RESUMEN
Ovarian cancer patients with persistent (platinum-resistant) or progressive (platinum-refractory) disease respond poorly to second line chemotherapy and have low survival expectancy. New and improved therapeutic approaches are needed and immune biologics are one possibility. Interleukin-2 (IL-2) is a T-cell growth factor believed to be important in anti-tumor immunity. We performed a phase II clinical trial with intraperitoneal (IP) recombinant IL-2 administered in weekly infusions of 6 x 10(5) IU/m2. Thirty-one subjects were sequentially entered into the study and clinical responses were surgically confirmed in 24 patients. The primary end point of this study was clinical response with immunologic measurements as secondary end points. The IP regimen was generally well tolerated. Of the 24 patients assessed for response, there were 6 (4 complete, 2 partial) responses for an overall response rate of 25.0% [95% confidence interval (CI) of 11-45]. The median survival of the 31 patient cohort was 2.1 years (95% CI of 1.3-4.4), but for the 6 patients with responses the median survival has not been reached (range 24-120+ months). Eosinophil and lymphocyte numbers were continuously monitored during treatment. Peripheral blood eosinophils were markedly increased at the completion of treatment (p < 0.0001) and associated with increased circulating eotaxin (p = 0.03). We also found significant associations between changes in CD3 counts and survival (p = 0.05) and between IFNγ- secreting CD8 T cells at early time points and survival (p = 0.04). This study provides important evidence for IP IL-2 in platinum-resistant ovarian cancer and identifies several immune correlates of survival.
Asunto(s)
Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos , Interleucina-2/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Eosinofilia/inmunología , Femenino , Humanos , Inyecciones Intraperitoneales , Interleucina-2/administración & dosificación , Interleucina-2/efectos adversos , Linfocitos/inmunología , Linfocitosis/inmunología , Persona de Mediana Edad , Neoplasias Ováricas/mortalidad , Compuestos de Platino/uso terapéutico , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Understanding host factors modulating immunity to Neisseria gonorrhoeae infection may benefit work on vaccine development. METHODS: We analyzed longitudinal data collected from 485 male and female adolescents to determine genetic correlates of genital gonorrhea. Cytokine data from 388 females were analyzed to assess immunologic markers of gonorrhea and their relationship to genetic correlates. RESULTS: The T-G haplotype defining interleukin-2 (IL-2) gene promoter and intron 1 polymorphisms (-330T and -166G) was more frequently found in individuals who had gonorrhea (relative odds = 3.2, P = 0.01). Among 3 endocervical cytokines measured, IL-10 and IL-12 concentrations were higher and IL-2 lower when gonorrhea was detected. The decrease in endocervical IL-2 after gonorrhea acquisition was mostly restricted to subjects with the IL2 T-G haplotype, which may reflect involvement of a pathogen-specific and genetically mediated mechanism for differential IL-2 responses at genital mucosa. In addition, 2 human leukocyte antigen variants (Cw*04 and DQB1*05) were also independently associated with gonorrhea (adjusted relative odds = 1.9 and 0.5, respectively; P <0.05 for both). CONCLUSIONS: Confirmation of immunogenetic correlates of gonorrhea in larger cohorts may be useful in guiding further research on both innate and adaptive immune responses to N. gonorrhoeae.
Asunto(s)
Predisposición Genética a la Enfermedad , Gonorrea/epidemiología , Gonorrea/genética , Interleucina-2/genética , Neisseria gonorrhoeae , Adolescente , Servicios de Salud del Adolescente , Población Negra/estadística & datos numéricos , Citocinas/genética , Femenino , Gonorrea/sangre , Gonorrea/etiología , Gonorrea/inmunología , Antígenos HLA/genética , Humanos , Leucocitos Mononucleares/metabolismo , Estudios Longitudinales , Masculino , Polimorfismo de Nucleótido Simple , Factores Sexuales , Estados Unidos/epidemiologíaRESUMEN
Antigen presentation and immune activation are essential to the effective control of infectious diseases. In 485 North American adolescents at high risk for genital Chlamydia trachomatis infection, we found 2 human leukocyte antigen variants (DRB1*03-DQB1*04 and DQB1*06) to be associated with recurrent Chlamydia infection (adjusted relative odds [RO], >2.0; P<.01, for both variants). A G-C-C haplotype corresponding to variants at IL10 (encoding interleukin-10 [IL-10]) promoter positions -1082, -819, and -592 was underrepresented in individuals with recurrent infection (RO, 0.59; P=.046). These genetic associations were independent of nongenetic factors, including number of sex partners, race, sex, duration of follow-up, and human immunodeficiency virus type 1 seropositivity. Consistent with the observed IL10 association, cervical secretions in female adolescents without the IL10 G-C-C haplotype had elevated IL-10 concentrations after Chlamydia infection, which may reflect involvement of a Chlamydia-specific mechanism for genetically mediated, differential IL-10 expression in the genital tract.
