Efficacy of the clinical agent VT-1161 against fluconazole-sensitive and -resistant Candida albicans in a murine model of vaginal candidiasis.

Vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC) remain major health problems for women. VT-1161, a novel fungal CYP51 inhibitor which has potent antifungal activity against fluconazole-sensitive Candida albicans, retained its in vitro potency (MIC50 of ≤0.015 and MIC90 of 0.12 µg/ml) against 10 clinical isolates from VVC or RVVC patients resistant to fluconazole (MIC50 of 8 and MIC90 of 64 µg/ml). VT-1161 pharmacokinetics in mice displayed a high volume of distribution (1.4 liters/kg), high oral absorption (73%), and a long half-life (>48 h) and showed rapid penetration into vaginal tissue. In a murine model of vaginal candidiasis using fluconazole-sensitive yeast, oral doses as low as 4 mg/kg VT-1161 significantly reduced the fungal burden 1 and 4 days posttreatment (P < 0.0001). Similar VT-1161 efficacy was measured when an isolate highly resistant to fluconazole (MIC of 64 µg/ml) but fully sensitive in vitro to VT-1161 was used. When an isolate partially sensitive to VT-1161 (MIC of 0.12 µg/ml) and moderately resistant to fluconazole (MIC of 8 µg/ml) was used, VT-1161 remained efficacious, whereas fluconazole was efficacious on day 1 but did not sustain efficacy 4 days posttreatment. Both agents were inactive in treating an infection with an isolate that demonstrated weaker potency (MICs of 2 and 64 µg/ml for VT-1161 and fluconazole, respectively). Finally, the plasma concentrations of free VT-1161 were predictive of efficacy when in excess of the in vitro MIC values. These data support the clinical development of VT-1161 as a potentially more efficacious treatment for VVC and RVVC.

CD8 T cells and E-cadherin in host responses against oropharyngeal candidiasis.

BACKGROUND: Oropharyngeal candidiasis (OPC) is the most common oral infection in HIV(+) persons. Previous studies suggest a role for CD8(+) T cells against OPC when CD4(+) T cells are lost, but enhanced susceptibility to infection occurs when CD8(+) T-cell migration is inhibited by reduced tissue E-cadherin. OBJECTIVE: To conduct a longitudinal study of tissue CD8(+) T-cells and E-cadherin expression before, during, and after the episodes of OPC. METHODS: Oral fungal burden was monitored and tissue was evaluated for CD8(+) T cells and E-cadherin over a 1-year period in HIV(+) persons with a history of, or an acute episode of, OPC. RESULTS: While longitudinal analyses precluded formal interpretations, point prevalence analyses of the data set revealed that when patients experiencing OPC were successfully treated, tissue E-cadherin expression was similar to that in patients who had not experienced OPC, and higher numbers of CD8(+) T cells were distributed throughout OPC(-) tissue under normal expression of E-cadherin. CONCLUSION: These results suggest that (1) reduction in tissue E-cadherin expression in patients with OPC(+) is not permanent, and (2) high numbers of CD8(+) T cells can be distributed throughout OPC(-) tissue under normal E-cadherin expression. Together, these results extend our previous studies and continue to support a role for CD8(+) T cells in host defense against OPC.

Candida-host interactions in HIV disease: implications for oropharyngeal candidiasis.

