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Natural killer cells and fertility: unwarranted treatments flourish amid misinformation and poor regulation

9 November 2015
By Dr Norman Shreeve
Academic Clinical Fellow in Obstetrics & Gynaecology, University of Cambridge, Addenbrooke's Hospital
Appeared in BioNews 827

Natural killer (NK) cells are a type of lymphocyte (white blood cell) vital to the body's immune defence system. They are highly important mediators in the fight against bacteria, viruses and other pathogens, and also help control cancer. These cells, which circulate in the blood, were named 'natural killer' because they are able to identify and attack foreign material without the usual recognition system that the major lymphocytes in the body (T lymphocytes) use.

Since Nobel laureate Sir Peter Medawar first postulated the notion in the 1950s (1), investigating how the maternal immune system tolerates and regulates early pregnancy has been a hotly debated topic. In the early 1990s, scientists discovered lymphocytes with some features similar to NK cells in the endometrium, the lining of the uterus (uterine NK, uNK) (2). They were especially abundant at the maternal–fetal interface in early pregnancy, where the placenta invades into the uterine lining (known as decidua in pregnancy). Despite belonging to the natural-killer cell lineage, uNK in fact behave quite differently from their NK counterparts that circulate in the blood. They display none of the innate cytotoxic ability to attack or kill cell lines that blood NK are so adept at (3).

Since their initial discovery, scientists have suggested that the functional importance of these cells is in the essential job of remodelling maternal blood vessels to allow appropriate nourishment of the growing fetus. This is achieved by placental cell invasion of maternal arteries. In other words, they are involved in drawing a boundary between two individuals. Indeed, both experimental animal models and genetic human studies have highlighted that a sufficient degree of activation of uNK cells is necessary in avoiding pregnancy complications related to deficient placental formation, including miscarriage, pre-eclampsia and fetal growth restriction (4).

Unfortunately, the 'killer' label is a complete misnomer and has given rise to an entire industry within assisted reproductive technology (ART), e.g. IVF or ICSI and recurrent miscarriage clinics aimed at targeting these cells. It has now become common practice for these clinics to charge patients significant sums of money for measurements of uNK cells or blood NK (or both). Providers of such tests have invented a rationale in which they claim that raised levels of NK cells leads to the body 'rejecting' or 'attacking' the embryo, resulting in early pregnancy loss. There is absolutely no evidence that this ever occurs. Especially in cases where other causes cannot be identified, blaming pregnancy loss on uNK cells can give frustrated and hopeless couples a much-welcomed reason for their failed attempts at parenthood.

The HFEA, Human Fertilisation and Embryology Authority, is the ART regulatory body in the UK. They license and regularly review all providers in the private and public sectors. Unfortunately, they do not currently regulate adjunctive treatments offered alongside IVF/ICSI cycles. In recent years a range of treatments aimed at suppressing uNK activity have sprung up, including intravenous immunoglobulin, Intralipid, corticosteroids (e.g. prednisolone), anti-tumour necrosis factor, tacrolimus and granulocyte-colony stimulating factor. These medications can have significant and dangerous side effects, and in other conditions their administration is reserved for hospital settings where appropriate medical support exists.

As the exact role of uNK in pregnancy is still unknown, targeting uNK in this way (even if the treatments do actually affect them somehow) has no scientific rationale and is potentially dangerous for the following reasons:

a) there is no universally accepted normal reference range for uNK cell levels or even a protocol for how to count them, therefore results and their interpretation vary widely from clinic to clinic;

b) there is no relationship between blood NK levels and uNK cytotoxicity so testing blood NKs is pointless;

c) there is no good-quality experimental or clinical evidence to support immune suppression as a method for improving pregnancy outcome;

d) many of the treatments offered have significant side effects related to suppressing the body's natural immunity. The maternal immune system is not normally suppressed during pregnancy and uterine NK cells have a physiological role in cooperating with the fetal/placental cells to optimise placentation. This interaction is not a conflict but a compromising dialogue.

So where does this leave the patient? Probably quite confused. In fact, it is actually rather straightforward – there is no evidence to suggest that any currently available measurement of NK cells, be it in peripheral blood or the uterus, can reliably guide treatment of infertility (5). There is also no good evidence for the use of any immune-modulating therapies in recurrent miscarriage (or recurrent implantation failure in ART). Others within the scientific and clinical community have called for such treatments to be confined to research settings only (6). In otherwise healthy young women, it is impossible to see how the risks of taking these drugs could currently outweigh the unproven benefit in pregnancy outcome.

1) Medawar PB. Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates: revention of allogeneic fetal rejection by tryptophan catabolism.
Symp Soc Exp Biol 1953;7:320–338. |  25 May 2022
2) King A, Loke YW. On the nature and function of human uterine granular lymphocytes.
Immunol Today 1991;12:432–435. |  25 May 2022
3) King A, Birkby C, Loke YW. Early human decidual cells exhibit NK activity against the K562 cell line but not against first trimester trophoblast.
Cell Immunol 1989;118:337–344. |  25 May 2022
4) Xiong S, Sharkey AM, Kennedy PR, Gardner L, Farrell LE, Chazara O, Bauer J, Hiby SE, Colucci F, Moffett A. Maternal uterine NK cell-activating receptor KIR2DS1 enhances placentation.
J Clin Invest. 2013 Oct;123(10):4264-72. doi: 10.1172/JCI68991 |  25 May 2022
5) Moffett A, Shreeve N. First do no harm: uterine natural killer (NK) cells in assisted reproduction.
Hum Reprod. 2015 Jul;30(7):1519–1525. |  25 May 2022
6) Alecsandru D, García-Velasco JA. Immune testing and treatment: still an open debate.
Hum Reprod. 2015 Aug;30(8):1994. doi: 10.1093/humrep/dev140 |  25 May 2022
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