Manipulating CD4+ T Cell Pathways to Prevent Preeclampsia

Abstract

Preeclampsia (PreE) is a placental disorder characterized by hypertension (HTN), proteinuria, and oxidative stress. Individuals with PreE and their children are at an increased risk of serious short- and long-term complications, such as cardiovascular disease, end-organ failure, HTN, neurodevelopmental disorders, and more. Currently, delivery is the only cure for PreE, which remains a leading cause of morbidity and mortality among pregnant individuals and neonates. There is evidence that an imbalance favoring a pro-inflammatory CD4+ T cell milieu is associated with the inadequate spiral artery remodeling and subsequent oxidative stress that prime PreE's clinical symptoms. Immunomodulatory therapies targeting CD4+ T cell mechanisms have been investigated for other immune-mediated inflammatory diseases, and the application of these prevention tactics to PreE is promising, as we review here. These immunomodulatory therapies may, among other things, decrease tumor necrosis factor alpha (TNF-α), cytolytic natural killer cells, reduce pro-inflammatory cytokine production [e.g. interleukin (IL)-17 and IL-6], stimulate regulatory T cells (Tregs), inhibit type 1 and 17 T helper cells, prevent inappropriate dendritic cell maturation, and induce anti-inflammatory cytokine action [e.g. IL-10, Interferon gamma (IFN-γ)]. We review therapies including neutralizing monoclonal antibodies against TNF-α, IL-17, IL-6, and CD28; statins; 17-hydroxyprogesterone caproate, a synthetic hormone; adoptive exogenous Treg therapy; and endothelin-1 pathway inhibitors. Rebalancing the maternal inflammatory milieu may allow for proper spiral artery invasion, placentation, and maternal tolerance of foreign fetal/paternal antigens, thereby combatting early PreE pathogenesis.

Keywords: CD4+ T cells; early pregnancy; preeclampsia; prevention; treatment.

FIGURE 1

Dendritic cells are modulated by T cells and NK cells in preeclampsia. Oxidative and vascular stress contribute to preeclamptic conditions. In preeclampsia, there is an increase of cytolytic, type 1 NK cells and precocious maturation of DCs, as well as increased production of pro-inflammatory cytokines. There is a simultaneous decrease in non-cytolytic, type 2 NK cells and anti-inflammatory cytokines. All three cell types interact to aggravate the elevated pro-inflammatory status that contributes to and occurs in preeclampsia. NK, natural killer; DC, dendritic cells. Created with https://biorender.com.

FIGURE 2

CD4+ T cell pro-inflammation and processes may be targeted in preeclampsia. Induction of anti-inflammatory CD4+ T cells (Th2s) and Tregs, and inhibition of pro-inflammatory CD4+ T cells (Th17s, TH1s) may be one pathway for preeclampsia treatment and prevention. Collectively, modulation of these processes may ameliorate the overly pro-inflammatory immune response in preeclampsia. Shifting the ratio of pro-to anti-inflammatory CD4+ T cells may prevent preeclampsia by allowing proper placentation and reducing resultant oxidative stress. This can be done by 1) promoting an anti-inflammatory milieu (Th2, Treg, IFN-γ, IL-10) with anti-CD28, statins that induce PLGF and VEGF, or 2) inhibiting a pro-inflammatory milieu (Th1, Th17, IL-2, IL-6, IL-17, and TNF-α) with anti-CD28 or spironolactone, or inhibiting sFlt-1using statins. Specific cytokines may also be inhibited, such as IL-6 by anti-TLR5 or anti-IL-6; IL-17 by IL-10, ET_A inhibitors, IL-17RC, and anti-IL-17; or TNF-α by anti-TNF-α. The anti-inflammatory CD4+ T cell response may result in tolerance and a healthy pregnancy while the pro-inflammatory CD4+ T cell response may lead to fetal rejection, endothelial dysfunction, and clinical preeclampsia signs. DC, dendritic cells; mAbs, monoclonal antibodies; Th, Helper T cell; Treg, regulatory T cell; IL, interleukin; IFN-γ, interferon gamma; TNF-α, tumor necrosis factor alpha; anti, antibody; ET_A, endothelin-1 receptor A; sFlt-1, soluble Fms-like Tyrosine Kinase-1; PLGF, placental growth factor; VEGF, vascular endothelial growth factor; IL-17RC mouse IL-17 receptor C; TLR5, toll like receptor 5. Created with https://biorender.com.

FIGURE 3

Cytolytic NK cells may be targeted in preeclampsia. Induction of non-cytolytic NK cells and inhibition of cytolytic NK cells is one potential avenue for the treatment and prevention of preeclampsia. Anti-TLR5, anti-IL-6, and anti-CD28 inhibit IL-6’s activation of pro-apoptotic cytolytic type 1 NK cells. Anti-CD28 also directly inhibits type 1 NK cells, and promotes non-cytolytic, type 2 NK cells and the anti-apoptotic cytokines IL-10 and IFN-γ. 17-OHPC works similarly to promote type 2 NK cells. Together, these reduce the cytolytic NK cell response, which can lead to improper placentation and subsequent preeclampsia. 17-OHPC, 17-hydroxyprogesterone caproate; anti, antibody; IFN-γ, interferon gamma; NK2, non-cytolytic, type 2 Natural Killer cells; IL, interleukin; NK1, cytolytic, type 1 Natural Killer cells; TNF-α, tumor necrosis factor alpha; TLR5, toll like receptor 5. Created with https://biorender.com.

FIGURE 4

DC cells maturation and function may be targeted in preeclampsia. Inhibition of mature CDs and induction of tolerogenic, immature DCs is one promising route for preeclampsia treatment and prevention. Targets to achieve this include exogenous Treg transfer, IVIgs to promote tolerogenic DCs (e.g., via CTLA-4), CoPPIX induced HO-1 activation, and ET_A antagonists. IVIg via CTLA-4, anti-CD28, ET_A antagonists, and CoPPIX via HO-1 inhibit mature DC function, which can be pro-inflammatory to CD4+ T cells. Treg, regulatory T cell; 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. Created with https://biorender.com.