TABLE 1.

Immunomodulation offers promise for preeclampsia (PreE) prevention. This table describes potential preeclampsia prevention targets, the directionality of target abnormality in PreE, drugs that modulate the targets, and the effects of each drug on PreE-related biological processes. Treg, regulatory T cell; NK, natural killer; DC, dendritic cell; CTLA-4, cytotoxic T lymphocyte-associated antigen-4; IVIg, intravenous immunoglobulin G; ET_A, endothelin-1 receptor A; anti, antibody; CoPPIX, cobalt protoporphyrin; HO-1, heme oxygenase 1, mAbs, monoclonal antibodies; Th, Helper T cell; Treg, regulatory T cell; IL, interleukin; IFN-γ, interferon gamma; TNF-α, tumor necrosis factor alphasFlt-1, soluble Fms-like Tyrosine Kinase-1; PLGF, placental growth factor; VEGF, vascular endothelial growth factor; IL-17RC mouse IL-17 receptor C; 17-OHPC, 17-hydroxyprogesterone caproate; NK2, non-cytolytic, type 2 Natural Killer cells; NK1, cytolytic, type 1 Natural Killer cells; TLR5, toll like receptor five; AT1-AA, Angiotensin II Type 1 Receptor Agonistic Autoantibody.

Target	Change in targets in preeclampsia	Drug	Drug effect on preeclampsia mechanisms	Citation
TNF-α	Increase	anti-TNF-α neutralizing mAb	Less pro-inflammatory T cell differentiation via DC maturation and IL-10-dependant inhibition of CD4+ T cell expansion	Yuan et al. (2015), Alijotas-Reig et al. (2017)
			Decreased vasoconstriction, coagulation, vascular permeability, and microvascular leakage	LaMarca et al. (2005), Kaplanski et al. (1997)
			Decreased endothelial dysfunction; trophoblastic apoptosis inactivation	Alexander et al. (2001), Huppertz and Kingdom (2004), Chen et al. (2010), Ibrahim et al. (2017)
CD28	Decrease	CD28 superagonist TGN1412/TAB08	Treg promotion	Tabares et al. (2014)
			Reduced pro-inflammatory response	Ibrahim et al. (2017)
			Reduced cytolytic NK cell activation during placental invasion	Ibrahim et al. (2017)
IL-10	Decrease	IL-10 administration	Promote macrophage maturation to anti-inflammatory M2	Harmon et al. (2015)
Treg	Decrease	adoptive transfer	Promote mast cell repair of the placental and vascular defects	Maganto-García et al. (2011), Matrougui et al. (2011), Woidacki et al. (2015)
			Reduced oxidative stress	Jafri and Ormiston (2017), Dall'Era et al. (2019), Chen et al. (2010)
IL-6	Increase	anti-TLR-5	Increased anti-inflammation	Narazaki et al. (2017)
		anti-IL-6		Tousoulis et al. (2016), Narazaki et al. (2017), Trivedi and Adams (2018)
IL-17	Increase	anti-IL-17	Prevents offspring neurodevelopmental defects	Amador et al. (2014), Reed et al. (2020)
			Improved vascularization; decreased AT1-AA and oxidative stress	Amador et al. (2014)
		ETA antagonists	Downregulated mature DCs; decreased vascular permeability and vasoconstriction	Alexander et al. (2001); Tanaka et al. (2014); Morris et al. (2016)
		IL-17RC	Improved vascularization; decreased IL-17 activation of cytolytic NK cells and decreased pro-inflammation	Cornelius et al. (2013); Travis et al. (2020)
		Spironolactone	Decreased Th17 activation and increased FoxP3-dependent Treg differentiation	Amador et al. (2014)
			Improved placentation via competitive binding of aldosterone	Birukov et al. (2019)
HMG-CoA reductase		Statins	Improved placentation; reduced sFlt-1; increased pro-survival/antiapoptotic factors; upregulated PLGF and VEGF	Youssef et al. (2002); Kumasawa et al. (2011); McDonnold et al. (2014); Esteve-Valverde et al. (2018); 82
Cytolytic NK cells	Increase	17-OHPC	Decreased pro-inflammation	Gupta and Roman (2012); Elfarra et al. (2020)
		CD28 mAbs	Decrease IL-6/IL-2-mediated activation of cytolytic NK cells	Ibrahim et al. (2017)
DCs	skewed towards pro-inflammatory	CTLA-4	Decreased DC maturation and subsequent pro-inflammatory T cell and cytolytic NK cell activations	Gu et al. (2012)
		CoPPIX-mediated HO-1 induction
		IVIg		Bayry et al. (2003)