Chlamydia trachomatis infection and Vγ9Vδ2 Τ cells in women with recurrent spontaneous abortions.

PROBLEM: Vγ9Vδ2 T cells (γ9δ2) are involved in antibacterial immune responses. The aim of this study was to look for associations between peripheral blood (PB) γ9δ2 T cells and cervix/vaginal Chlamydia trachomatis (Ct) infection in women with recurrent spontaneous abortions (RSA). METHOD OF STUDY: Peripheral blood samples were obtained from 201 RSA women within 10 days after they experienced a new miscarriage. γ9δ2 T cells and their percentage in total γδ T cells were compared between women who had been found and women who had not been found infected with Ct (last 6 months). Fertile women (82) served as control subjects. RESULTS: The difference of mean percentages of γ9δ2 T cells between the abortion and control groups, and the Chlamydia (+) and Chlamydia (-) groups was highly statistically significant (P<.00001). Significant difference was also found between the Chlamydia (+) and Chlamydia (-) group and the control group (ANOVA). CONCLUSION: The measurement of γ9δ2T cells may be useful to suspect possibly undiagnosed chlamydial infection in RSA women.

A pilot study in prostate cancer patients treated with the AE37 Ii-key-HER-2/neu polypeptide vaccine suggests that HLA-A*24 and HLA-DRB1*11 alleles may be prognostic and predictive biomarkers for clinical benefit.

Recently, several types of immunotherapies have been shown to induce encouraging clinical results, though in a restricted number of patients. Consequently, there is a need to identify immune biomarkers to select patients who will benefit from such therapies. Such predictive biomarkers may be also used as surrogates for overall survival (OS). We have recently found correlations between immunologic parameters and clinical outcome in prostate cancer patients who had been vaccinated with a HER-2/neu hybrid polypeptide vaccine (AE37) and received one booster 6 months post-primary vaccinations. Herein, we aimed to expand these retrospective analyses by studying the predictive impact of HLA-A*24 and HLA-DRB1*11 alleles, which are expressed at high frequencies among responders in our vaccinated patients, for clinical and immunological responses to AE37 vaccination. Our data show an increased OS of patients expressing the HLA-DRB1*11 or HLA-A*24 alleles, or both. Vaccine-induced immunological responses, measured as interferon γ (IFN-γ) responses in vitro or delayed-type hypersensitivity reactions in vivo, were also higher in these patients and inversely correlated with suppressor elements. Preexisting (i.e., before vaccinations with AE37) levels of vaccine-specific IFN-γ immunity and plasma TGF-ß, among the HLA-A*24 and/or HLA-DRB1*11 positive patients, were strong indicators for immunological responses to AE37 treatment. These data suggest that HLA-DRB1*11 and HLA-A*24 are likely to be predictive factors for immunological and clinical responses to vaccination with AE37, though prospective validation in larger cohorts is needed.

Are educators at high risk of sub-fertility? A multicenter study.

PROBLEM: A high percentage of women schoolteachers having fertility problems were observed by three independent teams. METHOD: Expected percentage of educators was calculated in 4650 sub-fertile women and 2,062,891 women at reproductive age. To explore the possibility that schoolteachers' contact with childhood viral infections results in alterations of peripheral blood natural killer (NK) cells, a multiple linear regression analysis for profession, age, difficulty to conceive, number of abortions/implantation failures (predictor variables) was performed in childless educators (210) and housewives (184). RESULTS: The difference between observed and expected percentage of sub-fertile schoolteachers was statistically significant (17.6% vs 6.86%, P < 0.0001). The mean percentage of PB NK cells was slightly higher in educators compared to housewives (12.48% vs 11.56%, P = 0.10), and the multiple linear regression analysis revealed that the profession (schoolteacher or not) was the only predictive variable for higher NK% values (P = 0.044). CONCLUSION: Teachers' sub-fertility appears as an 'occupational disease'. Τhe possibility that results from their exposure to childhood viral infections has to be further explored.