Oropharyngeal candidiasis (OPC), caused primarily by Candida albicans, is the most common oral infection in HIV(+) persons. Although Th1-type CD4(+) T cells are the predominant host defense mechanism against OPC, CD8(+) T cells and epithelial cells become important when blood CD4(+) T cells are reduced below a protective threshold during progression to AIDS. In an early cross-sectional study, OPC(+) tissue biopsied from HIV(+) persons had an accumulation of activated memory CD8(+) T cells at the oral epithelial-lamina propria interface, with reduced expression of the adhesion molecule E-cadherin, suggesting a protective role for CD8(+) T cells but a dysfunction in the mucosal migration of the cells. In a subsequent 1-year longitudinal study, OPC(-) patients with high oral Candida colonization (indicative of a preclinical OPC condition), had higher numbers of CD8(+) T cells distributed throughout the tissue, with normal E-cadherin expression. In OPC(+) patients, where lack of CD8(+) T cell migration was associated with reduced E-cadherin, subsequent evaluations following successful treatment of infection revealed normal E-cadherin expression and cellular distribution. Regarding epithelial cell responses, intact oral epithelial cells exhibit fungistatic activity via an acid-labile protein moiety. A proteomic analysis revealed that annexin A1 is a strong candidate for the effector moiety. The current hypothesis is that under reduced CD4(+) T cells, HIV(+) persons protected from OPC have CD8(+) T cells that migrate to the site of a preclinical infection under normal expression of E-cadherin, whereas those with OPC have a transient reduction in E-cadherin that prohibits CD8(+) T cells from migrating for effector function. Oral epithelial cells concomitantly function through annexin A1 to keep Candida in a commensal state but can easily be overwhelmed, thereby contributing to susceptibility to OPC.

Innate immunity including epithelial and nonspecific host factors: workshop 1B.

The majority of HIV infections are initiated at mucosal sites. The oral mucosal tissue has been shown to be a potential route of entry in humans and primates. Whereas HIV RNA, proviral DNA, and infected cells are detected in the oral mucosa and saliva of infected individuals, it appears that the oral mucosa is not permissive for efficient HIV replication and therefore may differ in susceptibility to infection when compared to other mucosal sites. Since there is no definitive information regarding the fate of the HIV virion in mucosal epithelium, there is a pressing need to understand what occurs when the virus is in contact with this tissue, what mechanisms are in play to determine the outcome, and to what degree the mechanisms and outcomes differ between mucosal sites. Workshop 1B tackled 5 important questions to define current knowledge about epithelial cell-derived innate immune agents, commensal and endogenous pathogens, and epithelial cells and cells of the adaptive immune system and how they contribute to dissemination or resistance to HIV infection. Discovering factors that explain the differential susceptibility and resistance to HIV infection in mucosal sites will allow for the identification and development of novel protective strategies.

HIV infection and specific mucosal immunity: workshop 4B.

Most HIV infections are transmitted across mucosal epithelium. An area of fundamental importance is understanding the role of innate and specific mucosal immunity in susceptibility or protection against HIV infection, as well as the effect of HIV infection on mucosal immunity, which leads to increased susceptibility to bacterial, fungal, and viral infections of oral and other mucosae. This workshop attempted to address 5 basic issues-namely, HIV acquisition across mucosal surfaces, innate and adaptive immunity in HIV resistance, antiviral activity of breast milk as a model mucosal fluid, neutralizing immunoglobulin A antibodies against HIV, and progress toward a mucosal vaccine against HIV. The workshop attendants agreed that progress had been made in each area covered, with much recent information. However, these advances revealed how little work had been performed on stratified squamous epithelium compared with columnar epithelium, and the attendants identified several important biological questions that had not been addressed. It is increasingly clear that innate immunity has an important biological role, although basic understanding of the mechanisms of normal homeostasis is still being investigated. Application of the emerging knowledge was lacking with regard to homeostatic mucosal immunity to HIV and its role in changing this homeostasis. With regard to breast milk, a series of studies have demonstrated the differences between transmitters and nontransmitters, although whether these findings could be generalized to other secretions such as saliva was less clear. Important progress toward an oral mucosal HIV vaccine has been made, demonstrating proof of principle for administering vaccine candidates into oral lymphoid tissues to trigger anti-HIV local and systemic immune responses. Similarly, experimental data emphasized the central role of neutralizing antibodies to prevent HIV infection via mucosal routes.

New approaches to Candida and oral mycotic infections: Workshop 2A.

