rats at the third round of infection. We identified two subsets of OX62(+) VDCs differing in the expression of CD4 molecule in both noninfected and Candida-infected rats. The OX62(+) CD4(+) subset of VDCs displayed a lymphoid cell-like morphology and expressed the T-cell antigen CD5, whereas the OX62(+) CD4(-) VDC subset exhibited a myeloid morphology and was CD5 negative. Candida infection resulted in VDC maturation with enhanced expression of CD80 and CD134L on both CD4(+) and CD4(-) VDC subsets at 2 and 6 weeks after Candida infection. CD5(-) CD4(-) CD86(-) CD80(-) CD134L(+) VDCs from infected, but not noninfected, rats spontaneously released large amounts of interleukin-12 (IL-12) and tumor necrosis factor alpha, whereas all VDC subsets released comparable levels of IL-10 and IL-2 cytokines. Furthermore, OX62(+) VDCs from infected rats primed naïve CD4(+) T-cell proliferation and release of cytokines, including gamma interferon, IL-2, IL-6, and IL-10, in response to staphylococcal enterotoxin B stimulation in vitro. Adoptive transfer of highly purified OX62(+) VDCs from infected rats induced a significant acceleration of fungal clearance compared with that in rats receiving naive VDCs, suggesting a protective role of VDCs in the anti-Candida mucosal immunity. Finally, VDC-mediated protection was associated with their ability to rapidly migrate to the vaginal mucosa and lymph nodes, as assessed by adoptive transfer of OX62(+) VDCs labeled with 5 (and 6-)-carboxyfluorescein diacetate succinimidyl ester.

Chronic inflammation of the peritoneum and vagina: review of its significance, immunologic pathogenesis, investigation and rationale for treatment.

Chronic inflammation is not an infrequent histologic finding in symptomatic gynecologic patients. It is present in 14.6% of peritoneal biopsies in women with chronic pelvic pain in whom no other cause of pain is evident. It is found in almost all vaginal biopsies in noninfected women with dyspareunia and discharge of vaginal mucosal origin. It represents a local immunologically activated inflammatory disorder. When investigations are car ried out as to whether it is a local representation of a systemic disorder, numerous systemic inflammatory and autoimmune disorders are discovered. A study of chronic pain reveals that the immune system is intimately involved in the production, conduction and exacerbation of pain and of its clinicalfeatures, such as hyperalgesia and allodynia. Immune modification using local steroids and disease-modifying antirheumatic drugs, such as hydroxychloroquine, are known to inhibit inflammatory cells and cytokines, such as interleukin-1, interleukin-6 and tumor necrosis factor, which are responsible for pain and tissue damage. These drugs are found to be effective in the treatment of chronic pelvic pain when of an inflammatory nature and for symptomatic chronic inflammation of the vagina.

Chronic inflammation of the vagina: treatment and relationship to autoimmunity.

OBJECTIVE: To investigate noninfective, symptomatic, chronic inflammation (CI) of the vaginal mucosa to determine its prevalence and immunologic basis and to initiate an immunologic approach to treatment and assess the response. STUDY DESIGN: A prospective, observational, clinical study of 55 women with dyspareunia and/or discharge of vaginal mucosal origin. Vaginal biopsies and immune investigations were carried out. Treatment was instituted utilizing immune-modifying agents. RESULTS: The prevalence of CI of the vagina in symptom-free women was 0-4.3% and in the symptomatic group, 89%. Systemic immune activation was demonstrated in 43 of the 55, with 21 suffering from an autoimmune disease or a condition in which immune activation plays a part, including endometriosis in 20. Thirty-one were treated; intravaginal hydrocortisone acetate 10% foam was given in 24, giving full relief in 14 and inadequate relief in 10. Hydroxychloroquine, an immune-modifying, antirheumatic drug, was added and largely gave relief in these 10. Hydroxychloroquine alone was given in 4 and was effective in 3. Overall, immune-modifying drugs were successful in 97%. CONCLUSION: CI of the vaginal mucosa stems from local immune activation and is generally associated with evidence of other immune abnormalities, including autoimmune diseases and disorders in which immune activation play a part, including endometriosis. It can be successfully treated by immune modification.

Immunotherapeutic approaches to enhance protective immunity against Candida vaginitis.

Protective host defense mechanisms against vaginal Candida infections are poorly understood. While cell-mediated immunity (CMI) is the predominant host-defense mechanism against most mucosal Candida infections, no protective role for systemic or local Candida-specific CMI or antibodies has been identified against vaginal candidiasis. Rather, evidence exists for immunoregulation in vaginal tissue, which may inhibit a more profound protective Th1-type response. This study evaluated immunotherapy and gene therapy approaches in the murine model to potentially overcome immunoregulation and promote enhanced protection against vaginal candidiasis. In the first set of studies, the intravaginal and systemic administration of Thl-type cytokines and anti-IL-10 and anti-TGF-beta antibodies failed to enhance protection against a vaginal Candida infection. In a second set of studies, the novel intravaginal administration of Adenoviruses encoding Th1-type cytokines (IFN-gamma and IL-12) and the chemokine, MCP-1, showed substantial, but transient (24 h) expression of each in vaginal tissue and draining lymph nodes, even with a second administration. Unfortunately, treatment with these Adenoviral vectors did not enhance protection against experimental vaginitis. Construction of a new vector encoding IFN-gamma with a stronger promoter produced substantial IFN-gamma in vitro, but lower amounts in vivo and no extended expression. Taken together, while gene therapy can be used to induce cytokine expression in vaginal tissue, there appear to be strong regulatory mechanisms that additional manipulations or alternative approaches will have to overcome if protection against vaginitis is to be enhanced.