Abstract 173: Depletion of CLIP+ Immune Cells Prevents Toll-Like Receptor-Induced Preeclampsia in Mice
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abstract
Preeclampsia (PE) is a pregnancy-specific disorder of vascular endothelial dysfunction and inflammation which manifests as hypertension and proteinuria and may result from maladaptation of the maternal immune system. Activation of the dsRNA receptor Toll-like receptor 3 (TLR3) or the ssRNA receptor TLR7 elicits pregnancy-dependent hypertension and endothelial dysfunction in mice in part by increasing pro-inflammatory immune cells. Polyclonal activation of immune cells is associated with expression of Class II-Associated Invariant Peptide Chain (CLIP) in MHC class II which prevents T cell-dependent death leading to persistent immune cell activation. We hypothesized that removal of CLIP reduces pro-inflammatory immune cells and prevents the development of PE in mice. Pregnant mice were given ip injections of normal saline (P), poly I:C (TLR3 agonist; P-PIC), or R837 (TLR7 agonist; P-R837) with or without TPP, a custom-targeted peptide that removes CLIP from MHC class II, on gestational days 13, 15, and 17 and euthanized on day 18. TPP treatment significantly decreased pro-inflammatory CD3+/ T cells and increased anti-inflammatory CD4+/CD25+ regulatory T cells in TLR3-induced PE mice as well as TLR7-induced PE mice. TPP treatment also prevented the hypertension (GD17 SBP in mmHg: P=1023, P+TPP=1054, P-PIC=1474*, P-PIC+TPP=1032, P-R837=1332*, P-R837+TPP=1064; *p<0.05 vs. P), proteinuria, and endothelial dysfunction in TLR3-induced and TLR7-induced PE mice while having no detrimental effects in normal pregnant mice. Based on our results, the TPP-mediated decrease in detrimental immune cells positively modulated T cell subsets and prevented the development of PE-like symptoms in mice. CLIP removal from MHC class II with TPP may be a promising therapy for women with PE.