This workshop reviewed aspects of the following: oral fungal disease in HIV-infected patients and the predictive value of oral mucosal disease in HIV progression; the role of the oral biofilms in mucosal disease; microbial virulence factors and the pseudomembranous oral mucosal disease process; the role that oral mucosal disease may have in HIV transmission; and the available topical antifungal treatment. This article summarizes the ensuing discussions and raises pertinent problems and potential research directions associated with oral fungal disease in HIV-infected patients, including the frequency of oral candidosis, the role of the intraoral biofilm in the development of oral mucosal disease, and host-pathogen interactions, as well as the development of the fetal oral mucosa, neonatal nutrition, and the role of oral candidosis in this setting. Finally, discussions are summarized on the use of inexpensive effective antifungal mouthwashes in resource-poor countries, the potential stigmata that may be associated with their use, as well as novel topical medications that may have clinical applicability in managing oral candidal infections in HIV-infected patients.

Fabrication of a multi-applicable removable intraoral denture system for rodent research.

The objective was to engineer an inexpensive intraoral removable denture system for rodents that can be utilised in numerous oral health research applications. At the forefront is biofilm research related to Candida-associated denture stomatitis. Previously described intraoral devices are primitive and inadequate. The denture system was engineered consisting of a fixed part that is anchored to the posterior palate by orthodontic wires and acrylic resin and a removable part fitted to the anterior palate that is retained by magnets embedded in the fixed part. Both parts are custom fitted to the rodent palate by impression making and cast fabrication. Rats fitted with the intraoral denture system maintained body weight and normal activity with the device maintaining integrity and durability for upwards of 8 weeks. The denture system was used successfully to establish a working model of denture stomatitis. This newly engineered inexpensive intraoral removable denture system for rodents can be utilised in numerous oral health research applications, including denture-associated infections, biofilms and a variety of biomaterial applications. The removable portion is advantageous for longitudinal analyses and charging/discharging of biomaterials.

Candida albicans forms biofilms on the vaginal mucosa.

Current understanding of resistance and susceptibility to vulvovaginal candidiasis challenges existing paradigms of host defence against fungal infection. While abiotic biofilm formation has a clearly established role during systemic Candida infections, it is not known whether C. albicans forms biofilms on the vaginal mucosa and the possible role of biofilms in disease. In vivo and ex vivo murine vaginitis models were employed to examine biofilm formation by scanning electron and confocal microscopy. C. albicans strains included 3153A (lab strain), DAY185 (parental control strain), and mutants defective in morphogenesis and/or biofilm formation in vitro (efg1/efg1 and bcr1/bcr1). Both 3153A and DAY815 formed biofilms on the vaginal mucosa in vivo and ex vivo as indicated by high fungal burden and microscopic analysis demonstrating typical biofilm architecture and presence of extracellular matrix (ECM) co-localized with the presence of fungi. In contrast, efg1/efg1 and bcr1/bcr1 mutant strains exhibited weak or no biofilm formation/ECM production in both models compared to wild-type strains and complemented mutants despite comparable colonization levels. These data show for the first time that C. albicans forms biofilms in vivo on vaginal epithelium, and that in vivo biotic biofilm formation requires regulators of biofilm formation (BCR1) and morphogenesis (EFG1).

Annexin-A1 identified as the oral epithelial cell anti-Candida effector moiety.

Innate and adaptive immunity are considered critical to protection against mucosal candidal infections. Among innate anti-Candida mechanisms, oral and vaginal epithelial cells have antifungal activity. The mechanism is fungistatic, acid-labile and includes a requirement for cell contact by intact, but not necessarily live, epithelial cells. The purpose of this study was to use the acid-labile property to further characterize the effector moiety. Surface material extracted from phosphate-buffered saline (PBS) -treated, but not acid-treated, epithelial cells significantly inhibited the growth of Candida blastoconidia in a dose-dependent manner which was abrogated by prior heat and protease treatment. Proteins extracted from PBS-treated cells bound blastoconidia and hyphae more intensely than those from acid-treated cells. Proteins from PBS-treated cells eluted from Candida revealed two unique bands of approximately 33 and 45 kDa compared with acid-treated cells. Mass spectrometry identified these proteins as Annexin-A1 and actin, respectively. Oral epithelial cells stained positive for Annexin-A1, but not actin. Western blots showed reduced Annexin-A1 in proteins from acid-treated epithelial cells compared with those from PBS-treated epithelial cells. Lastly, it was demonstrated that immunoprecipitation of Annexin-A1 from proteins extracted from PBS-treated oral epithelial cells resulted in abrogation of inhibitory activity. Taken together, these results indicate that Annexin-A1 is a strong candidate for the epithelial cell anti-Candida effector protein.

