Correlation of NK Cell Activation and Inhibition Markers with NK Cytoxicity Among Women Experiencing Immunologic Implantation Failure After In Vitro Fertilization and Embryo Transfer
Purpose: The pivotal event in determining successful from unsuccessful cycles after in vitro fertilization is implantation. The purpose of this study was to compare the percentage of circulating NK cells expressing activation and inhibition markers between infertile and fertile control women and to determine the correlation between these markers and those of the NK cytotoxicity activation assay. Lastly, we wish to determine the ability of each of these markers to predict pregnancy outcome after IVF/ET (in vitro fertilization/embryo transfer).
Methods: Blood samples from 22 infertile women undergoing IVF/ET during the November 2001 cycle were drawn on cycle Day 9 and analyzed for expression of CD69+, HLA-DR, CD161+, CD94+, and CD158a+ as well as NK cytotoxicity using immunoflluorescent labeling and flow cytometry. Results were compared with those from 26 fertile control women and correlated to pregnancy outcome that of cycle.
Results: Infertile women had significantly higher expression of NK cell activation markers of CD69+ and CD161+ than fertile women. NK cytotoxicity correlated inversely with expression of NK cells bearing the inhibition marker of CD94+. None of the successfully pregnant women of that cycle had elevated levels of NK cytotoxicity whereas 50% of those experiencing a chemical pregnancy loss and those not becoming pregnant had elevated levels of NK cytotoxicity.
Conclusions: Immunologic markers can identify mechanisms involved in implantation failure. Activation markers of CD69+ and CD161+ expressed on NK cells as well as NK cytotoxicity can be added to the previously reported risk factors for immunologic implantation failure.
Implantation failure NK cell activation and inhibition markers NK cytotoxicity
Wilcox AJ, Weinberg CR, O'Connor JF, Baird DD, Schlatterer JP, Canfield RE, Armstrong EG, Nisula BC: Incidence of early loss of pregnancy. N Engl J Med 1988;319:189–194PubMedGoogle Scholar
Coulam CB: Implantation failure and immunotherapy. Hum Reprod 1995;10:1338–1340PubMedGoogle Scholar
Munne S, Alikani M, Tomkin G, Grifo J, Cohen J: Embryo morphology, development rates, and maternal age are correlated with chromosomal abnormalities. Fertil Steril 1995;64:382–391PubMedGoogle Scholar
Gianaroli L, Masgli C, Ferratetti AP, Munne S: Preimplantation diagnosis for aneuploidies in patients undergoing in vitro fertilization with a poor prognosis: Identification of the categories for which it should be proposed. Fertil Steril 1999;72:837–844PubMedGoogle Scholar
ASRM/SART : Assisted reproductive technology in the United States: 1998 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry. Fertil Steril 2002;77:18–31Google Scholar
King A, Loke YW: On the nature and function of human uterine granular lymphocytes. Immunol Today 1991;12:432–435PubMedGoogle Scholar
Clark DA, Vince G, Flanders K, Hirte H, Starkey P: CD56+ lymphoid cells in human first trimester pregnancy decidua as a source of novel transforming growth factor beta 2 related immunosuppressive factors. Hum Reprod 1994;9:2270–2277PubMedGoogle Scholar
Michel M, Underwood J, Clark DA, Mowbray J, Beard RW: Histologic and immunologic study of uterine biopsy tissue of incipiently aborting women. Am J Obstet Gynecol 1989;161:409–414PubMedGoogle Scholar
Lea RG, Underwood J, Flanders KC, Hirte H, Banwatt D, Finotto S, Ohno I, Michel M, Daya S, Harley C, Mowbray JF, Clark DA: A subset of patients with recurrent spontaneous abortion is deficient in transforming growth factor beta 2 producing suppressor cells in decidua near the placental attachment site. Am J Reprod Immunol 1995;34:52–61PubMedGoogle Scholar
Coulam CB, Goodman C, Roussev RG, Thomason EJ, Beaman KG: Systemic CD56+ cells can predict pregnancy outcome. Am J Reprod Immunol 1995;33:40–46PubMedGoogle Scholar
Lachapelle MH, Miron P, Hemmings R, Roy DA: Endometrial T, B, and NK cells in patients with recurrent abortion: Altered profile and pregnancy outcome. J Immunol 1996;156:4227–4234Google Scholar
King A, Hiby SE, Verma S, Burrows T, Gardner L, Loke YW: Uterine NK cells and trophoblast class I molecules. Am J Reprod Immunol 1997;37:459–462PubMedGoogle Scholar
Beer AE, Kwak JY, Ruiz JE: Immunophenotypic profiles of peripheral blood lymphocytes in women with recurrent pregnancy losses and in infertile women with multiple failed in vitro fertilization cycles. Am J Reprod Immunol 1996;35:376–382PubMedGoogle Scholar
Roussev RG, Kaider BD, Price DE, Coulam CB: Laboratory evaluation of women experiencing reproductive failure. Am J Reprod Immunol 1996;35:415–420PubMedGoogle Scholar
Kaider AS, Kaider BD, Janowicz PB, Roussev RG: Immunologic evaluation in women with reproductive failure. Am J Reprod Immunol 1999;42:335–346PubMedGoogle Scholar
Coulam CB, Roussev RG: Chemical pregnancies: Immunologic and ultrsonographic studies. Am J Reprod Immunol 2002;48:323–328.PubMedGoogle Scholar
Fukui A, Fujii S, Yamaguchi E, Kimura H, Sato S, Saito Y: Natural killer cell subpopulations and cytotoxicity for infertilepatients undergoing in vitro fertilization. Am J Reprod Immunol 1999;41:413–422PubMedGoogle Scholar
Clark DA, Lea RG, Podor T, Daya S, Banwatt D, Harley C: Cytokines determining the success or failure of pregnancy. Ann N Y Acad Sci 1991;626:524–536PubMedGoogle Scholar
Kane KL, Ashton FA, Schmitz JL, Folds JD: Determinations of natural killer cell function by flow cytometry. Clin Diagn Lab Immunol 1996;3:295–300PubMedGoogle Scholar
Ntrivalas EI, Kwak-Kim JY, Gilman-Sachs A, Chung-Bang H, Ng SC, Beaman KD, Mantouvalos HP, Beer A: Status of peri-pheral blood natural killer cells in women with recurrent spontaneous abortions and infertility of unknown aetiology. Hum Reprod 2001;16:855–861PubMedGoogle Scholar
Wegmann TG, Lin H, Guilbert L, Mosmann TR: Bidirectional cytokine interactions in the maternal-fetal relationship: Is successful pregnancy a TH2 phenomenon? Immunol Today 1993;14:353–356PubMedGoogle Scholar
Raghupathy R: Th 1type immunity is incompatible with successful pregnancy. Immunol Today 1997;18:478–482PubMedGoogle Scholar
Coulam CB, Krysa LW, Bustillo M: Intravenous immunoglobulin for in vitro fertilization failure. Hum Reprod 1994;9:2265–2269PubMedGoogle Scholar
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