Comparative analysis of peripheral natural killer cells in the two phases of the ovarian cycle.

PROBLEM: Changes in endometrial Natural Killer (NK) cells during the luteal phase of the ovarian cycle are important in initiating/maintaining a subsequent pregnancy. In the present study it was investigated whether during the menstrual cycle changes occur also in peripheral blood (PB) NKs. METHOD OF STUDY: Blood samples during the follicular and the luteal phase were collected from 30 women without fertility problems. Samples were analyzed by flow-cytometry for: (1) NK cells (CD3(-)CD16+CD56+) and (2) intracellular production of interferon-gamma (IFN-gamma) by NK cells. For the comparison and correlation of the two populations between the two phases, Wilcoxon signed-rank test and Spearman's Coefficient were used. RESULTS: The differences in percentages of CD3(-)CD16+CD56+ cells and that of CD3(-)CD16+CD56+/IFN-gamma+ cells between the follicular and the luteal phase were not statistically significant (10.61 +/- 5.11 versus 9.76 +/- 4.57 and 6.48 +/- 7.90 versus 7.30 +/- 6.77, respectively, P > 0.05). The correlation between the two variables (NK% and NK/IFN-gamma%) was weakly positive (P = 0.07) only in the follicular phase. CONCLUSION: The study did not reveal menstrual cycle-depended changes in PB NK cells. Thus, a suggestion to measure these cells in a specific phase of the cycle in order to predict the outcome of a subsequent pregnancy in women with fertility problems is objected.

How valuable is measurement of peripheral blood natural killer cells at the time of abortion?

PROBLEM: Increased peripheral blood natural killer (NK) cells are associated to immune-mediated abortion, but their diagnostic value when measured at the time of miscarriage is unknown. METHOD OF STUDY: In women with therapeutic (A = 79) or elective (C = 34) pregnancy termination, the NK-cell percentage was measured before and 5 days after curettage. Additionally, immune-mediated lesions (scored 0-3) and CD56(+) and CD16(+) decidual NKs (scored 1-3) were detected on the abortion material. RESULTS: Aborters differed from controls in histological scores (P = 0.000) and in NK percentage (>12%) only in the measurement 5 days after the operation (P = 0.038). In comparison to histological lesions, NK measurement was found to have sensitivity 70%, specificity 73.68%, positive prognostic value 89.39% and negative prognostic value 43.75%. CONCLUSION: An Increased NK-cell percentage 5 days after the pregnancy termination could be a marker of immune aetiology of miscarriage, as the probability of an aborter with NK >12% to have an immune-mediated abortion is almost 90%.

Natural killer (NK) cell receptors' repertoire in couples with recurrent spontaneous abortions.

PROBLEM: Natural killer (NK) cell receptors (NKRs) have been suggested to protect trophoblast, but their function at the fetomaternal interface remains unknown. To investigate if the outcome of pregnancy depends on women's NKRs, we studied the NKR repertoire in couples with recurrent spontaneous abortions (RSA). METHODS: Twenty-six childless couples with > or = 2 abortions, characterized by alloimmune abnormalities, and 26 control couples were genotyped for five killer immunoglobulin-like receptors (KIR) and two CD94/NKG receptors, known to have as ligands human leukocyte antigen (HLA) class I molecules with trophoblastic expression: inhibitory 2DL1,2,3 and activating 2DS1,4 KIRs, inhibitory NKG2A and activating NKG2C. Detected repertoires of women and partners were compared between the two groups. RESULTS: Less aborters than controls were found to have all three inhibitory KIRs (30.77% versus 69.23%, P = 0.01), some of them had only one inhibitory KIR (19.23% versus 3.85%, P = 0.08) and most of them were lacking inhibitory KIRs possessed by their husbands (57.69% versus 15.38%, P = 0.001). CONCLUSIONS: Women with alloimmune abortions have a limited inhibiting KIR repertoire and such miscarriages may occur because trophoblastic HLA class I molecules are recognized by decidual NK cells lacking the appropriate inhibitory KIRs.