Chemokine receptor expression in HIV-positive persons with oropharyngeal candidiasis.

OBJECTIVE: In HIV+ persons with reduced CD4+ T cells, oropharyngeal candidiasis (OPC) is often associated with the accumulation of CD8+ T cells at the epithelial/lamina propria interface within the lesion together with increased tissue-associated cytokines and chemokines. Despite this reactivity, a dysfunction in the ability of the CD8+ cells to reach the organism at the outer epithelium is postulated. The purpose of this study was to examine chemokine receptors present in the OPC lesions for a potential role in susceptibility to infection. METHODS: Biopsies taken from buccal mucosa of HIV- persons, healthy mucosa of HIV+ OPC- persons, and OPC lesions were processed for protein immunohistochemical staining or RNA analysis by real-time PCR and Superarray. RESULTS: There was little change in expression of chemokine receptors at the protein or RNA level between OPC+ and OPC- tissue. At the protein level, increases occurred in OPC+ persons only if associated with CD8 cells. In the Superarray, of the 22 chemokine receptor mRNAs expressed, c. 90% remained unchanged (< 1.0-fold change) between HIV- and HIV+ tissue and between HIV+ OPC- and HIV+ OPC+ tissue. CONCLUSION: Tissue-associated chemokine receptor expression does not appear to contribute to the dysfunction in cellular migration associated with susceptibility to OPC.

Candida-induced oral epithelial cell responses.

OBJECTIVE: Oropharyngeal candidiasis (OPC), caused by Candida albicans, is the most common oral infection in HIV(+) persons. Oral epithelial cells are considered important for innate host defense against OPC with production of cytokines in response to C. albicans and the ability to inhibit Candida growth in vitro. The purpose of this study was to determine if Candida similarly induces cytokines by oral epithelial cells from HIV(+) persons, including those with OPC, as well as to determine if cytokines can influence the oral epithelial cell anti-Candida activity. METHODS: Supernatants from oral epithelial cells from HIV(+) persons with and without OPC cultured with Candida were evaluated for cytokines by ELISA, or cytokines were added to the standard growth inhibition assay using epithelial cells from HIV(-) persons. RESULTS: Results showed low Candida-induced epithelial cell cytokine production from HIV(+) persons, but with some elevated proinflammatory cytokines (TNF-alpha, IL-6) in those with OPC compared to those without OPC. The addition of specific proinflammatory or Th cytokines had no effect on oral epithelial cell anti-Candida activity in healthy HIV(-) persons. CONCLUSION: These results suggest that oral epithelial cells from HIV(+) persons can contribute at some level to the oral cytokine milieu in response to Candida during OPC, but that cytokines do not appear to influence oral epithelial cell anti-Candida activity.

Candida-host interactions in HIV disease: relationships in oropharyngeal candidiasis.

