Natural Killer Cells in Implantation and Pregnancy

To the immune system of a pregnant woman, there is no doubt that a baby is a temporary graft of foreign tissue. A baby and its placenta express proteins on its cell surfaces that come from the father, and therefore are "foreign" and could potentially be rejected by a woman's immune system. Like all living species that gestate their young within the mother's body, humans have evolved mechanisms to protect the baby from rejection by the host mother's system. The last few years has seen an increased interest in the subject of the role of the immune system in implantation of embryos and maintenance of pregnancy. The clinical relevance of perceived abnormalities in the immune system of women with unexplained infertility, unexplained implantation failure and recurrent miscarriage is a controversial topic. Elaborate theories to explain these failures have been proposed but most have not yet stood up to the test of good science. One of the latest theories to lay blame is that of a class of immune cells (lymphocytes) known as "natural killer" cells. Natural killer (NK) cells are responsible for killing certain types of foreign cells. In the current theory, increased NK cell activity potentially leads to attack of placental cells and therefore rejection of the fetus. But NK cells will only kill lab-cultured placental cells in the presence of another protein, called interleukin-2. Yet interleukin-2 is not present in the uterine lining of the uterus at the time of implantation. NK cells are found in both the bloodstream and in the uterine lining. NK cells are present in the uterus only during the second half of the cycle and can be found concentrated at the site of implantation. In mice that have been genetically altered to no longer make NK cells, successful reproduction will only occur if NK cells are given back to these mice. This suggests that, at least for these mice, NK cells may be necessary for implantation. So are NK cells there to inhibit or promote embryo implantation? The answer is not clear. Further complicating the NK cell story is the fact that there are several kinds of specific NK cells. These types can be classified by the expression of specific receptor proteins on the surface of NK cells. As it turns out, NK cells in the uterus are different from the NK cells that circulate in the bloodstream. Therefore, using blood tests to determine if there are too many circulating NK cells would bear little reflection on what is going on within the population of uterine NK cells. Other blood tests have been devised to assess whether these uterine-specific NK cells are being over-produced, such as tests for Tumor Necrosis Factor a (TNF-a), and Interferon g (IFN-g). These are proteins secreted by a particular class of NK cells found in the uterus. Women identified by these blood tests as having elevated NK activity or increased levels of TNF-a or IFN-g have been told that they will never successfully conceive unless they receive treatment with various immune suppressing agents such as intravenous immunoglobulin infusions (IVIG), glucocorticoid (prednisone) medications or anti-TNFa medications. But these treatments are not free from risk. Anti-TNFa medications have been implicated in several serious diseases such as lymphomas and lupus-like syndromes. Glucocorticoids during pregnancy can be associated with an increased risk of pre-term rupture of the fetal membranes, increased risk of pre-eclampsia (high blood pressure during pregnancy) and gestational diabetes. Immunoglobulin infusion (IVIG) is the use of infusions of a pooled blood production (immune proteins) and can be associated with anaphylactic (shock) response, and a host of side effects. This is why the vast majority of reproductive endocrinologists do not support administration of these drugs to women, even if they have been told they have increased NK cell activity in their blood stream. Unfortunately, our understanding of the role of the immune system in implantation and pregnancy is very rudimentary at this point. Trying to take this limited knowledge and develop tests to predict who may or may not be experiencing abnormalities of the immune system is akin to going out on a long limb of unproven possibilities. Furthermore, determining that women with supposed abnormalities in their NK cell activity be treated with anti-TNFa medications, steroids or immunoglobulin infusions to globally suppress the immune system is akin to going out even further on a flimsy stem. These treatments can be expensive and potentially harmful. The good news in all of this is that there is extensive research under way to try to better understand the very complex nature of embryo implantation and the immune privilege of the fetus within the womb. The bad news is that we are still a long way from understanding whether or not there truly are immune system malfunctions that occur which could potentially block implantation or directly cause repeated miscarriage. To therefore say that we can run a clinical test on a woman or furthermore, develop a rational mode to safely treat a woman for such a syndrome is going way beyond the bounds of good clinical medicine. -- Carolyn Givens, MD

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