2)流産における免疫学的機序の解明 : 免疫グロブリン治療は流産抑止に有効か(シンポジウム1「流産の原因と対策」,第63回日本産科婦人科学会・学術講演会)

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Problem: Numoerous investigations have been performed focusing on the possible role of immunological abnormalities in unexplained recurrent spontaneous abortion (RSA). There are many controversies concerning abnormal helper T (Th)1/Th2 balance with Th1 predominance as the underlying pathophysiology in RSA women. The first part of the aim of this study was to assess the immunological mechanism of the unexplained RSA. Intravenous immunoglobulin (IVIg) has been used to treat RSA, but recent reports of meta-analysis and systematic review concerning efficacy of IVIg therapy are generally disappointing. Therefore, the second part of this study was to pursue the evidence of the effectiveness of IVIg as the treatment for RSA. Results: A: In the peripheral blood at the midluteal phases, no significant differences in the NKT cell percentages were found between RSA and control women. However, in RSA women, the CD4+IL-4+cell and CD8+IL-4+cell percentages were significantly higher, and the Th1/Th2 and Tc1/Tc2 cell ratios were significantly lower, than those in the control. B: In the endometrium at the midluteal phases, no significant differences in natural killer (NK) cell or natural killer T (NKT) cell percentages were found between RSA and control women. In RSA women compared with control women, however, the percentages of CD3+cells, CD4+IFN-g+cells and CD4+TNF-a+cells were significantly lower. The percentage of CD4+IFN-g-IL-4-cells was significantly higher in RSA women. C: In the decidua, no significant differences in NK cell or NKT cell percentages were found among miscarriage (MS) with normal chromosome karyotype (MSNK), MS with abnormal chromosome karyotype (MSAK) and induced abortion (IA). However, in MS compared with IA, the percentages of the Th2/Th1 cell ratio were significantly higher, and the percentage of CD8+IL-4+cells and Tc2/Tc1 cell ratio was significantly lower, but no significant difference was found between MSNK and MSAK in these parameters. D: Pre-conceptional NK cell activity/percentage values in women whose next pregnancies ended in MSNK were higher than those in MSAK or live births (LB). High values of pre-conceptional NK cell activity and percentage were found to predict MSNK in the next pregnancy. E: NK cell activity at 6〜7 gestational weeks in women with subsequent MSNK was significantly higher than those with subsequent MSAK or LB. F: A significant decrease in inhibitory CD158a expression was demonstrated in RSA women as compared with that in controls in peripheral NK cells at midluteal phases. G: The expressions of inhibitory receptors, CD 158a and CD94, in the decicual NK cells of MSNK were significantly decreased as compared with those of MSAK or IA. Conversely, the perforin expression on NK cells and cytotoxic T cells (Tc) cells in MSNK was significantly increased as compared with those in MSAK or IA. A positive correlation between CD94 and CD158a expressions on NK cells, negative correlations between CD94 on NK cells and perforin on NKcells/Tc cells, and between CD158a on NK cells and perforin on Tc cells were found. H: Macrophage migration inhibitory factor (MIF) concentrations during 4〜6 GW in the peripheral blood of RSA women with subsequent MSNK were significantly lower than those with subsequent MSAK or LB. I: In 1993, we started massive intravenous immunoglobulin (MIVIg) treatment for women with four or more RSA with unexplained etiology. Our administration protocol, in which a massive dose (100gr) of immunoglobulin over the course of 5 days is commenced at the detection of gonadal sac, differs from other regimens of IVIg treatment for RSA. The overall live birth rate was 91% among 46 women, excluding 10 MSAK cases. J: In animal, study, we have reported polyinosinic-polycytidylic acid sodium salt [poly (I:C)] induces enhancement of fetal resorption in the mating of CBA/Jx DBA/2J resorption-prone mouse model. Administration of high-dose intact human immunoglobulin (IH-Ig) significantly reduced the fetal resorption rate from 55% to 10%. We then performed adoptive transfer experiments. A remarkable anti-resorption effect was seen in poly (I:C)-injected pregnant recipients transferred with spleen cells from IH-Ig-treated donor mice. Flow cytometric analyses demonstrated that the proportion of CD11b-positive cells in the CFSE-labeled transferred cells was higher in placental mononuclear cells than in spleen. These results suggest that CD11b-positive macrophages are preferentially recruited to placentas compared with other cell populations. K: Pre-treatment IFN-g, TNF-a, IL-4 and IL-10 increased after MIVIg treatments on RSA women. The pre-infusion NK cell activity and percentages of CD56+16-NK cells and CD16+NK cells decreased after MIVIg treatment. Expression percentages of inhibitory CD94 on NK cells significantly increased after MIVIg therapy. Conclusions: Immunodystrophism detected as diminution of the Th1 cell population, decreased cytokine production by Th cells, decreased macrophage accumulation, and over activation of NK cells due to the decrease of the expression of inhibitory receptors may underlie the pathophysiology of unexplained RSA. MIVIg treatment showed a sufficient successful rate in our facilities with increased Th cytokine production, induced macrophages accumulation in placenta, and decreased NK cell activation with elevated expression of inhibitory receptors. Therefore, MIVIg treatment was shown to have a possibility to treat RSA women through its function to modify their status of immunodystrophism.
2011-12-01

2)流産における免疫学的機序の解明 : 免疫グロブリン治療は流産抑止に有効か(シンポジウム1「流産の原因と対策」,第63回日本産科婦人科学会・学術講演会)

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