Oropharyngeal candidiasis (OPC) caused by the commensal organism, Candida albicans, is the most common oral infection in HIV disease. Although cell-mediated immunity (CMI) by Th1-type CD4+ T-cells is considered the predominant host defense mechanism against OPC, other systemic or local immune mechanisms are critical when blood CD4+ T-cells are reduced below a protective threshold. For example, the Th cytokine profile in saliva may influence resistance or susceptibility to OPC. In OPC lesions, CD8+ T-cells become accumulated at the lamina propria-epithelium interface, suggesting some role for CD8+ T-cells against OPC. However, the absence of CD8+ T-cells close to Candida at the outer epithelium indicates that susceptibility to OPC involves a dysfunction in the CD8+ T-cells or in the micro-environment. Further evaluation of the buccal mucosa lesion showed that CD8 T-cell-associated cytokine and chemokine mRNA is increased compared with buccal mucosa from lesion-negative matched controls. The majority of CD8+ T-cells present possess the alphabeta T-cell receptor and several homing receptors (i.e., 4beta7, 4beta1, ebeta7). While several adhesion molecules are similar in OPC+ vs. OPC- persons, E-cadherin is reduced in the tissue of OPC+ persons. These results support evidence for a role for CD8+ T-cells against OPC, but suggest that a putative dysfunction in mucosal T-cell trafficking may be associated with susceptibility to infection. Similar levels of Candida-specific antibodies in persons with and without OPC confirmed a limited role for humoral immunity. Finally, oral epithelial cells inhibit the growth of Candida in vitro in a static rather than a cidal manner. Clinically, oral epithelial cell anti-Candida activity is reduced in HIV+ persons with OPC, compared with controls. The mechanism of action includes a strict requirement for cell contact by an acid-labile moiety on intact, but not necessarily live, epithelial cells, with no role for soluble factors. Taken together, host defense against OPC involves several levels of activity. The status and efficiency of local host defenses when blood CD4+ T-cells are not available appear to play a role in protection against or susceptibility to OPC.

(B1) Candida and mycotic infections.

Oral candidiasis (OC) is the most common mucosal manifestation of HIV infection. This workshop examined OC and other mycoses associated with HIV infection. Historically, blood CD4 cell numbers were the primary prognosticator for the development of OC. However, a study that statistically evaluated the predictive role of HIV viral load vs. CD4 cell counts revealed viral load to be a stronger predictor for OC. The role of biofilms and antifungal resistance in recalcitrant OC is unclear at present. In general, micro-organisms including yeasts in biofilms are more resistant to antifungals than their planktonic counterparts. When the remaining organisms are eliminated, the few resistant organisms may not be problematic, because they are present in low numbers. Unusual exotic mycoses in HIV-infected patients are more common in patients from the developing than the developed world. These infections may be recurrent and recalcitrant to therapy, be present in multiple and uncommon sites, increase with the progression of HIV disease, and may play a role similar to that of the more common mycoses. Typing and subtyping of yeasts are probably not critical to the clinical management of candidiasis caused by Candida albicans and non-albicans strains, including C. dubliniensis, because it is responsive to antifungal therapy. C. glabrata is probably the only exception. The presence of oral thrush in infants younger than 6 months of age is associated with an increased post-natal transmission risk of HIV infection. Thus, perinatal retroviral therapy should be combined with the treatment of oral thrush to prevent the post-natal acquisition of HIV.

The host cytokine responses and protective immunity in oropharyngeal candidiasis.

Over the last three decades, the prevalence of oropharyngeal fungal infections has increased enormously, mainly due to an increasing population of immunocompromised patients, including individuals with HIV infection, transplant recipients, and patients receiving cancer therapy. The vast majority of these infections are caused by Candida species. The presence of cytokines in infected tissues ultimately dictates the host defense processes that are specific to each pathogenic organism. During oral infection with Candida, a large number of pro-inflammatory and immunoregulatory cytokines are generated in the oral mucosa. The main sources of these cytokines are oral epithelial cells, which maintain a central role in the protection against fungal organisms. These cytokines may drive the chemotaxis and effector functions of innate and/or adaptive effector cells, such as infiltrating neutrophils and T-cells in immunocompetent hosts, and CD8(+) T-cells in HIV(+) hosts. Epithelial cells also have direct anti-Candida activity. Several studies have provided a potential link between lower levels of certain pro-inflammatory cytokines and susceptibility to oral C. albicans infection, suggesting that such cytokines may be involved in immune protection. The exact role of these cytokines in immune protection against oropharyngeal candidiasis is still incompletely understood and requires further investigation. Identification of such cytokines with the ability to enhance anti-fungal activities of immune effector cells may have therapeutic implications in the treatment of this oral infection in the severely immunocompromised host.

Oral and vaginal epithelial cell anti-Candida activity is acid labile and does not require live epithelial cells.

