Tumor Necrosis Factor-α, Uterine Natural Killer Cells, and Pregnancy
See related article, pp 1298–1307
Tumor necrosis factor-α (TNF-α) plays a role in any acute or chronic inflammatory disease. The gene was cloned in 1985,1 and the relevance was underscored by 40 years of subsequent research. Indeed, TNF-α inhibition has become a major pastime for many drug companies. Efficacy has been shown most convincingly for inflammatory bowel disease.2 Thus, the proof-of-principle has long since been established. However, moving the anti–TNF-α strategy forward has not been invariably successful. One criticism could be the fact that the approach is too general. Are to be sledgehammers be used when perhaps stilettoes would do?
Pregnancy is an immunologic miracle. Thus, the fact that TNF-α plays a role in maladaptive pregnancy, such as gestational hypertension or preeclampsia comes as no surprise; however, the relationships are complex.3 TNF-α and a host of other cytokines join with other molecules, such as soluble fms-like tyrosine kinase-1, endoglin, and the angiotensin II type 1 receptor autoantibody as contributors to preeclampsia.4,5 Preeclampsia covers only a limited portion of pregnancies with suboptimal outcomes. Hypertensive pregnant women who do not develop overt preeclampsia, women with insulin-resistance syndromes, older pregnant women, or those with other risks and factors should also be considered. The question is whether the condition can be modeled.
Small et al6 directed their attention to a venerable workhorse, namely the stroke-prone spontaneously hypertensive rat (SHRSP). The normotensive counterpart is the Wistar–Kyoto rat. The SHRSP do not have preeclampsia. Nonetheless, they reproduce less well. The authors document the activation of innate immunity in SHRSP, compared with Wistar–Kyoto rat and were struck by the amount of TNF-α overproduction by pregnant SHRSP. Clinical treatments exist to reduce the effects of TNF-α. Small et al,6 therefore, treated SHRSP with etanercept, an antagonist of TNF activity.7 Etanercept lowered blood pressure in SHRSP (slightly) and improved reproductive outcome. Natural killer (NK) cells in maternal blood and placenta were increased in pregnant SHRSP, compared with pregnant Wistar–Kyoto rat. These cells were implicated as the source for TNF-α. Etanercept treatment reduced these cells in the placenta. More importantly, uterine artery function as monitored was improved toward control values.
In the past years, uterine NK cells have become the stars in reproductive immunology. Their beneficial influence on placentation, trophoblast-cell invasion, and pregnancy maintenance is well described. However, their role in late pregnancy complications, such as preeclampsia and gestational hypertension, as well as the exact mechanism of action especially on a molecular level, needs to be elucidated. Small et al6 added new knowledge into the uterine NK cell (mine)-field in 3 important points. First, their study is the first to show a role of tissue-resident placental NK cells with gestational hypertension. Second, the results of Small et al6 demonstrate that placental NK cells might not be merely beneficial for pregnancy, but instead NK cells could play an ambiguous role for pregnancy. Pregnant hypertensive SHRSP rats display more NK cells in the maternal blood and placenta than control rats. TNF-α blockade lowers systolic blood pressure in parallel to NK cell number in placenta. Third, the presence of a CD3-negative and CD161-low positive subpopulation of NK cells in SHRSP placentas underscores the complexity and probable plasticity of NK cell receptor expression at the fetal–maternal interface. A proper characterization of uterine NK cells, especially to define these cells in relation to the recently emerging family of uterine innate lymphoid cells, is urgently warranted.8
The translational aspects of these results are predicated on the use of anti–TNF-α drugs in pregnancy. Published experiences of TNF-α inhibition during pregnancy consist of case reports, miniscule series, and registry data in patients with arthritis and inflammatory bowel disease.9 Dermatologists deal with anti–TNF-α drugs regularly. They report that women who become pregnant while taking infliximab or other anti–TNF-α agents can be reassured about the continuation of pregnancy.9 More recent assessments support that view.10,11
Is etanercept a treatment for hypertensive pregnancy or preeclampsia? Far more heroic plasma-separation experiments for preeclampsia have been performed.12 An anti–TNF-α strategy in such patients could be considered. Of course, the SHRSP data presented here do not warrant such a trial. Animal models for preeclampsia are a matter of debate, and SHRSP do not warrant the discussion. Nonetheless, the data presented here are a basis for further studies. Solely, magnesium therapy and early delivery remains for these patients and there are always 2 (if not more) such patients.13 We need more options and the experiments presented here could provide at least food for thought.
Sources of Funding
M. Golic is a participant of the BIH-Charité Clinician Scientist Program funded by the Charité - Universitätsmedizin Berlin and the Berlin Institute of Health.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
- © 2016 American Heart Association, Inc.
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