Asunto(s)
Infecciones por Chlamydia/genética , Citocinas/genética , Predisposición Genética a la Enfermedad , Antígenos HLA/genética , Adolescente , Secreciones Corporales/inmunología , Infecciones por Chlamydia/epidemiología , Infecciones por Chlamydia/inmunología , Femenino , Marcadores Genéticos , Haplotipos , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Masculino , Regiones Promotoras Genéticas , RecurrenciaRESUMEN
Cervical cytobrushes provide a tool to sample endocervical T cells for assessment of local immunity. However, most previous studies in HIV-seropositive women have excluded samples containing blood and hence have analyzed selected populations of patients. As determined by multiple-parameter flow cytometric analysis of T lymphocytes from two sequential cytobrushes and concurrently collected blood samples, this study found a minimal effect of blood contamination on cervical T cell phenotypic parameters in normal women. The consequences of blood in endocervical samples will ultimately depend on the design and objective of each study, but these data suggest studies could be more inclusive and should not automatically discard samples that contain red blood cells.
Asunto(s)
Cuello del Útero/inmunología , Inmunidad Celular , Linfocitos T/inmunología , Femenino , Citometría de Flujo , HumanosRESUMEN
Interindividual variations in host immune responses to HPV infection are thought to be important determinants of viral persistence and progression to cervical intraepithelial neoplasia and cancer. However, few studies have measured local immune markers at the site of infection (e.g., the cervical mucosa). We sought to determine biologic correlates of IL-10 and IL-12 concentrations in cervical secretions. Cervical secretions were passively collected using a WeckCel sponge from 247 women participating in a natural history study of human papillomavirus infection as part of an immunologic ancillary study. IL-10 and IL-12 concentrations were determined using standard ELISA assays. In general, IL-10 and IL-12 levels were significantly intercorrelated (Pearson's correlation coefficient = 0.6) but had somewhat different determinants. Significant increases (P < 0.05) in IL-10 concentrations were observed for nonovulatory phases of the menstrual cycle, postmenopausal status, recent use of oral contraceptives (OC), low secretion volume, macrolevels of heme contamination, and high vaginal pH. Increasing IL-10 levels were also observed among smokers, women with increasing numbers of lifetime sex partners, and women who report having less frequent sex (less than once per week), however, these results were not statistically significant. Significantly higher IL-12 concentrations were observed among recent OC users, women with low secretion volume, and women with a high vaginal pH. There was a non-statistically significant observation of increasing IL-12 levels among nonsmokers, women with increasing numbers of lifetime and recent pregnancies, and increasing levels of heme contamination. We failed to observe a significant association between HPV and IL-10 or IL-12 levels in this crosssectional sample. Future analyses of cervical cytokine levels and HPV infection should control for the inherent variation of local cytokine levels due to hormonal influences, hemoglobin contamination, pH, and cervical secretion volume differences.
Asunto(s)
Moco del Cuello Uterino/química , Cuello del Útero/metabolismo , Interleucina-10/análisis , Interleucina-12/análisis , Adulto , Moco del Cuello Uterino/inmunología , Cuello del Útero/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Membrana Mucosa/inmunología , Membrana Mucosa/metabolismo , Papillomaviridae , Infecciones por Papillomavirus/inmunologíaRESUMEN
OBJECTIVE: The purpose of this study was to evaluate the safety of the administration of a bacterial expression plasmid encoding a 13 amino acid sequence that is highly homologous with human papillomavirus E7 within poly (lactide-co-glycolide) microparticles (ZYC101) in women with HLA A2+ antigen and persistent cervical intraepithelial neoplasia grade 2/3 and human papillomavirus 16. STUDY DESIGN: Fifteen women entered an institutional review board-approved dose-escalating phase I study with the use of three levels of blood monitoring and urine studies, Papanicolaou tests, and colposcopy. Escalation required no serious adverse events. Immunologic responses were evaluated in peripheral blood with the use of human papillomavirus peptide-stimulated interferon gamma enzyme-linked immunosorbent assay for T-cell reactivity. In cervical secretions, immunoglobulin A anti-human papillomavirus 16 E2 concentrations were measured. Three doses every 3 weeks were followed 4 weeks later by surgical excision. RESULTS: No serious adverse events occurred. Five women had complete histologic responses; 11 women had human papillomavirus-specific T-cell responses. Four of five complete histologic responses developed immunoglobulin A anti-E2-specific antibody. CONCLUSION: ZYC101 warrants further investigation because of a 33% complete histologic responses, a 73% immunologic response, and no serious adverse events.
