Viktor Pavlovich Chernyshov

Висока цитотоксичність натуральних кіллерів є несприятливим фактором репродуктивного процесу. Вона як знижує імовірність імплантації, так і збільшує частоту завмирань вагітності першого триместру. Підходи до терапії високої NK-цитотоксичності (NKц), як і в цілому до терапії репродуктивних втрат, дискутуються вже більше 20 років і основною проблемою у цій дискусії є висока контраверсійність результатів, що отримується у різних клінічних групах. На нашу думку причиною таких розбіжностей є неврахування особливостей імунофентипу та гормонального статусу у поєднанні із клініко-анамнестичною рандомізацією. У цій роботі ми продемонструємоефективністьтакого підходу. Ретроспективно проаналізовані результати лікування комбінацією метилпреднізолон + інтравенозний імуноглобулін (ІВІГ) у 46 пацієнток із високою NK-цитотоксичністю та гіперандрогенним статусом, що мали у анамнезі звичайне невиношування вагітності.45 із 46 пацієнток народили здорову дитину, а показники NK-цитотоксичності у переважної більшості демонстрували високу чутливість до лікування.

Problem Many studies have demonstrated the negative impact of high rates of NK cytotoxicity (NKc) on reproductive processes, but there is no agreement as to the appropriateness and feasibility of using the NKc for routine diagnostic in IVF patients. This study conducted a retrospective analysis of embryo transfer (ET) success rates and live birth rates (LBR) in patients with different NKc values. Method of study 1854 cycles of ET were selected and divided into three groups according to NKc levels, and randomized by anamnesis and age: normal (nNKc, n = 871), elevated (eNKc, n = 759), and reduced NKc (rNKc, n = 123). ET with donors’ embryos (n = 101) were analyzed separately. NKc-to-K562 was measured in PBMC (peripheral blood mononuclear cells) by flow cytometry before ET. The patients did not obtain any additional treatments. Results Patients with eNKc, in addition to having reduced clinical pregnancy rates (OR1.59, p < 0.0001), had increased levels of subsequent pregnancy failures (OR2.545, p < 0.0001) when compared to nNKc patients. As a result, patients with eNKc had almost half the LBR than patients with nNKc (OR2.2, p < 0.0001). In patients with rNKc, LBR was also lowered. eNKc was equally unfavorable for implantation and delivery in cryo- or fresh cycles. Markedly, eNKc was much more unfavorable for reproduction than slightly elevated NKc. The donor’s embryos were implanted irrespective of the recipient’s NKc levels, but the later stages of pregnancy were worse in patients with eNKc. Conclusions Our findings highlighted the negative impact of high levels of NK cytotoxicity on pregnancy outcomes.

Immune profiles in endometrium may be changed in patients with IVF failure and its possible correlations with immune parameters in peripheral blood are important for the diagnostic approach. Such correlations in healthy women are unknown and have been studied in the present research. The expression of CD56, CD158a, HLA DR, CD69 in T lymphocytes, CD4 T lymphocytes, CD8+ T lymphocytes and NK cells were studied by flow-cytometry in endometrium and peripheral blood in healthy 24 donors of oocytes aged 25-32 years. Levels of T lymphocyte and T helper cells were lower in endometrium and no differences in CD8 T lymphocytes were registered between endometrium and peripheral blood. The expression of HLA DR and especially CD69 was higher in CD3, CD4, CD8 T cells in endometrium in comparison with peripheral blood. The endometrium lymphocyte population was enriched by NK cells that were generally CD56++ with a higher expression of HLA DR and almost in total were CD69 positive. Strong positive correlations of CD8 expression in NK cells (r = 0.6478, p < 0.001) and HLA DR expression in CD8 T cells (r = 0.6107, p < 0.01) between peripheral blood and endometrium were registered in fertile women. The endometrial CD56 expression in CD8+ T cells negatively correlated with endometrial CD8 expression in NK cells (r = –0.5252, p < 0.01) which possibly reflected a suppressive and regulating mechanism in the endometrium. CD8+ NK cells and HLA DR+ CD8 T cells in endometrium were related to the same subsets in peripheral blood.