BACKGROUND: Candida albicans is the causative agent of oral and vaginal candidiasis. Innate host defenses against C. albicans are important against each infection. Among these are oral and vaginal epithelial cells that have anti-Candida activity. The mechanism of action includes a requirement for cell contact with no role for soluble factors, and a putative role for carbohydrates based on the sensitivity of the activity to periodic acid. METHODS: Periodic acid treatment of epithelial cells as well as the property of partial resistance of antifungal activity to fixation was used to further dissect the mechanism of action. RESULTS: The results herein effectively now challenge a role for carbohydrates alone. Firstly, the putative carbohydrate(s) released into supernatants of periodic acid-treated epithelial cells could not compete with fresh epithelial cells for activity, and equivalent abrogation of activity was observed by periodic acid-treated cells irrespective of the amount of carbohydrate released. Instead, the similar abrogation of activity following treatment with other acids or when cocultured under acidic conditions suggests that the activity is acid-labile. Finally, while activity requires intact epithelial cells, it does not require live cells; activity was minimally affected by fixing epithelial cells prior to coculture where the majority of cells remained impermeable to Trypan blue but were defined as non-viable by positive nuclear staining with propidium iodide. CONCLUSION: These results suggest that antifungal activity is dependent on contact by intact, but not necessarily live, epithelial cells through an acid-labile mechanism.

Lack of evidence for local immune activity in oral hairy leukoplakia and oral wart lesions.

BACKGROUND: Oral warts, caused by human papillomavirus (HPV), and oral hairy leukoplakia (OHL) caused by Epstein-Barr virus (EBV), are common oral manifestations in HIV-infected persons. Although both conditions occur most often with reduced blood CD4+ T-cell numbers, oral warts and OHL rarely occur simultaneously, suggesting that dysfunctions in other secondary local immune parameters are also involved. The present study evaluated tissue-associated proinflammatory and T-helper cytokine and chemokine mRNA expression and the presence of T cells in each lesion. METHODS: Biopsies were taken from lesion-positive and adjacent lesion-negative sites of HIV+ persons with oral warts or OHL and lesion-negative sites from HIV+ persons who were oral HPV or EBV DNA-positive (matched controls). Cytokine/chemokine mRNA expression was quantified by real-time polymerase chain reaction. CD3, CD4, and CD8 cells were identified by immunohistochemistry. RESULTS: No differences were detected in tissue-associated cytokine/chemokine mRNA expression in warts or OHL when compared to lesion-negative sites. Immunohistochemical analysis of T cells showed CD8+ cells exclusively, but few cells were present in either lesion. No differences were detected between lesion-positive and -negative control sites of each pathologic condition. CONCLUSION: Little evidence was found for local immune reactivity to either oral warts and OHL, suggesting that CD4+ T cells are a primary host defense against both oral warts and OHL, but with nonimmune factors potentially responsible for the divergent prevalence of each.

Vaginal yeast colonisation, prevalence of vaginitis, and associated local immunity in adolescents.

OBJECTIVES: To evaluate point prevalence vaginal yeast colonisation and symptomatic vaginitis in middle adolescents and to identify relation of these yeast conditions with reproductive hormones, sexual activity, sexual behaviours, and associated local immunity. METHODS: Middle adolescent females (n = 153) were evaluated for sexually transmitted infections (STIs), asymptomatic yeast colonisation, and symptomatic vulvovaginal candidiasis (VVC) by standard criteria. Also evaluated were local parameters, including vaginal associated cytokines, chemokines, and antibodies, vaginal epithelial cell antifungal activity, and Candida specific peripheral blood lymphocyte responses. Correlations between yeast colonisation/vaginitis and local immunomodulators, reproductive hormones, douching, sexual activity, condom use, and STIs were identified. RESULTS: Rates of point prevalence asymptomatic yeast colonisation (22%) were similar to adults and similarly dominated by Candida albicans, but with uncharacteristically high vaginal yeast burden. In contrast with the high rate of STIs (18%), incidence of symptomatic VVC was low (<2%). Immunological properties included high rates of Candida specific systemic immune sensitisation, a Th2 type vaginal cytokine profile, total and Candida specific vaginal antibodies dominated by IgA, and moderate vaginal epithelial cell anti-Candida activity. Endogenous reproductive hormones were in low concentration. Sexual activity positively correlated with vaginal yeast colonisation, whereas vaginal cytokines (Th1, Th2, proinflammatory), chemokines, antibodies, contraception, douching, or condom use did not. CONCLUSION: Asymptomatic vaginal yeast colonisation in adolescents is distinct in some ways with adults, and positively correlates with sexual activity, but not with local immunomodulators or sexual behaviours. Despite several factors predictive for VVC, symptomatic VVC was low compared to STIs.