Asunto(s)
Antígenos Virales/genética , ADN Viral/administración & dosificación , Inmunoterapia , Proteínas Oncogénicas Virales/genética , Displasia del Cuello del Útero/terapia , Neoplasias del Cuello Uterino/terapia , Adulto , Anticuerpos Antivirales/inmunología , Especificidad de Anticuerpos , Cápsulas , Proteínas de Unión al ADN/inmunología , Relación Dosis-Respuesta a Droga , Electrocirugia , Femenino , Humanos , Inmunoterapia/métodos , Proteínas Oncogénicas Virales/inmunología , Papillomaviridae , Proteínas E7 de Papillomavirus , Tamaño de la Partícula , Plásmidos , Plasminógeno , Linfocitos T/inmunología , Resultado del Tratamiento , Neoplasias del Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/cirugía , Virión , Displasia del Cuello del Útero/inmunología , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/cirugíaRESUMEN
This study sought to characterize mucosal immunity of the adolescent genital tract during the cycle and determine if adolescents have more suppressed immunoglobulin levels in the follicular phase than adults. Daily from cycle day 9 until ovulation, then every other day until menses, cervical secretions for IgA, IgG, and cytokines were collected via Weck-Cel sponge and serum for luteinizing hormone (LH), estradiol, and progesterone was obtained from three adolescent girls (mean age 16.8 years). Immunoglobulin and cytokine levels varied during the menstrual cycle, reaching their nadir around ovulation. Compared with 13 adults, adolescents had a greater drop in IgG in the follicular phase (mean beta-953 vs. -269 microg/mL/day, p = .045), but a similar rate of rise in IgG in the luteal phase (mean beta +118 vs. +100 microg/mL/day, p = .252). Rates of change in IgA did not differ between adolescents and adults for either phase. Although limited by the small sample size, these findings suggest that adolescents may be more sensitive to unopposed estrogen and warrant further investigation.
Asunto(s)
Moco del Cuello Uterino/inmunología , Genitales Femeninos/inmunología , Ciclo Menstrual/inmunología , Enfermedades de Transmisión Sexual/inmunología , Enfermedades de Transmisión Sexual/transmisión , Adolescente , Moco del Cuello Uterino/química , Citocinas/análisis , Estradiol/sangre , Femenino , Humanos , Inmunidad Mucosa , Inmunoglobulina A/análisis , Inmunoglobulina G/análisis , Hormona Luteinizante/sangre , Progesterona/sangre , Pubertad/inmunología , Enfermedades de Transmisión Sexual/prevención & controlRESUMEN
OBJECTIVE: To determine if dividing loop electrosurgical excision procedure (LEEP) specimens to provide tissue for research increases rates of LEEP specimen misdiagnosis and recurrent cervical intraepithelial neoplasia. MATERIALS AND METHODS: In this chart review, 42 women with biopsy-confirmed cervical intraepithelial neoplasia (CIN) 2,3 had up to 20% of their LEEP specimens sectioned and used for immunologic analysis. The remainder of each specimen was assessed routinely. Follow-up cytologic analyses and cervical biopsies also were assessed. This cohort was compared with a control cohort of 80 patients with biopsy confirmed CIN 2,3 whose LEEP specimens were not divided. Statistical significance was defined as a p value of < .05. RESULTS: There were no statistically significant differences between the groups with regard to histologic assessment of LEEP specimens or follow-up outcomes. CONCLUSIONS: Use of up to 20% of LEEP specimens for research purposes neither adversely affects histologic evaluation of LEEP specimens nor leads to poorer follow-up outcomes.
RESUMEN
Human papillomavirus (HPV) infects the transformation zone of the cervix and is the primary cause of cervical cancer. The infection is localized to the cervix and mucosal immunity is likely to be an important determinant for viral clearance. Previous studies of immunity to HPV have measured immune markers in the blood, but the relationship of systemic immunity to cervical immunity is poorly understood. In this study of 70 women enrolled in the ASCUS-LSIL Triage Study (ALTS), a clinical trial for management of low-grade cytologic abnormalities of the cervix, we collected paired plasma and cervical secretions to investigate the relationship between cervical concentrations of interleukin-10 (IL-10) and interleukin-12 (IL-12) and plasma levels. Neither IL-10 (p = 0.11), or IL-12 (p = -0.04) nor the ratio of IL-12 to IL-10 (p = 0.06) were correlated between blood and cervical secretions. Except for weak correlations of IL-10 among nonsmokers (p = 0.35. P = 0.019) and those in day 18-27 of their menstrual cycle (p = 0.51, P = 0.015), this lack of correlation persisted in all subgroups defined by genital inflammation or infection, current oral contraceptive use, heme contamination and volume of collected secretions, HPV16 seropositivity, and repeat HPV infection and/or cytologic abnormalities. The lack of correlation and high concentrations in cervical secretions indicate that the cervical IL-10 and IL-12 concentrations exceed what could be expected from blood as a principle source of IL-10 and IL-12 and suggest that cytokine concentrations in cervical secretions are predominantly the result of local cytokine production.