Local immune responsiveness following intravaginal challenge with Candida antigen in adult women at different stages of the menstrual cycle.

Recurrent vulvovaginal candidiasis (RVVC) is a significant problem in women of childbearing age and is most often caused by Candida albicans that asymptomatically colonizes mucosal tissues. Although some form of local immune dysfunction is postulated to precipitate bouts of RVVC, the normal protective vaginal host response to C. albicans is poorly understood. In an effort to stimulate the natural adaptive response to yeast in healthy women without a history of VVC, commercial Candida skin test antigen was introduced intravaginally and changes in cytokines/immunomodulators were monitored in vaginal lavage fluid pre- and post-antigen challenge. In an earlier pilot study using small numbers of women without controlling for stages of the menstrual cycle, we reported elevated cytokines in vaginal secretions of antigen challenged women. The present study, however, that employed a similar design in a large number of women during each stage of the menstrual cycle showed no evidence of local immune stimulation, including changes in Th and proinflammatory cytokines, IgE, histamine, and prostaglandin, despite a natural modulation of vaginal cytokines over the course of the menstrual cycle. Taken together, these results suggest that either some form of vaginal immunoregulation/tolerance is evident in response to yeast or that more advanced clinical designs are required to detect the normal protective vaginal response to C. albicans.

Influence of periodontal disease on Th1/Th2-type cytokines in saliva of HIV-positive individuals.

Cytokines present during immune responses have a tremendous influence on resistance/susceptibility to oral diseases including periodontal disease and oral opportunistic infections in the immunocompromised individual, as seen by altered Th cytokines in saliva with human immunodeficiency virus (HIV) disease progression and oropharyngeal candidiasis. This study was designed to evaluate whether the presence of severe periodontal disease has any influence on Th cytokines in saliva of HIV-positive persons. For this, saliva from a cohort of HIV-positive persons with mild or severe periodontitis was evaluated for Th cytokines. A dominant Th2-type cytokine profile in saliva was validated in HIV-positive subjects with considerable immune suppression, irrespective of periodontal disease status. However, no significant differences in concentrations of Th1- or Th2-type cytokines in saliva were observed when stratified by periodontal status. Thus, the lack of salivary influences by periodontitis eliminates periodontal disease as a variable in interpretations regarding correlates of local cytokines during oral manifestations of HIV.

Salivary cytokine profiles in the immunocompetent individual with Candida-associated denture stomatitis.

Cell-mediated immunity conferred by CD4+ T helper cells is considered the predominant host defense against mucosal Candida infections, with Thelper (Th1)-type responses associated with resistance to infection and Th2-type responses associated with susceptibility to infection. Oropharyngeal candidiasis, the most common oral opportunistic infection in HIV-infected persons, is associated with a Th2-type cytokine profile in saliva. To obtain more direct evidence for a role of salivary cytokines in susceptibility to oropharyngeal candidiasis during immunosuppression, we evaluated Th1/Th2-type cytokines in the saliva of those with denture stomatitis, a form of oropharyngeal candidiasis not related to immunosuppression. Results showed that HIV-negative denture wearers with and without denture stomatitis demonstrated a mixed Th1/Th2 cytokine profile with no significant differences found between the groups. These results suggest that a local Th cytokine dichotomy in saliva is not associated with susceptibility to denture stomatitis in immunocompetent persons.